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Archive for the ‘Liver & Digestive Diseases Research’ Category


Glucokinase target for type 2 diabetes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04991532-a-hepatoselective-glucokinase-activator-clinical-candidate-for-treating-type-2-diabetes-mellitus/

 

PF 04991532

GKA PF-04991532

(S)-6-{3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido}nicotinic acid

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid

(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid

MW 396.36, MF C18 H19 F3 N4 O3

CAS 1215197-37-7

3-​Pyridinecarboxylic acid, 6-​[[(2S)​-​3-​cyclopentyl-​1-​oxo-​2-​[4-​(trifluoromethyl)​-​1H-​imidazol-​1-​yl]​propyl]​amino]​-

http://www.biochemj.org/content/441/3/881

 

Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic affecting over 300 million people worldwide. This disease is characterized by elevated fasting plasma glucose (FPG), insulin resistance, abnormally elevated hepatic glucose production (HGP), and reduced glucose-stimulated insulin secretion (GSIS). Moreover, long-term lack of glycemic control increases risk of complications from neuropathic, microvascular, and macrovascular diseases.

The standard of care for T2DM is metformin followed by sulfonylureas, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and thiazolidinediones (TZD) as second line oral therapies. As disease progression continues, patients typically require injectable agents such as glucagon-like peptide-1 (GLP-1) analogues and, ultimately, insulin to help maintain glycemic control. Despite these current therapies, many patients still remain unable to safely achieve and maintain tight glycemic control, placing them at risk of diabetic complications and highlighting the need for novel therapeutic options.

 

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia.

While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index.

 

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM.

As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type II diabetes and the metabolic syndrome” Nature414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

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PATENT

US 20100063063

http://www.google.com/patents/US20100063063

SYNTHESIS CONSTRUCTION

6-aminonicotinic acid

 

BENZYL BROMIDE

 

Figure US20100063063A1-20100311-C00076

FIRST KEY INTERMEDIATE

 

SECOND SERIES FOR NEXT INTERMEDIATE

CONDENSED WITH

4-Trifluoromethyl-1H-imidazole

TO  GIVE PRODUCT SHOWN BELOW

 

Figure US20100063063A1-20100311-C00025

(S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

 

CONVERTED TO ACID CHLORIDE, (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

AND CONDENSED WITH

Figure US20100063063A1-20100311-C00076

WILL GIVE BENZYL DERIVATIVE

THEN DEBENZYLATION TO FINAL PRODUCT

 

 

 

1H NMR (400 MHz, DMSO-d6) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H), 8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H), 1.29-1.64 (8H), 1.04-1.07 (1H); m/z 397.3 (M+H)+.

 

Organic Process Research & Development (2012), 16(10), 1635-1645

http://pubs.acs.org/doi/abs/10.1021/op300194c

Abstract Image

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (1)

 

Journal of Medicinal Chemistry (2012), 55(3), 1318-1333

http://pubs.acs.org/doi/abs/10.1021/jm2014887

Abstract Image

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Bioorganic & Medicinal Chemistry Letters (2013), 23(24), 6588-6592

http://www.sciencedirect.com/science/article/pii/S0960894X13012638

Image for unlabelled figure

 

Structure of Hepatoselective GKA PF-04991532 (1).

Figure 1.

Structure of Hepatoselective GKA PF-04991532 (1).

 

Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04937319-glucokinase-activators-for-the-treatment-of-type-2-diabetes/

Graphical abstract: Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

PF 04937319

N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide

MW 432.43

MF C22 H20 N6 O4
CAS 1245603-92-2
2-​Pyrimidinecarboxamid​e, N,​N-​dimethyl-​5-​[[2-​methyl-​6-​[[(5-​methyl-​2-​pyrazinyl)​amino]​carbonyl]​-​4-​benzofuranyl]​oxy]​-
N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide
Pfizer Inc. clinical candidate currently in Phase 2 development.
CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)
Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

 

SYNTHESIS

PF 319 SYN

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

 

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

*Corresponding authors
aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421
Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract

http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

Graphical abstract: Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28).

 

PAPER

 

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

 

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578

http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Glucokinase activators 1 and 2.

Figure 1.

Glucokinase activators 1 and 2.

 

PATENT

Pfizer Inc.

WO 2010103437

https://www.google.co.in/patents/WO2010103437A1?cl=en

Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Figure imgf000011_0001
PF 319 SYN

Preparations of Starting Materials and Key Intermediates

 

 

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

 

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

 

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)

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reducing obesity-related inflammation

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

NIH researchers find potential target for reducing obesity-related inflammation

Study sheds light on preventing or reversing certain obesity-associated diseases.

http://www.nih.gov/news-events/news-releases/nih-researchers-find-potential-target-reducing-obesity-related-inflammation

Scientists at the National Institutes of Health have identified a potential molecular target for reducing obesity-related inflammation. Researchers have known that overeating (that is, excess calorie consumption) by individuals with obesity often triggers inflammation, which has been linked to such diseases as asthma and Type 2 diabetes. In their study, published recently in The Journal of Clinical Investigation (Nov. 3, 2015, online version(link is external)), the investigators found that a protein called SIRT3 provides resistance to this inflammatory response and could potentially prevent or reverse obesity-associated diseases of inflammation.

Lead researcher Michael N. Sack, M.D., Ph.D., a senior investigator at NIH’s National Heart, Lung, and Blood Institute, explained that he and his team identified the role of SIRT3 through an investigation involving 19 healthy volunteers who fasted for a 24-hour period.

“Previous research has shown that intermittent fasting or intermittent calorie restriction — by way of eating fewer calories for a few days a month — reduces inflammation,” said Dr. Sack. “We found through our study that this effect is mediated, in part, on a molecular level when SIRT3 blocks the activity of another molecule known as the NLRP3 inflammasome.” He explained that NLRP3 inflammasomes are components of an intracelluar immune response triggered when mitochondria undergo stress, such as from excess calorie intake.

By using cultured cells from a group of eight volunteers who did not fast, Dr. Sack and his team found evidence suggesting that SIRT3 can be activated not only through fasting, but also through the use of nicotinamide riboside, a vitamin B derivative. “Taken together, these early results point to a potential mechanism for addressing obesity-related inflammation, and thus diseases linked to this type of inflammation, such as asthma, Type 2 diabetes, rheumatoid arthritis, and atherosclerosis — conditions associated with a reduced quality of life and/or premature death,” Dr. Sack said.

Obesity remains a substantial health problem for the nation, affecting more than a third of adults and 17 percent of children, according to the Centers for Disease Control and Prevention. Efforts to manage weight, however, can be hindered by the effects of obesity-related diseases. “It is a vicious cycle,” said Dr. Sack. “Take asthma for example. An increase in obesity incidence has been associated with an increase in asthma incidence, but asthma makes it difficult for some to be physically active enough to lose weight.”

Dr. Sack and colleagues — who include researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Weill Cornell Medical College — are conducting a follow-up study at the NIH Clinical Center to determine whether the vitamin B derivative nicotinamide riboside can specifically reduce bronchial inflammation in individuals with asthma. If the results of the study are promising, Dr. Sack and colleagues will aim to conduct larger clinical trials to validate the findings and potentially inform treatment of obesity-related inflammation in asthma.

The National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

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Seaweed in Diet

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

7 Ways to Eat More Seaweed

http://www.integrativenutrition.com/blog/2015/11/7-ways-to-eat-more-seaweed-and-why-you-should

 

http://amznstatic01.integrativenutrition.com/styles/panopoly_image_original/shutterstock_255225709.jpg?itok=0EzFp2t6

 

Seaweed, is making waves again thanks to the discovery of a seaweed that tastes like bacon and is better for you than kale. This could be good news given the World Health Organization’s recent declaration that eating processed meats such as bacon and sausage can increase the risk of colorectal cancer.

But why is seaweed so good for you? And can it actually taste good?

Nutrition-wise, it’s a powerhouse of vitamins and minerals. Seaweeds contain dietary fiber, essential amino acids, vitamins, A, B, C, and E, Omega-3 fats, and minerals such as iodine, calcium, iron, zinc, and magnesium. All of these nutrients combine to reduce inflammation, lift your energy, maintain strong bones and teeth, support thyroid health and hormonal balance, and even reduce your risk of cancer.

It’s no wonder seaweed has been a staple in Asian cuisine for centuries!

While some may have concerns in recent years that seaweed is becoming a potentially harmful food due to the increasing pollution of our oceans, there has not been any evidence to support this despite ongoing testing. That being said, it’s always best to seek out quality products. We recommend finding brands that grow seaweed in sustainable ways and in pure or tested waters.

Let’s get cookin’!

While seaweed hasn’t quite risen to popularity as a superfood like kale or other leafy greens, it’s so versatile and easy to prepare we have a feeling it’ll win you over.

Here are some delicious ways to incorporate more seaweed into your diet:

1. Cook your beans with kombu.
Try adding a strip of kombu when cooking your dried beans to add a rich array of vitamins and minerals to your dish while enhancing the flavor and making the beans more digestible!

2. Snack on nori.
Nori is lightweight and easy to pack yet also nutritious and surprisingly filling.  It’s the perfect thing to throw into your bag for a quick snack at work or on the go, and is a healthy alternative for those with salty cravings. Even your kids will enjoy its crispy texture. Want another great way to use nori? Try these delicious seaweed breakfast wraps!

3. Enhance your smoothies with spirulina.
Powdered seaweed such as spirulina is a great source of natural protein, making it a morning and pre- or post-workout favorite among Health Coaches and smoothie-lovers alike.  Start with a teaspoon added to your preferred smoothie combo (it goes especially well with avocado, banana, or pineapple) and adjust the amount as you get used to it.

4. Add a dash of seaweed flakes to every meal.
Health food stores or Asian markets will have a variety of packaged salts and seasoning that include seaweed. Or you can make your own by combining fine-chopped or ground nori, kombu, dulse, sea salt, black pepper, and sesame seeds. Keep this right along with your most frequently used seasonings and sprinkle it over daily meals.

 5. Mix in kelp or kombu to stocks, soups, and stews.
Add seaweed to any savory liquid-based foods! If you make your own vegetable stock from veggie scraps toss in a strip of seaweed and strain it out along with the other ingredients. If adding directly to soups or stews remove the solid strip before serving but don’t worry about any small pieces left in, they’re edible and will enhance the overall meal.

6. Stir it into your salad dressing.
Sprinkle some powdered seaweed into any salad dressing you’re using, allow it to sit for a minute to mix and absorb, shake well, then toss into your salad.

7. Toss together a seaweed salad.
Wakame and arame are best for a salad made predominantly of seaweed.  Combine with vinegar, sesame oil, garlic, and scallions. You can also incorporate other veggies like cucumbers, carrots, or radishes. Experiment to find your favorite combination and share it as a unique side dish at your next potluck.

 

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Excess Eating, Overweight, and Diabetic

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

You Did NOT Eat Your Way to Diabetes!

http://www.phlaunt.com/diabetes/14046739.php

 

The myth that diabetes is caused by overeating also hurts the one out of five people who are not overweight when they contract Type 2 Diabetes. Because doctors only think “Diabetes” when they see a patient who fits the stereotype–the grossly obese inactive patient–they often neglect to check people of normal weight for blood sugar disorders even when they show up with classic symptoms of high blood sugar such as recurrent urinary tract infections or neuropathy.

Where Did This Toxic Myth Come From?

The way this myth originated is this: Because people with Type 2 Diabetes are often overweight and because many people who are overweight have a syndrome called “insulin resistance” in which their cells do not respond properly to insulin so that they require larger than normal amounts of insulin to lower their blood sugar, the conclusion was drawn years ago that insulin resistance was the cause of Type 2 Diabetes.

It made sense. Something was burning out the beta cells in these people, and it seemed logical that the something must be the stress of pumping out huge amounts of insulin, day after day. This idea was so compelling that it was widely believed by medical professionals, though few realized it had never been subjected to careful investigation by large-scale research.

That is why any time there is an article in the news about Type 2 Diabetes you are likely to read something that says, “While Type 1 diabetes (sometimes called Juvenile Diabetes) is a condition where the body does not produce insulin, Type 2 Diabetes is the opposite: a condition where the body produces far too much insulin because of insulin resistance caused by obesity.”

When your doctor tells you the same thing, the conclusion is inescapable: your overeating caused you to put on excess fat and that your excess fat is what made you diabetic.

Blaming the Victim

This line of reasoning leads to subtle, often unexpressed, judgmental decisions on the part of your doctor, who is likely to believe that had you not been such a pig, you would not have given yourself this unnecessary disease.

And because of this unspoken bias, unless you are able to “please” your doctor by losing a great deal of weight after your diagnosis you may find yourself treated with a subtle but callous disregard because of the doctor’s feeling that you brought this condition down on yourself. This bias is similar to that held by doctors who face patients who smoke a pack a day and get lung cancer and still refuse to stop smoking.

You also see this bias frequently expressed in the media. Articles on the “obesity epidemic” blame overeating for a huge increase in the number of people with diabetes, including children and teenagers who are pictured greedily gorging on supersized fast foods while doing no exercise more strenuous than channel surfing. In a society where the concepts “thin” and “healthy” have taken on the overtones of moral virtue and where the only one of the seven deadly sins that still inspires horror and condemnation is gluttony, being fat is considered by many as sure proof of moral weakness. So it is not surprising that the subtext of media coverage of obesity and diabetes is that diabetes is nothing less than the just punishment you deserve for being such a glutton.

Except that it’s not true.

Obesity Has Risen Dramatically While Diabetes Rates Have Not

The rate of obesity has grown alarmingly over the past decades, especially in certain regions of the U.S. The NIH reports that “From 1960-2 to 2005-6, the prevalence of obesity increased from 13.4 to 35.1 percent in U.S. adults age 20 to 74.7.”

If obesity was causing diabetes, you’d exect to see a similar rise in the diabetes rate. But this has not happened. The CDC reports that “From 1980 through 2010, the crude prevalence of diagnosed diabetes increased …from 2.5% to 6.9%.” However, if you look at the graph that accompanies this statement, you see that the rate of diabetes diagnoses rose only gradually through this period–to about 3.5% until it suddenly sped upward in the late 1990s. This sudden increase largely due to the fact that in 1998 the American Diabetes Association changed the criteria by which diabetes was to be diagnosed, lowering the fasting blood sugar level used to diagnose diabetes from 141 mg/dl to 126 mg/dl. (Details HERE)

Analyzing these statistics, it becomes clear that though roughtly 65 million more Americans became fat over this period, only 13 million more Americans became diabetic.

And to further confuse the matter, several factors other than the rise in obesity and the ADA’s lowering of the diagnostic cutoff also came into play during this period which also raised the rate of diabetes diagnoses:

Diabetes becomes more common as people age as the pancreas like other organs, becames less efficient. In 1950 only 12% of the U.S. population was over 65. By 2010 40% was, and of those 40%, 19% were over 75.(Details HERE.)

At the same time, the period during which the rate of diabetes rose was also the period in which doctors began to heavily prescribe statins, a class of drugs we now know raises the risk of developing diabetes. (Details HERE.)

Why Obesity Doesn’t Cause Diabetes: The Genetic Basis of Diabetes

While people who have diabetes are often heavy, one out of five people diagnosed with diabetes are thin or normal weight. And though heavy people with diabetes are, indeed, likely to be insulin resistant, the majority of people who are overweight will never develop diabetes. In fact, they will not develop diabetes though they are likely to be just as insulin resistant as those who do–or even more so.

The message that diabetes researchers in academic laboratories are coming up with about what really causes diabetes is quite different from what you read in the media. What they are finding is that to get Type 2 Diabetes you need to have some combination of a variety of already-identified genetic flaws which produce the syndrome that we call Type 2 Diabetes. This means that unless you have inherited abnormal genes or had your genes damaged by exposure to pesticides, plastics and other environmental toxins known to cause genetic damage, you can eat until you drop and never develop diabetes.

Now let’s look in more depth at what peer reviewed research has found about the true causes of diabetes

Twin Studies Back up a Genetic Cause for Diabetes

Studies of identical twins showed that twins have an 80% concordance for Type 2 Diabetes. In other words, if one twin has Type 2 Diabetes, the chance that the other will have it two are 4 out of 5. While you might assume that this might simply point to the fact that twins are raised in the same home by mothers who feed them the same unhealthy diets, studies of non-identical twins found NO such correlation. The chances that one non-identical twin might have Type 2 Diabetes if the other had it were much lower, though these non-identical twins, born at the same time and raised by the same caregivers were presumably also exposed to the same unhealthy diets.

This kind of finding begins to hint that there is more than just bad habits to blame for diabetes. A high concordance between identical twins which is not shared by non-identical twins is usually advanced as an argument for a genetic cause, though because one in five identical twins did not become diabetic, it is assumed that some additional factors beyond the inherited genome must come into play to cause the disease to appear. Often this factor is an exposure to an environmental toxin which knocks out some other, protective genetic factor.

The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity. John E. Gerich. Endocrine Reviews 19(4) 491-503, 1998.

The List of Genes Associated with Type 2 Keeps Growing

Here is a brief list of some of the abnormal genes that have been found to be associated with Type 2 Diabetes in people of European extraction: TCF7L2, HNF4-a, PTPN, SHIP2, ENPP1, PPARG, FTO, KCNJ11, NOTCh3, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX.

People from non-European ethnic groups have been found to have entirely different sets of diabetic genes than do Western Europeans, like the UCP2 polymorphism found in Pima Indians and the three Calpain-10 gene polymorphisms that have been found to be associated with diabetes in Mexicans. The presence of a variation in yet another gene, SLC16A11, was recently found to be associated with a 25% higher risk of a Mexican developing Type 2 diabetes.

The More Diabetes Genes You Have The Worse Your Beta Cells Perform

A study published in the Journal Diabetologia in November 2008 studied how well the beta cells secreted insulin in 1,211 non-diabetic individuals. They then screened these people for abnormalities in seven genes that have been found associated with Type 2 Diabetes.

They found that with each abnormal gene found in a person’s genome, there was an additive effect on that person’s beta cell dysfunction with each additional gene causing poorer beta cell function.

The impact of these genetic flaws becomes clear when we learn that in these people who were believed to be normal, beta cell glucose sensitivity and insulin production at meal times was decreased by 39% in people who had abnormalities in five genes. That’s almost half. And if your beta cells are only putting out half as much insulin as a normal person’s it takes a lot less stress on those cells to push you into becoming diabetic.

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles L. Pascoe et al. Diabetologia, Volume 51, Number 11 / November, 2008.

Gene Tests Predict Diabetes Independent of Conventional “Risk Factors”

A study of 16,061 Swedish and 2770 Finnish subjects found that

Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCh3, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of Type 2 Diabetes independently of clinical risk factors [i.e. family history, obesity etc.]; variants in 8 of these genes were associated with impaired beta-cell function.

Note that though the subjects here were being screened for Type 2 Diabetes, the defect found here was NOT insulin resistance, but rather deficient insulin secretion. This study also found that:

The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased.

In short, the longer these people were studied, the more likely the people with these gene defects were to develop diabetes.

Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes Valeriya Lyssenko, M.D. et. al. New England Journal of Medicine, Volume 359:2220-2232, November 20, 2008,Number 21.

What A Common Diabetes Gene Does

A study published in July of 2009 sheds light on what exactly it is that an allele (gene variant) often found associated with diabetes does. The allele in question is one of TCF7L2 transcription factor gene. The study involved 81 normal healthy young Danish men whose genes were tested. They were then given a battery of tests to examine their glucose metabolisms. The researchers found that:

Carriers of the T allele were characterised by reduced 24 h insulin concentrations … and reduced insulin secretion relative to glucose during a mixed meal test … but not during an IVGTT [intravenous glucose tolerance test].

This is an interesting finding, because what damages our bodies is the blood sugar we experience after eating “a mixed meal” but so much research uses the artificial glucose tolerance (GTT) test to assess blood sugar health. This result suggests that the GTT may be missing important signs of early blood sugar dysfunction and that the mixed meal test may be a better diagnostic test than the GTT. I have long believed this to be true, since so many people experience reactive lows when they take the GTT which produces a seemingly “normal reading” though they routinely experience highs after eating meals. These highs are what damage our organs.

Young men with the TCF7L2 allele also responded with weak insulin secretion in response to the incretin hormone GLP-1 and “Despite elevated hepatic [liver] glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations … suggesting altered alpha cell function.”

Here again we see evidence that long before obesity develops, people with this common diabetes gene variant show highly abnormal blood sugar behavior. Abnormal production of glucose by the liver may also contribute to obesity as metformin, a drug that that blocks the liver’s production of glucose blocks weight gain and often causes weight loss.

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. K. Pilgaard et al. Diabetologia, Issue Volume 52, Number 7 / July, 2009. DOI 10.1007/s00125-009-1307-x

Genes Linked to African Heritage Linked to Poor Carbohydrate Metabolism

It has long been known that African-Americans have a much higher rate of diabetes and metabolic syndrome than the American population as a whole. This has been blamed on lifestyle, but a 2009 genetic study finds strong evidence that the problem is genetic.

The study reports,

Using genetic samples obtained from a cohort of subjects undergoing cardiac-related evaluation, a strict algorithm that filtered for genomic features at multiple levels identified 151 differentially-expressed genes between Americans of African ancestry and those of European ancestry. Many of the genes identified were associated with glucose and simple sugar metabolism, suggestive of a model whereby selective adaptation to the nutritional environment differs between populations of humans separated geographically over time.

In the full text discussion the authors state,

These results suggest that differences in glucose metabolism between Americans of African and European may reside at the transcriptional level. The down-regulation of these genes in the AA cohorts argues against these changes being a compensatory response to hyperglycemia and suggests instead a genetic adaptation to changes in the availability of dietary sugars that may no longer be appropriate to a Western Diet.

In conclusion the authors note that the vegetarian diet of the Seventh Day Adventists, often touted as proof of the usefulness of the “Diet Pyramid” doesn’t provide the touted health benefits to people of African American Heritage. Obviously, when hundreds of carbohydrate metabolizing genes aren’t working properly the diet needed is a low carbohydrate diet.

The study is available in full text here:

Stable Patterns of Gene Expression Regulating Carbohydrate Metabolism Determined by Geographic AncestryJonathan C. Schisler et. al. PLoS One 4(12): e8183. doi:10.1371/journal.pone.0008183

Gene that Disrupts Circadian Clock Associated with Type 2 Diabetes

It has been known for a while that people who suffer from sleep disturbances often suffer raised insulin resistance. In December of 2008, researchers identified a gene, “rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose.” They conclude,

Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.

Melatonin levels appear to control the body clock which, in turn, regulates the secretion of substances that modify blood pressure, hormone levels, insulin secretion and many other processes throughout the body.

A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nabila Bouatia-Naji et al. Nature Genetics Published online: 7 December 2008, doi:10.1038/ng.277

There’s an excellent translation of what this study means, translated into layman’s terms at Science Daily:

Body Clock Linked to Diabetes And High Blood Sugar In New Genome-wide Study

 

The Environmental Factors That Push Borderline Genes into Full-fledged Diabetes

We’ve seen so far that to get Type 2 Diabetes you seem to need to have some diabetes gene or genes, but that not everyone with these genes develops diabetes. There are what scientists call environmental factors that can push a borderline genetic case into full fledged diabetes. Let’s look now at what the research has found about what some of these environmental factors might be.

 

Your Mother’s Diet During Pregnancy May Have Caused Your Diabetes

Many “environmental factors” that scientists explore occur in the environment of the womb. Diabetes is no different, and the conditions you experienced when you were a fetus can have life-long impact on your blood sugar control.

Researchers following the children of mothers who had experienced a Dutch famine during World War II found that children of mothers who had experienced famine were far more likely to develop diabetes in later life than a control group from the same population whose mothers had been adequately fed.

Glucose tolerance in adults after prenatal exposure to famine. Ravelli AC et al.Lancet. 1998 Jan 17;351(9097):173-7.,

A study of a Chinese population found a link between low birth weight and the development of both diabetes and impaired glucose regulation (i.e. prediabetes) that was independent of “sex, age, central obesity, smoking status, alcohol consumption, dyslipidemia, family history of diabetes, and occupational status.” Low birth weight in this population may well be due to less than optimal maternal nutrition during pregnancy.

Evidence of a Relationship Between Infant Birth Weight and Later Diabetes and Impaired Glucose Regulation in a Chinese Population Xinhua Xiao et. al. Diabetes Care31:483-487, 2008.

This may not seem all that relevant to Americans whose mothers have not been exposed to famine conditions. But to conclude this is to forget how many American teens and young women suffer from eating disorders and how prevalent crash dieting is in the group of women most likely to get pregnant.

It is also true that until the 1980s obstetricians routinely warned pregnant women against gaining what is now understood to be a healthy amount of weight. When pregnant women started to gain weight, doctors often put them on highly restrictive diets which resulted in many case in the birth of underweight babies.

Your Mother’s Gestational Diabetes May Have Caused Your Diabetes

Maternal starvation is not the only pre-birth factor associated with an increased risk of diabetes. Having a well-fed mother who suffered gestational diabetes also increases a child’s risk both of obesity and of developing diabetes.

High Prevalence of Type 2 Diabetes and Pre-Diabetes in Adult Offspring of Women With Gestational Diabetes Mellitus or Type 1 Diabetes The role of intrauterine hyperglycemia Tine D. Clausen, MD et al. Diabetes Care 31:340-346, 2008

Pesticides and PCBs in Blood Stream Correlate with Incidence of Diabetes

A study conducted among members of New York State’s Mohawk tribe found that the odds of being diagnosed with diabetes in this population was almost 4 times higher in members who had high concentrations of PCBs in their blood serum. It was even higher for those with high concentrations of pesticides in their blood.

Diabetes in Relation to Serum Levels of Polychlorinated Biphenyls and Chlorinated Pesticides in Adult Native Americans Neculai Codru, Maria J. Schymura,Serban Negoita,Robert Rej,and David O. Carpenter.Environ Health Perspect. 2007 October; 115(10): 1442-1447.Published online 2007 July 17. doi: 10.1289/ehp.10315.

It is very important to note that there is no reason to believe this phenomenon is limited to people of Native American heritage. Upstate NY has a well-known and very serious PCB problem–remember Love Canal? And the entire population of the U.S. has been overexposed to powerful pesticides for a generation.

More evidence that obesity may be caused by exposure to toxic pollutants which damage genes comes in a study published January of 2009. This study tracked the exposure of a group of pregnant Belgian woman to several common pollutants: hexachlorobenzene, dichlorodiphenyldichloroethylene (DDE) , dioxin-like compounds, and polychlorinated biphenyls (PCBs). It found a correlation between exposure to PCBs and DDE and obesity by age 3, especially in children of mothers who smoked.

Intrauterine Exposure to Environmental Pollutants and Body Mass Index during the First 3 Years of Life Stijn L. Verhulst et al., Environmental Health Perspectives. Volume 117, Number 1, January 2009

These studies, which garnered no press attention at all, probably have more to tell us about the reason for the so-called “diabetes epidemic” than any other published over the last decade.

BPA and Plasticizers from Packaging Are Strongly Linked to Obesity and Insulin Resistance

BPA, the plastic used to line most metal cans has long been suspected of causing obesity. Now we know why. A study published in 2008 reported that BPA suppresses a key hormone, adiponectin, which is responsible for regulating insulin sensitivity in the body and puts people at a substantially higher risk for metabolic syndrome.

Science Daily: Toxic Plastics: Bisphenol A Linked To Metabolic Syndrome In Human Tissue

The impact of BPA on children is dramatic. Analysis of 7 years of NHANES epidemiological data found that having a high urine level of BPA doubles a child’s risk of being obese.

Bisphenol A and Chronic Disease Risk Factors in US Children. Eng, Donna et al.Pediatrics Published online August 19, 2013. doi: 10.1542/peds.2013-0106

You, and your children are getting far more BPA from canned foods than what health authorities assumed they were getting. A research report published in 2011 reported that the level of BPA actually measured in people’s bodies after they consumed canned soup turned out to be extremely high. People who ate a serving of canned soup every day for five days had BPA levels of 20.8 micrograms per liter of urine, whereas people who instead ate fresh soup had levels of 1.1 micrograms per liter.

Canned Soup Consumption and Urinary Bisphenol A: A Randomized Crossover Trial Carwile, JL et al. JAMA. November 23/30, 2011, Vol 306, No. 20

Nevertheless, the FDA caved in to industry pressure in 2012 and refused to regulate BPA claiming that, as usual, more study was needed. (FDA: BPA)

BPA is not the only toxic chemical associated with plastics that may be promoting insulin resistance. . Phthalates are compounds added to plastic to make it flexible. They rub off on our food and are found in our blood and urine. A study of 387 Hispanic and Black, New York City children who were between six and eight years old measured the phthalates in their urine and found that the more phthalates in their urine, the fatter the child was a year later.

Associations between phthalate metabolite urinary concentrations and body size measures in New York City children.
Susan L. Teitelbaum et al.Environ Res. 2012 Jan;112:186-93.

This finding was echosed by another study:

Urinary phthalates and increased insulin resistance in adolescents Trasande L, et al. Pediatrics 2013; DOI: 10.1542/peds.2012-4022.

And phthalates are everywhere. A study of 1,016 Swedes aged 70 years and older found that four phthalate metabolites were detected in the blood serum of almost all the participants. High levels of three of these were associated with the prevalence of diabetes. The researchers explain that one metabolite was mainly related to poor insulin secretion, whereas two others were related to insulin resistance. The researchers didn’t check to see whether this relationship held for prediabetes.

Circulating Levels of Phthalate Metabolites Are Associated With Prevalent Diabetes in the Elderly.Lind, MP et al. Diabetes. Published online before print April 12, 2012, doi: 10.2337/dc11-2396

Chances are very good that these same omnipresent phthalates are also causing insulin resistance and damaging insulin secretion in people whose ages fall between those of the two groups studied here.

Use of Herbicide Atrazine Maps to Obesity, Causes Insulin Resistance

A study published in April of 2009 mentions that “There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30.”

It found that when rats were given low doses of this pesticide in thier water, “Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level.” In short the animals got fat even without changing their food intake. When the animals were fed a high fat,high carb diet, the weight gain was even greater.

Insulin resistance was increased too, which if it happens in people, means that people who have genetically-caused borderline capacity to secrete insulin are more likely to become diabetic when they are exposed to this chemical via food or their drinking water.

Chronic Exposure to the Herbicide, Atrazine, Causes Mitochondrial Dysfunction and Insulin Resistance PLoS ONE Published 13 Apr 2009

2,4-D A Common Herbicide Blocks Secretion of GLP-1–A Blood Sugar Lowering Gastric Peptide

In 2007 scientists at New York’s Mount Sinai Hospital discovered that the intestine has receptors for sugar identical to those found on the tongue and that these receptors regulate secretion of glucagon-like peptide-1 (GLP-1). GLP-1 is the peptide that is mimicked by the diabetes drug Byetta and which is kept elevated by Januvia and Onglyza. You can read about that finding in this Science Daily report:

Science Daily: Your Gut Has Taste Receptors

In November 2009, these same scientists reported that a very common herbicide 2,4 D blocked this taste receptor, effectively turning off its ability to stimulate the production GLP-1. The fibrate drugs used to lower cholesterol were also found to block the receptor.

Science Daily: Common Herbicides and Fibrates Block Nutrient-Sensing Receptor Found in Gut and Pancreas

What was even more of concern was the discovery that the ability of these compounds to block this gut receptor “did not generalize across species to the rodent form of the receptor.” The lead researcher was quoted as saying,

…most safety tests were done using animals, which have T1R3 receptors that are insensitive to these compounds,

This takes on additional meaning when you realize that most compounds released into the environment are tested only on animals, not humans. It may help explain why so many supposedly “safe” chemicals are damaging human glucose metabolisms.

Trace Amounts of Arsenic in Urine Correlate with Dramatic Rise in Diabetes

A study published in JAMA in August of 2008 found of 788 adults who had participated in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) found those who had the most arsenic in their urine, were nearly four times more likely to have diabetes than those who had the least amount.

The study is reported here:

Arsenic Exposure and Prevalence of Type 2 Diabetes in US Adults. Ana Navas-Acien et al. JAMA. 2008;300(7):814-822.

The New York Times report about this study (no longer online) added this illuminating bit of information to the story:

Arsenic can get into drinking water naturally when minerals dissolve. It is also an industrial pollutant from coal burning and copper smelting. Utilities use filtration systems to get it out of drinking water.

Seafood also contains nontoxic organic arsenic. The researchers adjusted their analysis for signs of seafood intake and found that people with Type 2 Diabetes had 26 percent higher inorganic arsenic levels than people without Type 2 Diabetes.

How arsenic could contribute to diabetes is unknown, but prior studies have found impaired insulin secretion in pancreas cells treated with an arsenic compound.

Prescription Drugs, Especially SSRI Antidepressants Cause Obesity and Possibly Diabetes

Another important environmental factor is this: Type 2 Diabetes can be caused by some commonly prescribed drugs. Beta blockers and atypical antipsychotics like Zyprexa have been shown to cause diabetes in people who would not otherwise get it. This is discussed here.

There is some research that suggests that SSRI antidepressants may also promote diabetes. It is well known that antidepressants cause weight gain.

Spin doctors in the employ of the drug companies who sell these high-profit antidepressants have long tried to attribute the relationship between depression and obesity to depression, rather than the drugs used to treat the condition.

However, a new study published in June 2009 used data from the Canadian National Population Health Survey (NPHS), a longitudinal study of a representative cohort of household residents in Canada and tracked the incidence of obesity over ten years.

The study found that, “MDE [Major Depressive Episode] does not appear to increase the risk of obesity. …Pharmacologic treatment with antidepressants may be associated with an increased risk of obesity. [emphasis mine]. The study concluded,

Unexpectedly, significant effects were seen for serotonin-reuptake-inhibiting antidepressants [Prozac,Celexa, Lovox, Paxil, Zoloft] and venlafaxine [Effexor], but neither for tricyclic antidepressants nor antipsychotic medications.

Scott B. Patten et al. Psychother Psychosom 2009;78:182-186 (DOI: 10.1159/000209349)

Here is an article posted by the Mayo Clinic that includes the statement “weight gain is a reported side effect of nearly all antidepressant medications currently available.

Antidepressants and weight gain – Mayoclinic.com

Here is a report about a paper presented at the 2006 ADA Conference that analyzed the Antidepressant-Diabetes connection in a major Diabetes prevention study:

Medscape: Antidepressant use associated with increased type 2 diabetes risk.

Treatment for Cancer, Especially Radiation, Greatly Increases Diabetes Risk Independent of Obesity or Exercise Level

A study published in August 2009 analyzed data for 8599 survivors in the Childhood Cancer Survivor Study. It found that after adjusting for body mass and exercise levels, survivors of childhood cancer were 1.8 times more likely than the siblings to report that they had diabetes.

Even more significantly, those who had had full body radiation were 7.2 times more likely to have diabetes.

This raises the question of whether exposure to radiation in other contexts also causes Type 2 diabetes.

Diabetes Mellitus in Long-term Survivors of Childhood Cancer: Increased Risk Associated With Radiation Therapy: A Report for the Childhood Cancer Survivor Study.Lillian R. Meacham et al. Arch. Int. Med.Vol. 169 No. 15, Aug 10/24, 2009.

More Insight into the Effect of Genetic Flaws

Now that we have a better idea of some of the underlying physiological causes of diabetes, lets look more closely at the physiological processes that takes place as these genetic flaws push the body towards diabetes.

Insulin Resistance Develops in Thin Children of People with Type 2 Diabetes

Lab research has come up with some other intriguing findings that challenge the idea that obesity causes insulin resistance which causes diabetes. Instead, it looks like the opposite happens: Insulin resistance precedes the development of obesity.

One of these studies took two groups of thin subjects with normal blood sugar who were evenly matched for height and weight. The two groups differed only in that one group had close relatives who had developed Type 2 Diabetes, and hence, if there were a genetic component to the disorder, they were more likely to have it. The other group had no relatives with Type 2 Diabetes. The researchers then and examined the subjects’ glucose and insulin levels during a glucose tolerance test and calculated their insulin resistance. They found that the thin relatives of the people with Type 2 Diabetes already had much more insulin resistance than did the thin people with no relatives with diabetes.

Insulin resistance in the first-degree relatives of persons with Type 2 Diabetes. Straczkowski M et al. Med Sci Monit. 2003 May;9(5):CR186-90.

This result was echoed by a second study published in November of 2009.

That study compared detailed measurements of insulin secretion and resistance in 187 offspring of people diagnosed with Type 2 diabetes against 509 controls. Subjects were matched with controls for age, gender and BMI. It concluded:

The first-degree offspring of type 2 diabetic patients show insulin resistance and beta cell dysfunction in response to oral glucose challenge. Beta cell impairment exists in insulin-sensitive offspring of patients with type 2 diabetes, suggesting beta cell dysfunction to be a major defect determining diabetes development in diabetic offspring.

Beta cell (dys)function in non-diabetic offspring of diabetic patients M. Stadler et al. Diabetologia Volume 52, Number 11 / November, 2009, pp 2435-2444. doi 10.1007/s00125-009-1520-7

Mitochondrial Dysfunction is Found in Lean Relatives of People with Type 2 Diabetes

One reason insulin resistance might precede obesity was explained by a landmark 2004 study which looked at the cells of the “healthy, young, lean” but insulin-resistant relatives of people with Type 2 Diabetes and found that their mitochondria, the “power plant of the cells” that is the part of the cell that burns glucose, appeared to have a defect. While the mitochondria of people with no relatives with diabetes burned glucose well, the mitochondria of the people with an inherited genetic predisposition to diabetes were not able to burn off glucose as efficiently, but instead caused the glucose they could not burn and to be stored in the cells as fat.

Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. Petersen KF et al. New England J Med 2004 Feb 12; 350(7);639-41

More Evidence that Abnormal Insulin Resistance Precedes Weight Gain and Probably Causes It

A study done by the same researchers at Yale University School of Medicine who discovered the mitochondrial problem we just discussed was published in Proceedings of the National Academy of Science (PNAS) in July 2007. It reports on a study that compared energy usage by lean people who were insulin resistant and lean people who were insulin sensitive.

The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome Petersen,KF et al. PNAS July 31, 2007 vol. 104 no. 31 12587-12594.

Using new imaging technologies, the researchers found that lean but insulin resistant subjects converted glucose from high carbohydrate meals into triglycerides–i.e. fat. Lean insulin-sensitive subjects, in contrast, stored the same glucose in the form of muscle and liver glycogen.

The researchers conclude that:

the insulin resistance, in these young, lean, insulin resistant individuals, was independent of abdominal obesity and circulating plasma adipocytokines, suggesting that these abnormalities develop later in the development of the metabolic syndrome.”

In short, obesity looked to be a result, not a cause of the metabolic flaw that led these people to store carbohydrate they ate in the form of fat rather than burn it for energy.

The researchers suggested controlling insulin resistance with exercise. It would also be a good idea for people who are insulin resistant, or have a family history of Type 2 Diabetes to cut back on their carb intake, knowing that the glucose from the carbs they eat is more likely to turn into fat.

Beta Cells Fail to Reproduce in People with Diabetes

A study of pancreas autopsies that compared the pancreases of thin and fat people with diabetes with those of thin and fat normal people found that fat, insulin-resistant people who did not develop diabetes apparently were able to grow new beta-cells to produce the extra insulin they needed. In contrast, the beta cells of people who developed diabetes were unable to reproduce. This failure was independent of their weight.

Beta-Cell Deficit and Increased Beta-Cell Apoptosis in Humans With Type 2 Diabetes. Alexandra E. Butler, et al. Diabetes 52:102-110, 2003

Once Blood Sugars Rise They Impair a Muscle Gene that Regulates Insulin Sensitivity

Another piece of the puzzle falls into place thanks to a research study published on Feb 8, 2008.

Downregulation of Diacylglycerol Kinase Delta Contributes to Hyperglycemia-Induced Insulin Resistance. Alexander V. Chibalin et. al. Cell, Volume 132, Issue 3, 375-386, 8 February 2008.

As reported in Diabetes in Control (which had access to the full text of the study)

The research team identified a “fat-burning” gene, the products of which are required to maintain the cells insulin sensitivity. They also discovered that this gene is reduced in muscle tissue from people with high blood sugar and type 2-diabetes. In the absence of the enzyme that is made by this gene, muscles have reduced insulin sensitivity, impaired fat burning ability, which leads to an increased risk of developing obesity.

“The expression of this gene is reduced when blood sugar rises, but activity can be restored if blood sugar is controlled by pharmacological treatment or exercise”, says Professor Juleen Zierath. “Our results underscore the importance of tight regulation of blood sugar for people with diabetes.”

In short, once your blood sugar rises past a certain point, you become much more insulin resistant. This, in turn, pushes up your blood sugar more.

A New Model For How Diabetes Develops

These research findings open up a new way of understanding the relationship between obesity and diabetes.

Perhaps people with the genetic condition underlying Type 2 Diabetes inherit a defect in the beta cells that make those cells unable to reproduce normally to replace cells damaged by the normal wear and tear of life.Or perhaps exposure to an environmental toxin damages the related genes.

Perhaps, too, a defect in the way that their cells burn glucose inclines them to turn excess blood sugar into fat rather than burning it off as a person with normal mitochondria might do.

Put these facts together and you suddenly get a fatal combination that is almost guaranteed to make a person fat.

Studies have shown that blood sugars only slightly over 100 mg/dl are high enough to render beta cells dysfunctional.

Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Gastaldelli A, et al. Diabetologia. 2004 Jan;47(1):31-9. Epub 2003 Dec 10.

In a normal person who had the ability to grow new beta cells, any damaged beta cells would be replaced by new ones, which would keep the blood sugar at levels low enough to avoid further damage. But the beta cells of a person with a genetic heritage of diabetes are unable to reproduce So once blood sugars started to rise, more beta cells would succumb to the resulting glucose toxicity, and that would, in turn raise blood sugar higher.

As the concentration of glucose in their blood rose, these people would not be able to do what a normal person does with excess blood sugar–which is to burn it for energy. Instead their defective mitochondria will cause the excess glucose to be stored as fat. As this fat gets stored in the muscles it causes the insulin resistance so often observed in people with diabetes–long before the individual begins to gain visible weight. This insulin resistance puts a further strain on the remaining beta cells by making the person’s cells less sensitive to insulin. Since the person with an inherited tendency to diabetes’ pancreas can’t grow the extra beta cells that a normal person could grow when their cells become insulin resistant this leads to ever escalating blood sugars which further damage the insulin-producing cells, and end up in the inevitable decline into diabetes.

Low Fat Diets Promote the Deterioration that Leads to Diabetes in People with the Genetic Predisposition

In the past two decades, when people who were headed towards diabetes begin to gain weight, they were advised to eat a low fat diet. Unfortunately, this low fat diet is also a high carbohydrate diet–one that exacerbates blood sugar problems by raising blood sugars dangerously high, destroying more insulin-producing beta-cells, and catalyzing the storage of more fat in the muscles of people with dysfunctional mitochondria. Though they may have stuck to diets to low fat for weeks or even months these people were tormented by relentless hunger and when they finally went off their ineffective diets, they got fatter. Unfortunately, when they reported these experiences to their doctors, they were almost universally accused of lying about their eating habits.

It has only been documented in medical research during the past two years that that many patients who have found it impossible to lose weight on the low fat high carbohydrate can lose weight–often dramatically–on a low carbohydrate diet while improving rather than harming their blood lipids.

Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia differently in overweight men. Sharman MJ, et al. J Nutr. 2004 Apr;134(4):880-5.

An isoenergetic very low carbohydrate diet improves serum HDL cholesterol and triacylglycerol concentrations, the total cholesterol to HDL cholesterol ratio and postprandial lipemic responses compared with a low fat diet in normal weight, normolipidemic women. Volek JS, et al. J Nutr. 2003 Sep;133(9):2756-61.

The low carb diet does two things. By limiting carbohydrate, it limits the concentration of blood glucose which often is enough to bring moderately elevated blood sugars down to normal or near normal levels. This means that there will be little excess glucose left to be converted to fat and stored.

It also gets around the mitochondrial defect in processing glucose by keeping blood sugars low so that the body switches into a mode where it burns ketones rather than glucose for muscle fuel.

Relentless Hunger Results from Roller Coaster Blood Sugars

There is one last reason why you may believe that obesity caused your diabetes, when, in fact, it was undiagnosed diabetes that caused your obesity.

Long before a person develops diabetes, they go through a phase where they have what doctors called “impaired glucose tolerance.” This means that after they eat a meal containing carbohydrates, their blood sugar rockets up and may stay high for an hour or two before dropping back to a normal level.

What most people don’t know is that when blood sugar moves swiftly up or down most people will experience intense hunger. The reasons for this are not completely clear. But what is certain is that this intense hunger caused by blood sugar swings can develop years before a person’s blood sugar reaches the level where they’ll be diagnosed as diabetic.

This relentless hunger, in fact, is often the very first diabetic symptom a person will experience, though most doctors do not recognize this hunger as a symptom. Instead, if you complain of experiencing intense hunger doctors may suggest you need an antidepressant or blame your weight gain, if you are female, on menopausal changes.

This relentless hunger caused by impaired glucose tolerance almost always leads to significant weight gain and an increase in insulin resistance. However, because it can take ten years between the time your blood sugar begins to rise steeply after meals and the time when your fasting blood sugar is abnormal enough for you to be diagnosed with diabetes, most people are, indeed, very fat at the time of diagnosis.

With better diagnosis of diabetes (discussed here) we would be able to catch early diabetes before people gained the enormous amounts of weight now believed to cause the syndrome. But at least now people with diabetic relatives who are at risk for developing diabetes can go a long way towards preventing the development of obesity by controlling their carbohydrate intake long before they begin to put on weight.

You CAN Undo the Damage

No matter what your genetic heritage or the environmental insults your genes have survived, you can take steps right now to lower your blood sugar, eliminate the secondary insulin resistance caused by high blood sugars, and start the process that leads back to health. The pages linked here will show you how.

How To Get Your Blood Sugar Under Control

What Can You Eat When You Are Cutting The Carbs?

What is a Normal Blood Sugar

Research Connecting Blood Sugar Level with Organ Damage

The 5% Club: They Normalized Their Blood Sugar and So Can You

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Blood-Gut Barrier

Larry H Bernstein, MD, FCAP, Curator

PLBI

 

Blood-Gut Barrier

Scientists identify a barrier in mice between the intestine and its blood supply, and suggest how Salmonella sneaks through it.

By Ruth Williams | November 12, 2015

Salmonella invading an immune cell   WIKIMEDIA, NIAID

http://www.the-scientist.com/images/News/Nov2015/Salmonella.jpg

A person’s gut is full of microbes—some beneficial, some not. Friend or foe, these bacteria must be prevented from accessing the rest of the body, where they could cause harm. In a paper published in Science today (November 12), researchers describe a barrier in mice between the intestine and the adjacent blood vessels that restricts the size of particles that can pass through. The team also shows, however, that Salmonella bacteria can suppress a chemical pathway critical to barrier function, enabling the bugs to invade.

“First of all, [the authors] are really defining and showing the existence of this barrier and in what way it resembles the brain [barrier],” said immunologist Bana Jabri of the University of Chicago who was not involved in the study. “Then they show a pathogen that apparently has evolved to modulate that barrier to its own favor.”

The intestine is lined with epithelial cells covered in mucus. These cells provide both a physical barrier against microbial intrusion—they are tightly packed together—as well as biochemical one—they secrete antimicrobial proteins. In addition, the mucus itself “acts like a rip tide,” continuously washing the bacteria away from the epithelial shore, said gastroenterologist and immunologist Andrew Macpherson of the University of Bern in Switzerland who also did not participate in the work.

Aside from keeping the bacteria at bay, the epithelial cells’ job is to absorb digested food molecules. These nutrients enter the blood vessels adjacent to the intestine and ultimately reach the liver via the hepatic portal vein. What puzzled Maria Rescigno of the European Institute of Oncology in Milan, however, was why commensal bacteria, if they did beat the odds and enter the body, tended to end up in the nearby lymph nodes but were not found in the liver.

“Why would bacteria get to the lymphatics but not into the blood vessels which are very close to the epithelium?” she asked. And she began wondering: “is there something else other than just the epithelial barrier?”

For clues, Rescigno and her colleagues turned to probably the best-characterized barrier in the body: the blood-brain barrier. “We wondered whether the endothelium of the blood vessels [in the gut] would resemble the endothelium of the blood vessels in the brain,” she said.

There were indeed similarities. Endothelial cells of the blood-brain barrier have characteristically strong connections, called tight junctions and adherens junctions, and are surrounded by astrocytes—essential for barrier function. Endothelial cells of mouse intestinal blood vessels on the other hand had their own distinctive tight and adherens junctions, and were surrounded by enteric glial cells, “similar to the astrocytes” said Rescigno. These features also appeared to be present in human intestinal blood vessels, Rescigno’s team showed.

Furthermore the intestinal blood vessels of mice exhibited barrier function: while 4 kilodalton particles injected into the vessels could pass across the endothelium freely, 70 kilodalton particles could not. The blood-brain barrier by comparison prevents passage of any particles bigger than 500 Daltons.

Although this barrier appears to prevent most bacteria from entering the bloodstream, certain pathogenic species—including some Salmonella—are capable of establishing infections in the blood, liver and other organs. Rescigno and colleagues therefore investigated how Salmonella bacteria manage to squeeze through.

It turned out that infection of cultured endothelium with Salmonella suppressed the cells’ Wnt/β-catenin signaling pathway—known to be essential for blood-brain barrier function. Furthermore, the forced overexpression of β-catenin in endothelial cells of live mice, prevented Salmonella bacteria present in the animals’ guts from propagating around their bodies.

Prior to this study, the gut epithelium was considered the extent of the intestinal boundary, explained Macpherson, so “highlighting this vascular barrier is actually a rather important step forward.”

Depending on the species and serotype of Salmonella as well as on the health of the patient, some infections will lead to an acute illness limited to the gastrointestinal tract, while others will disseminate systemically and become chronic. If it were possible to develop treatments that close the vascular barrier, suggested Jabri, it might be possible to give such a drug alongside antibiotics. “In people who get acute infection one could address this barrier problem immediately,” she said, “so that [the infection] could not become chronic.”

I. Spadoni et al., “A gut-vascular barrier controls the systemic dissemination of bacteria,”Science, 350:830-34, 2015.

 

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Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Changing Face of Obesity

Science tells us obesity is a chronic disease. Why does the outmoded and injurious notion that it is a problem of willpower persist?

By Joseph Proietto | November 1, 2015   http://www.the-scientist.com//?articles.view/articleNo/44288/title/The-Changing-Face-of-Obesity/

In Dante Alighieri’s Divine Comedy the narrator meets a man named Ciacco who had been sent to Hell for the “Damning sin of Gluttony.” According to Catholic theology, in order to end up in Hell one must willfully commit a serious sin. So Dante believed that fat people chose to be fat. This antiquated view of the cause of obesity is still widespread, even among medical professionals. The consequences of this misconception are significant, because it forms the basis for the discrimination suffered by the obese; for the wasting of scarce resources in attempts to change lifestyle habits by public education; and for the limited availability of subsidized obesity treatments.

http://www.the-scientist.com/November2015/critic1.jpg

While obesity is often labeled a lifestyle disease, poor lifestyle choices alone account for only a 6 to 8 kg weight gain. The body has a powerful negative feedback system to prevent excessive weight gain. The strongest inhibitor of hunger, the hormone leptin, is made by fat cells. A period of increased energy intake will result in fat deposition, which will increase leptin production. Leptin suppresses hunger and increases energy expenditure. This slows down weight gain. To become obese, it may be necessary to harbor a genetic difference that makes the individual resistant to the action of leptin.

Evidence from twin and adoption studies suggests that obesity has a genetic basis, and over the past two decades a number of genes associated with obesity have been described. The most common genetic defect in European populations leading to severe obesity is due to mutations in the gene coding for the melanocortin 4 receptor (MCR4). Still, this defect can explain severe obesity in only approximately 6 percent to 7 percent of cases (J Clin Invest, 106:271-79, 2000). Other genes have been discovered that can cause milder increases in weight; for example, variants of just one gene (FTO) can explain up to 3 kg of weight variation between individuals (Science, 316:889-94, 2007).

Genes do not directly cause weight gain. Rather, genes influence the desire for food and the feeling of satiety. In an environment with either poor access to food or access to only low-calorie food, obesity may not develop even in persons with a genetic predisposition. When there is an abundance of food and a sedentary lifestyle, however, an obesity-prone person will experience greater hunger and reduced satiety, increasing caloric intake and weight gain.

Since the 1980s, there has been a rapid rise in the prevalence of obesity worldwide, a trend that likely results from a variety of complex causes. There is increasing evidence, for example, that the development of obesity on individual or familial levels may be influenced by environmental experiences that occur in early life. For example, if a mother is malnourished during early pregnancy, this results in epigenetic changes to genes involved in the set points for hunger and satiety in the developing child. These changes may then become fixed, resulting in a tendency towards obesity in the offspring.

The biological basis of obesity is further highlighted by the vigorous defense of weight following weight loss. There are at least 10 circulating hormones that modulate hunger. Of these, only one has been confirmed as a hunger-inducing hormone (ghrelin), and it is made and released by the stomach. In contrast, nine hormones suppress hunger, including CCK, PYY, GLP-1, oxyntomodulin, and uroguanylin from the small bowel; leptin from fat cells; and insulin, amylin, and pancreatic polypeptide from the pancreas.

 

After weight loss, regardless of the diet employed, there are changes in circulating hormones involved in the regulation of body weight. Ghrelin levels tend to increase and levels of multiple appetite-suppressing hormones decrease. There is also a subjective increase in appetite. Researchers have shown that even after three years, these hormonal changes persist (NEJM, 365:1597-604, 2011; Lancet Diabetes and Endocrinology, 2:954-62, 2014). This explains why there is a high rate of weight regain after diet-induced weight loss.

Given that the physiological responses to weight loss predispose people to regain that weight, obesity must be considered a chronic disease. Data show that those who successfully maintain their weight after weight loss do so by remaining vigilant and constantly applying techniques to oppose weight regain. These techniques may involve strict diet and exercise practices and/or pharmacotherapy.

It is imperative for society to move away from a view that obesity is simply a lifestyle issue and to accept that it is a chronic disease. Such a change would not only relieve the stigma of obesity but would also empower politicians, scientists and clinicians to tackle the problem more effectively.

Joseph Proietto was the inaugural Sir Edward Dunlop Medical Research Foundation Professor of Medicine in the Department of Medicine, Austin Health at the University of Melbourne in Australia. He is a researcher and clinician investigating and treating obesity and type 2 diabetes.

 

 

A Weighty Anomaly

Why do some obese people actually experience health benefits?

By Jyoti Madhusoodanan | November 1, 2015     http://www.the-scientist.com//?articles.view/articleNo/44304/title/A-Weighty-Anomaly/

http://www.the-scientist.com/November2015/notebook4.jpg

THE ENDOCRINE THEORY: Some researchers have posited that fat cells may secrete molecules that affect glucose homeostasis in muscle or liver tissue.COURTESY OF MITCHELL LAZAR

In the early 19th century, Belgian mathematician Adolphe Quetelet was obsessed with a shape: the bell curve. While helping with a population census, Quetelet proposed that the spread of human traits such as height and weight followed this trend, also known as a Gaussian or normal distribution. On a quest to define a “normal man,” he showed that human height and weight data fell along his beloved bell curves, and in 1823 devised the “Quetelet Index”—more familiar to us today as the BMI, or body mass index, a ratio of weight to height.

Nearly two centuries later, clinicians, researchers, and fitness instructors continue to rely on this metric to pigeonhole people into categories: underweight, healthy, overweight, or obese. But Quetelet never intended the metric to serve as a way to define obesity. And now, a growing body of evidence suggests these categories fail to accurately reflect the health risks—or benefits—of being overweight.

Although there is considerable debate surrounding the prevalence of metabolically healthy obesity, when obesity is defined in terms of BMI (a BMI of 30 or higher), estimates suggest that about 10 percent of adults in the U.S. are obese yet metabolically healthy, while as many as 80 percent of those with a normal BMI may be metabolically unhealthy, with signs of insulin resistance and poor circulating lipid levels, even if they suffer no obvious ill effects. “If all we know about a person is that they have a certain body weight at a certain height, that’s not enough information to know their health risks from obesity,” says health-science researcher Paul McAuley of Winston-Salem State University. “We need better indicators of metabolic health.”

The dangers of being overweight, such as a higher risk of heart disease, type 2 diabetes, and other complications, are well known. But some obese individuals—dubbed the “fat fit”—appear to fare better on many measures of health when they’re heavier. Studies have found lower mortality rates, better response to hemodialysis in chronic kidney disease, and lower incidence of dementia in such people. Mortality, it’s been found, correlates with obesity in a U-shaped curve (J Sports Sci, 29:773-82, 2011). So does extra heft help or hurt?

To answer that question, researchers are trying to elucidate the metabolic reasons for this obesity paradox.

In a recent study, Harvard University epidemiologist Goodarz Danaei and his colleagues analyzed data from nine studies involving a total of more than 58,000 participants to tease apart how obesity and other well-known metabolic risk factors influence the risk of coronary heart disease. Controlling these other risk factors, such as hypertension or high cholesterol, with medication is simpler than curbing obesity itself, Danaei explains. “If you control a person’s obesity you get rid of some health risks, but if you control hypertension or diabetes, that also reduces health risks, and you can do the latter much more easily right now.”

Danaei’s team assessed BMI and metabolic markers such as systolic blood pressure, total serum cholesterol, and fasting blood glucose. The three metabolic markers only explained half of the increased risk of heart disease across all study participants. In obese individuals, the other half appeared to be mediated by fat itself, perhaps via inflammatory markers or other indirect mechanisms (Epidemiology, 26:153-62, 2015). While Danaei’s study was aimed at understanding how obesity hurts health, the results also uncovered unknown mechanisms by which excess adipose tissue might exert its effects. This particular study revealed obesity’s negative effects, but might these unknown mechanisms hold clues that explain the obesity paradox?

Other researchers have suggested additional possibilities—for example, that inflammatory markers such as TNF-α help combat conditions such as chronic kidney disease, or that obesity makes a body more capable of making changes to, and tolerating changes in, blood flow depending on systemic needs (Am J Clin Nutr, 81:543-54, 2005).

According to endocrinologist Mitchell Lazar at the University of Pennsylvania, the key to explaining the obesity paradox may be two nonexclusive ways fat tissue is hypothesized to function. One mechanism, termed the endocrine theory, suggests that fat cells secrete, or don’t secrete enough of, certain molecules that influence glucose homeostasis in other tissues, such as muscle or liver. The first such hormone to be discovered was leptin; later studies reported several other adipocyte-secreted factors, including adiponectin, resistin, and various cytokines.

The other hypothesis, dubbed the spillover theory, suggests that storing lipids in fat cells has some pluses. Adipose tissue might sequester fat-soluble endotoxins, and produce lipoproteins that can bind to and clear harmful lipids from circulation. When fat cells fill up, however, these endotoxins are stashed in the liver, pancreas, or other organs—and that’s when trouble begins. In “fat fit” people, problems typically linked to obesity such as high cholesterol or diabetes may be avoided simply because their adipocytes mop up more endotoxins.

“In this model, one could imagine that if you could store even more fat in fat cells, you could be even more obese, but you might be protected from problems [associated with] obesity because you’re protecting the other tissues from filling up with lipids that cause problems,” says Lazar. “This may be the most popular current model to explain the fat fit.”

Although obesity greatly increases the risk of type 2 diabetes—up to 93-fold in postmenopausal women, for example—not all obese people suffer from the condition. Similarly, a certain subtype of individuals with “normal” BMIs are at greater risk of developing insulin resistance and type 2 diabetes than others with BMIs in the same range. Precisely what distinguishes these two cohorts is still unclear. “Just as important as explaining why some obese people don’t get diabetes is to explain why other subgroups—normal-weight people or those with lipodystrophy—sometimes get it,” Lazar says. “If there are multiple subtypes of obesity and diabetes, can we figure out genetic aspects or biomarkers that cause one of these phenotypes and not the other?”

To Lazar, McAuley, and other researchers, it’s increasingly evident that BMI may not be that metric. Finding better ways to assess a healthy weight, however, has proven challenging. Researchers have tested measures, such as the body shape index (ABSI) or the waist-hip ratio, which attempt to gauge visceral fat—considered to be more metabolically harmful than fat in other body locations. However, these metrics have yet to be implemented widely in clinics, and few are as simple to understand as the BMI (Science, 341:856-58, 2013).

Independent of metrics, however, the health message regarding weight is still unanimous: exercise and healthy dietary choices benefit everyone. “At a certain point, despite all the so-called fit-fat people, the demographics say that there’s a huge risk of diabetes and heart disease at very high BMI,” notes Lazar. “We can’t assume we’ll be one of the lucky ones who will have a BMI in the obese category but will still be protected from heart disease.”

Correction (November 2): The original version of this article misattributed the pull quote above. The attribution for this quote has been corrected, and The Scientist regrets the error.

 

 

THE HEALTH RISK OF OBESITY—BETTER METRICS IMPERATIVE

 Science 23 Aug 2013;  341(6148): 856858     DOI: http://dx.doi.org:/10.1126/science.1241244
Obesity paradoxes.
In this review, we examine the original obesity paradox phenomenon (i.e. in cardiovascular disease populations, obese patients survive better), as well as three other related paradoxes (pre-obesity, “fat but fit” theory, and “healthy” obesity). An obesity paradox has been reported in a range of cardiovascular and non-cardiovascular conditions. Pre-obesity (defined as a body mass index of 25.0-29.9 kg · m⁻²) presents another paradox. Whereas “overweight” implies increased risk, it is in fact associated with decreased mortality risk compared with normal weight. Another paradox concerns the observation than when fitness is taken into account, the mortality risk associated with obesity is offset. The final paradox under consideration is the presence of a sizeable subset of obese individuals who are otherwise healthy. Consequently, a large segment of the overweight and obese population is not at increased risk for premature death. It appears therefore that low cardiorespiratory fitness and inactivity are a greater health threat than obesity, suggesting that more emphasis should be placed on increasing leisure time physical activity and cardiorespiratory fitness as the main strategy for reducing mortality risk in the broad population of overweight and obese adults.
Obesity, insulin resistance, and cardiovascular disease.
Recent Prog Horm Res. 2004;59:207-23.
The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance – namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations — is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.
Long-Term Persistence of Hormonal Adaptations to Weight Loss

Priya Sumithran, Luke A. Prendergast, Elizabeth Delbridge, Katrina Purcell, Arthur Shulkes, Adamandia Kriketos, and Joseph Proietto

N Engl J Med 2011; 365:1597-1604   October 27, 2011http://dx.doi.org:/10.1056/NEJMoa1105816

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.

Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).

What’s new in endocrinology and diabetes mellitus

Large genome wide association studies have demonstrated that variants in the FTO gene have the strongest association with obesity risk in the general population, but the mechanism of the association has been unclear. However, a nonocoding causal variant in FTO has now been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) with a fivefold decrease in mitochondrial thermogenesis [17]. When the effect of the variant was blocked in genetically engineered mice, thermogenesis increased and weight gain did not occur, despite eating a high-fat diet. Blocking the gene’s effect in human adipocytes also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. (See “Pathogenesis of obesity”, section on ‘FTO variants’.)

Liraglutide for the treatment of obesity (July 2015)

Along with diet, exercise, and behavior modification, drug therapy may be a helpful component of treatment for select patients who are overweight or obese. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, used for the treatment of type 2 diabetes, and can promote weight loss in patients with diabetes, as well as those without diabetes.

In a randomized trial in nondiabetic patients who had a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with dyslipidemia and/or hypertension, liraglutide 3 mg once daily, compared with placebo, resulted in greater mean weight loss (-8.0 versus -2.6 kg with placebo) [18]. In addition, cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life improved modestly. Gastrointestinal side effects transiently affected at least 40 percent of the liraglutide group and were the most common reason for withdrawal (6.4 percent). Liraglutide is an option for select overweight or obese patients, although gastrointestinal side effects (nausea, vomiting) and the need for a daily injection may limit the use of this drug. (See “Obesity in adults: Drug therapy”, section on ‘Liraglutide’.)

In a trial designed specifically to evaluate the effect of liraglutide on weight loss in overweight or obese patients with type 2 diabetes (mean weight 106 kg), liraglutide, compared with placebo, resulted in greater mean weight loss (-6.4 kg and -5.0 kg for liraglutide 3 mg and 1.8 mg, respectively, versus -2.2 kg for placebo) [19]. Treatment with liraglutide was associated with better glycemic control, a reduction in the use of oral hypoglycemic agents, and a reduction in systolic blood pressure. Although liraglutide is not considered as initial therapy for the majority of patients with type 2 diabetes, it is an option for select overweight or obese patients with type 2 diabetes who fail initial therapy with lifestyle intervention and metformin.  (See “Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus”, section on ‘Weight loss’.)

The Skinny on Fat Cells

Bruce Spiegelman has spent his career at the forefront of adipocyte differentiation and metabolism.

By Anna Azvolinsky | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44312/title/The-Skinny-on-Fat-Cells/

Bruce Spiegelman
Stanley J. Korsmeyer Professor of Cell Biology
and Medicine
Harvard Medical School
Director, Center for Energy Metabolism
and Chronic
Disease, Dana-Farber Cancer Institute, Boston

It’s hard to know whether you have the right stuff to be a scientist, but I had a passion for the research,” says Bruce Spiegelman, professor of cell biology at Harvard Medical School and the Dana-Farber Cancer Institute. After receiving his PhD in biochemistry from Princeton University in 1978, Spiegelman sent an application to do postdoctoral research to just one lab. “I wasn’t thinking I should apply to five different labs. I just marched forward more or less in a straight line,” he says. Spiegelman did know that he had no financial backup and depended on research fellowships throughout the early phase of his science career. “I thought it was fantastic, and still think so, that a PhD in science is supported by the government. I certainly appreciated that, because many of my friends in the humanities had to support themselves by cobbling together fellowships and teaching every semester, whereas we didn’t face similar challenges in the sciences.”

Since his graduate student days, Spiegelman has realized his potential, pioneering the study of adipose tissue biology and metabolism. He was introduced to the field in Howard Green’s laboratory, then at MIT, where Spiegelman began his one and only postdoc in 1978. Green had recently developed a system for culturing adipose cells and asked Spiegelman if he wanted to study fat cell differentiation. “I knew nothing about adipose tissue, but I was really interested in any model of how one cell switches to another. Whether skin or fat didn’t matter too much to me, because I was not coming at this from the perspective of physiology but from the perspective of how do these switches work at a molecular level?”

Spiegelman has stuck with studying the biology and differentiation of fat cells for more than 30 years. While looking for the master transcriptional regulator of fat development—which his laboratory found in 1994—Spiegelman’s group also discovered one of the first examples of a nuclear oncogene that functions as a transcription factor, and, more recently, the team found that brown fat and white fat come from completely different origins and that brown and beige fat are distinct cell types. Spiegelman was also the first to provide evidence for the connection between inflammation, insulin resistance, and fat tissue.

Here, Spiegelman talks about his strong affinity for the East Coast, his laboratory’s search for molecules that can crank up brown fat production and activity, and the culture of his laboratory’s weekly meeting.

Spiegelman Sets Out

First publication. Spiegelman grew up in Massapequa, New York, a town on Long Island. “Birds, insects, fish, and animals were fascinating to me. As a kid, I imagined I would be a wildlife ranger,” he says. Spiegelman and his brother were the first in their family to attend college; Spiegelman entered the College of William and Mary in 1970 thinking he would major in psychology. But before taking his first psychology course, he had to take a biology course, really loved it, and switched his major. For his senior thesis, he chose one of the few labs that did biochemistry-related research. He studied cultures of the filamentous fungus Aspergillus ornatus in which he induced the upregulation of a metabolic enzyme. Spiegelman applied a calculus transformation that related the age of the culture to the age of individual cells, something that had not been previously done. The work earned him his first first-author publication in 1975. “It was not a great breakthrough, but I think it showed that I was maybe applying myself more than the typical undergraduate.”

Full steam ahead. “My interest in laboratory research was intense. Even though it was not particularly inspired work, the first-author publication in a college where not many of the professors published a lot gave me a lot of confidence. It was probably out of proportion to the quality of the actual work.” That confidence and Spiegelman’s interest in the chemistry of living things led him to pursue a PhD in biochemistry at Princeton University. “Very early on, I felt that I couldn’t understand biology if it didn’t go to the molecular level. To me, just describing how an animal lived without understanding how it worked was very unsatisfying. I think it was one of the best decisions that I made in my life, to do a PhD in biochemistry,” he says, “because if you really want to understand living systems, you are very limited in how you can understand them without having a strong background in biochemistry because these are, essentially, chemical systems.”

Embracing molecular biology. Spiegelman initially joined Arthur Pardee’s laboratory, but switched when Pardee left Princeton for Harvard University in 1975. Because he was already collaborating with Marc Kirschner, a cell biologist and biochemist who studies the regulation of the cell cycle and how the cytoskeleton works, it was an easy transition to transfer to the new laboratory. In Kirschner’s group, Spiegelman became the cell biologist among many protein biochemists working on microtubule assembly in vitro. Rather than understanding how the proteins fit together to form the filamentous structures, Spiegelman wanted to understand what controlled their assembly inside cells. Working in mammalian cells, Spiegelman published three consecutive Cell papers on how microtubule assembly occurs in vivo. The firstpaper, from 1977, demonstrated that a nucleotide functions to stabilize the tubulin molecule rather than to regulate tubulin assembly in vivo.

Spiegelman Simmers

A new tool. For his next move, Spiegelman wanted to marry his background in biochemistry and molecular biology with a good cellular model system. He became interested in differentiation at the end of his PhD, while studying how the cytoskeleton is reorganized during neural differentiation, and settled on Green’s MIT laboratory for his postdoc. Green had developed a way to study both skin and fat cell differentiation. Again, Spiegelman was the odd man out, working on the molecular biology of fat cell differentiation while most of the graduate students and postdocs focused on the cellular biology of skin cell differentiation. While there, Spiegelman learned how to clone cDNA—a new method that some researchers thought was just another new fad, he says. “I thought it was pretty obvious that this was a tool that would be a game changer. I could see how I could clone some of the cDNAs and genes that were regulated in the fat cell lineage and then try to understand the regulation of these genes.”

Setting the stage. Spiegelman demonstrated that cAMP regulates the synthesis of certain enzymes in fat cells during differentiation. But while this was the most influential paper from his postdoc, says Spiegelman, it was his demonstration of cloning mRNAs from adipocytes, published in 1983, that set the stage for cloning fat-selective genes. The work, mostly done when Spiegelman was already a new faculty member at the Dana-Farber Cancer Institute, stemmed from his learning molecular cloning in Phillip Sharp’s lab at MIT and Bryan Roberts’s lab at Harvard. “This was the raw material from which we eventually cloned PPARγ and showed it to be the master regulator of fat [cell] development.”

Roots. Spiegelman became an assistant professor at the Harvard Medical School in 1982, when he was not yet 30. Although he had entertained the idea of moving to the West Coast with his wife, whom he had met at Princeton where she obtained a PhD in French literature, Spiegelman says he is really an East Coaster at heart. “My wife and I came to love Boston and were very comfortable there. Our families were both in New York, which was close, but not too close, and we really enjoyed the culture and pace of Boston; it was more ‘us.’ We really liked to visit California but didn’t particularly want to move there. We’re both real Northeastern people.”

Relating to Sisyphus. The transition from doing a postdoc to setting up his own laboratory was “very exciting and terribly stressful,” says Spiegelman. “When I think back, I always tried to be professional with my laboratory, but I was so stressed at suddenly being on my own with no management training.” The people resources he had encountered in his graduate and postdoctoral training labs were also not there yet, and he says his first publication as a principal investigator was like pushing a rock up a hill. But eventually, Spiegelman’s lab built a reputation and reached a critical mass of talented people who advanced the science. Again in 1983, Spiegelman produced a publication showing that morphological manipulation can affect gene expression and adipose differentiation.

End goal. Spiegelman’s goal was to find a master molecule that  orchestrates the conversion of adipocyte precursor cells into bona fide fat cells. Piece by piece, his lab identified the enhancers, promoters, and other regulatory elements involved in adipocyte differentiation. In 1994, graduate student Peter Tontonoz finallyfound that the PPARγ gene, inserted via a retroviral vector into fibroblasts, could induce the cells to become adipose cells. “It took 10 years,” Spiegelman says. Along the way, the laboratory found that c-fos, the product of a famous nuclear oncogene, bound to the promoters of fat-specific genes and worked as a transcription factor. “It was not really known how nuclear oncogenes worked. This was one of the first papers showing that these oncogenes bound to gene promoters and were transcription factors.”

A wider scope. In 1993, graduate student Gökhan Hotamisligil found that tumor necrosis factor-alpha(TNF-α), is induced in the fat tissue of rodent models of obesity and diabetes. The paper sparked the formation of the field of immunometabolism and resulted in the expansion of Spiegelman’s lab into the physiology arena, partly thanks to the guidance of C. Ronald Kahn and Jeff Flier, who both study metabolism and diabetes. But the work initially encountered pushback, says Spiegelman, partly because it was the merging of two fields.

Spiegelman Scales Up

Fat color palette. Brown fat tissue, abundant in infants but scarce in adults, is a metabolically active form of fat that is chock full of mitochondria and is found in pockets in the body distinct from white fat tissue.Pere Puigserver, then a postdoc in Spiegelman’s lab, found that the coactivator PCG-1, binding to PPARγ and other nuclear receptors, could stimulate mitochondrial biogenesis. The PCG-1 gene is turned on by stimuli such as exercise or a cold environment. Later, postdoc Patrick Seale, Spiegelman, and their colleagues showed brown fat cells derive from the same lineage that gives rise to skeletal muscle. “This was a big surprise, maybe the biggest surprise we ever uncovered in the lab,” says Spiegelman.

A paler shade of brown. More recently, in 2012, Spiegelman’s laboratory showed that within adult white adipose tissue, there are pockets of a yet another type of fat tissue that he called beige fat. “I think the evidence is very good from rodents that if you activate brown and beige fat, you get metabolic benefit both in obesity and diabetes. So the question now is: Can that be done in humans in a way that’s beneficial and not toxic?”  The lab is now looking to identify molecules that can either ramp up the activity of brown and beige fat or increase the production of both cell types as possible therapeutics for metabolic disorders or even cancer-associated cachexia. “Anyone who says that either approach will work better is being foolish. We just don’t know enough to go after just one or the other.”

On the irisin controversy. After reporting in 2012 that a muscle-related hormone called irisin could switch white fat to metabolically active brown fat, Spiegelman became embroiled in a media-covered debate about whether the molecule really exists; he was also the victim of a potential fraud plot. Most recently, Spiegelman provided thorough evidence that irisin does in fact exist. On the controversy, he says it’s a fine line between defending his scientific integrity and not adding more fuel to the fire or engaging with his harassers. “We have a long track record of doing credible and reproducible science and it was not that complicated to address the paper that claimed irisin was ‘a myth.’ That study used very outmoded scientific approaches.”

Raw talent. Many of Spiegelman’s trainees have gone on to become very successful scientists, including Tontonoz, Hotamisligil, Evan Rosen, and Randy Johnson. “It’s a quantum change in the experience of doing science when you get people who have their own visions. I would have thought that interacting with smart people would mainly help me get my scientific vision accomplished. And that was partly true, but also it changed my vision. When you have people challenging you on a day-to-day basis, you learn from them through the questions they ask and the way they challenge you in a constructive way. They made me a much better scientist.”

Rigorous mentorship.  “I feel very passionately that a major part of my job is to prepare the next generation of scientists. Everyone who comes through my lab will tell you that I take that very seriously. We make sure my students give a lot of talks and get critical assessments of their presentations to our lab group. I am very hands-on both scientifically and in developing the way students project their vision. I had a very good mentor, Marc Kirschner, and I’d like to think that I learned how to be a mentor from him. I want to make sure that when people walk out of my lab they are prepared to run independent research programs.”

Greatest Hits

  • Identified the master regulator of adipogenesis, the nuclear receptor PPARγ
  • Was the first to show that a nuclear oncogene, c-fos, codes for a transcription factor that binds to the promoters of genes
  • Demonstrated that adipose tissue synthesizes tumor necrosis factor-alpha (TNF-α), providing the first direct link between obesity, inflammation, insulin resistance, and fat tissue.
  • Showed that brown fat cells are not developmentally related to white fat
  • Identified beige fat as a distinct cell type, different from either white or brown fat

 

Fanning the Flames

Obesity triggers a fatty acid synthesis pathway, which in turn helps drive T cell differentiation and inflammation.

By Kate Yandell | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44306/title/Fanning-the-Flames/

EDITOR’S CHOICE IN IMMUNOLOGY

The paper
Y. Endo et al., “Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1,” Cell Reports, 12:1042-55, 2015.

Cell Rep. 2015 Aug 11;12(6):1042-55.   http://dx.doi.org:/10.1016/j.celrep.2015.07.014. Epub 2015 Jul 30.
Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1.
  • A high-fat diet augments Th17 cell development and the expression of Acaca
  • ACC1 controls Th17 cell development in vitro and Th17 cell pathogenicity in vivo
  • ACC1 modulates RORγt function in developing Th17 cells
  • Obesity in humans induces ACACA and IL-17A expression in CD4 T cells

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

Figure thumbnail fx1

http://www.cell.com/cms/attachment/2035221719/2050630604/fx1.jpg

 

 

http://www.the-scientist.com/November2015/NovMediLit_310px.jpg

FEEDING INFLAMMATION: When mice eat a diet high in fat, their CD4 T cells show increased expression of the fatty acid biosynthesis gene Acaca, which encodes the enzyme ACC1 (1). Products of the ACC1 fatty acid synthesis pathway encourage the transcription factor RORγt to bind near the gene encoding the cytokine IL-17A (2). There, RORγt recruits an enzyme called p300 to modify the genome epigenetically and turn on IL-17A. The memory T cells then differentiate into inflammatory T helper 17 cells.
See full infographic: PDF
© STEVE GRAEPEL

Obesity often comes with a side of chronic inflammation, causing inflammatory chemicals and immune cells to flood adipose tissue, the hypothalamus, the liver, and other areas of the body. Inflammation is a big part of what makes obesity such an unhealthy condition, contributing to Type 2 diabetes, heart disease, cancers, autoimmune disorders, and possibly even neurodegenerative diseases.

To better understand the relationship between obesity and inflammation, Toshinori Nakayama, Yusuke Endo, and their colleagues at Chiba University in Japan started with what often leads to obesity: a high-fat diet. They fed mice rich meals for a couple of months and looked at how gene expression in the animals’ T cells compared to gene expression in the T cells of mice fed a normal diet. Most notably, they found increased expression ofAcaca, a gene that codes for a fatty acid synthesis enzyme called acetyl coA carboxylase 1 (ACC1). They went on to show that the resulting increase in fatty acid levels pushed CD4 T cells to differentiate into inflammatory T helper 17 (Th17) cells.

Th17 cells help fight off invading fungi and some bacteria. But these immune cells can also spin out of control in autoimmune diseases such as multiple sclerosis. Nakayama’s team showed that either blocking ACC1 activity with a drug called TOFA or deleting a key portion of Acaca in mouse CD4 T cells reduced the generation of pathologic Th17 cells. Overexpressing Acaca increased Th17-cell generation.

The researchers also demonstrated that mice fed a high-fat diet had elevated susceptibility to a multiple sclerosis–like disease, and that TOFA reduced the symptoms.

“This is a very intriguing finding, suggesting not only that obesity can directly induce Th17 differentiation but also indicating that pharmacologic targeting of fatty acid synthesis may help to interfere with obesity-associated inflammation,” Tim Sparwasser of the Twincore Center for Experimental and Clinical Infection Research in Hannover, Germany, says in an email. Sparwasser and his colleagues had previously shown that ACC1 is required for the differentiation of Th17 cells in mice and humans.

Nakayama explains that CD4 T cells must undergo profound metabolic changes as they mature and differentiate. “The intracellular metabolites, including fatty acids, are essential for cell proliferation and cell growth,” he says in an email. When fatty acid levels in T cells increase, the cells are activated and begin to proliferate.

“It’s a nice illustration of how, really, immune response is so highly connected to the metabolic state of the cell,” says Gökhan S. Hotamisligil of Harvard University’s T.H. Chan School of Public Health who was not involved in the study. “The immune system launches its responses commensurate with the sources of nutrients and energy from the environment,” he adds in an email.

There are still missing pieces in the path from high-fat diet to increased Acaca expression to ACC1’s influence on T-cell differentiation. It also remains to be seen how this plays out in obese humans, although Nakayama and colleagues did show that inhibiting ACC1 reduced pathologic Th17 generation in human immune cell cultures, and that the T cells of obese humans contain elevated levels of ACC1 and show signs of increased differentiation into Th17 cells.

 

The prevalence of obesity has been increasing worldwide, and obesity is now a major public health problem in most developed countries (Gregor and Hotamisligil, 2011, Ng et al., 2014). Obesity-induced inflammation contributes to the development of various chronic diseases, such as autoimmune diseases, metabolic diseases, and cancer (Kanneganti and Dixit, 2012, Kim et al., 2014,Osborn and Olefsky, 2012, Winer et al., 2009a). A number of studies have pointed out the importance of reciprocal interactions between metabolic systems and immune cells in the pathogenesis of obesity-associated diseases (Kaminski and Randall, 2010, Kanneganti and Dixit, 2012, Kim et al., 2014, Mauer et al., 2014, Stienstra et al., 2012, Winer et al., 2011).

Elucidating the molecular mechanisms by which naive CD4 T cells differentiate into effector T cells is crucial for understanding helper T (Th) cell-mediated immune pathogenicity. After antigen stimulation, naive CD4 T cells differentiate into at least four distinct Th cell subsets: Th1, Th2, Th17, and inducible regulatory T (iTreg) cells (O’Shea and Paul, 2010, Reiner, 2007). Several specific master transcription factors that regulate Th1/Th2/Th17/iTreg cell differentiation have been identified, including T-bet for Th1 (Szabo et al., 2000), GATA3 (Yamashita et al., 2004, Zheng and Flavell, 1997) for Th2, retinoic-acid-receptor-related orphan receptor γt (RORγt) for Th17 (Ivanov et al., 2006), and forkhead box protein 3 (Foxp3) for iTreg (Sakaguchi et al., 2008). The appropriate expression and function of these transcription factors is essential for proper immune regulation by each Th cell subset.

Among these Th cell subsets, Th17 cells contribute to the host defense against fungi and extracellular bacteria (Milner et al., 2008). However, the pathogenicity of IL-17-producing T cells has been recognized in various autoimmune diseases, including multiple sclerosis, psoriasis, inflammatory bowel diseases, and steroid-resistant asthma (Bettelli et al., 2006, Coccia et al., 2012, Ivanov et al., 2006,Leonardi et al., 2012, McGeachy and Cua, 2008, Nylander and Hafler, 2012,Stockinger et al., 2007, Sundrud et al., 2009).

An HFD Promotes Th17 Cell Differentiation and Affects the Expression of Fatty Acid Enzymes in Memory CD4 T Cells In Vivo

Inhibition of ACC1 Function Results in Decreased Th17 Cell Differentiation and Ameliorates the Development of Autoimmune Disease

ACC1 Controls the Differentiation of Th17 Cells Both In Vitro and In Vivo

ACC1 Controls the Function, but Not Expression, of RORγt in Differentiating Th17 Cells

Extrinsic Fatty Acid Supplementation Restored Acaca−/− Th17 Cell Differentiation through the Functional Improvement of RORγt

Obese Subjects Show Upregulation of ACACA and Increased Th17 Cells in CD45RO+ Memory CD4 T Cells

We herein identified a critical role that ACC1 plays in Th17 cell differentiation and the pathogenicity of Th17 cells through the control of the RORγt function under obese circumstances. High-fat-induced obesity augments Th17 cell differentiation and the expression of enzymes involved in fatty acid metabolism, including ACC1. Pharmacological inhibition or genetic deletion of ACC1 resulted in impaired Th17 cell differentiation in both mice and humans. In contrast, overexpression of Acaca induced Th17 cells in vivo, leaving the expression ofIfng and Il4 largely unchanged. ACC1 modulated the binding of RORγt to theIl17a gene and the subsequent p300 recruitment in differentiating Th17 cells. Memory CD4 T cells from peripheral blood mononuclear cells (PBMCs) of obese subjects showed increased IL-17A production and ACACA expression. Furthermore, a strong correlation was detected between the proportion of IL-17A-producing cells and the expression level of ACACA in memory CD4 T cells in obese subjects. Thus, our findings provide evidence of a mechanism wherein obesity can exacerbate IL-17-mediated pathology via the induction of ACC1.

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Irreconciliable Dissonance in Physical Space and Cellular Metabolic Conception


Irreconciliable Dissonance in Physical Space and Cellular Metabolic Conception

Curator: Larry H. Bernstein, MD, FCAP

Pasteur Effect – Warburg Effect – What its history can teach us today. 

José Eduardo de Salles Roselino

The Warburg effect, in reality the “Pasteur-effect” was the first example of metabolic regulation described. A decrease in the carbon flux originated at the sugar molecule towards the end of the catabolic pathway, with ethanol and carbon dioxide observed when yeast cells were transferred from an anaerobic environmental condition to an aerobic one. In Pasteur´s studies, sugar metabolism was measured mainly by the decrease of sugar concentration in the yeast growth media observed after a measured period of time. The decrease of the sugar concentration in the media occurs at great speed in yeast grown in anaerobiosis (oxygen deficient) and its speed was greatly reduced by the transfer of the yeast culture to an aerobic condition. This finding was very important for the wine industry of France in Pasteur’s time, since most of the undesirable outcomes in the industrial use of yeast were perceived when yeasts cells took a very long time to create, a rather selective anaerobic condition. This selective culture media was characterized by the higher carbon dioxide levels produced by fast growing yeast cells and by a higher alcohol content in the yeast culture media.

However, in biochemical terms, this finding was required to understand Lavoisier’s results indicating that chemical and biological oxidation of sugars produced the same calorimetric (heat generation) results. This observation requires a control mechanism (metabolic regulation) to avoid burning living cells by fast heat released by the sugar biological oxidative processes (metabolism). In addition, Lavoisier´s results were the first indications that both processes happened inside similar thermodynamics limits. In much resumed form, these observations indicate the major reasons that led Warburg to test failure in control mechanisms in cancer cells in comparison with the ones observed in normal cells.

[It might be added that the availability of O2 and CO2 and climatic conditions over 750 million years that included volcanic activity, tectonic movements of the earth crust, and glaciation, and more recently the use of carbon fuels and the extensive deforestation of our land masses have had a large role in determining the biological speciation over time, in sea and on land. O2 is generated by plants utilizing energy from the sun and conversion of CO2. Remove the plants and we tip the balance. A large source of CO2 is from beneath the earth’s surface.]

Biology inside classical thermodynamics places some challenges to scientists. For instance, all classical thermodynamics must be measured in reversible thermodynamic conditions. In an isolated system, increase in P (pressure) leads to increase in V (volume), all this occurring in a condition in which infinitesimal changes in one affects in the same way the other, a continuum response. Not even a quantic amount of energy will stand beyond those parameters.

In a reversible system, a decrease in V, under same condition, will led to an increase in P. In biochemistry, reversible usually indicates a reaction that easily goes either from A to B or B to A. For instance, when it was required to search for an anti-ischemic effect of Chlorpromazine in an extra hepatic obstructed liver, it was necessary to use an adequate system of increased biliary system pressure in a reversible manner to exclude a direct effect of this drug over the biological system pressure inducer (bile secretion) in Braz. J. Med. Biol. Res 1989; 22: 889-893. Frequently, these details are jumped over by those who read biology in ATGC letters.

Very important observations can be made in this regard, when neutral mutations are taken into consideration since, after several mutations (not affecting previous activity and function), a last mutant may provide a new transcript RNA for a protein and elicit a new function. For an example, consider a Prion C from lamb getting similar to bovine Prion C while preserving  its normal role in the lamb when its ability to change Human Prion C is considered (Stanley Prusiner).

This observation is good enough, to confirm one of the most important contributions of Erwin Schrodinger in his What is Life:

“This little book arose from a course of public lectures, delivered by a theoretical physicist to an audience of about four hundred which did not substantially dwindle, though warned at the outset that the subject matter was a difficult one and that the lectures could not be termed popular, even though the physicist’s most dreaded weapon, mathematical deduction, would hardly be utilized. The reason for this was not that the subject was simple enough to be explained without mathematics, but rather that it was much too involved to be fully accessible to mathematics.”

After Hans Krebs, description of the cyclic nature of the citrate metabolism and after its followers described its requirement for aerobic catabolism two major lines of research started the search for the understanding of the mechanism of energy transfer that explains how ADP is converted into ATP. One followed the organic chemistry line of reasoning and therefore, searched for a mechanism that could explain how the breakdown of carbon-carbon link could have its energy transferred to ATP synthesis. One of the major leaders of this research line was Britton Chance. He took into account that relatively earlier in the series of Krebs cycle reactions, two carbon atoms of acetyl were released as carbon dioxide ( In fact, not the real acetyl carbons but those on the opposite side of citrate molecule). In stoichiometric terms, it was not important whether the released carbons were or were not exactly those originated from glucose carbons. His research aimed at to find out an intermediate proteinaceous intermediary that could act as an energy reservoir. The intermediary could store in a phosphorylated amino acid the energy of carbon-carbon bond breakdown. This activated amino acid could transfer its phosphate group to ADP producing ATP. A key intermediate involved in the transfer was identified by Kaplan and Lipmann at John Hopkins as acetyl coenzyme A, for which Fritz Lipmann received a Nobel Prize.

Alternatively, under possible influence of the excellent results of Hodgkin and Huxley a second line of research appears. The work of Hodgkin & Huxley indicated that the storage of electrical potential energy in transmembrane ionic asymmetries and presented the explanation for the change from resting to action potential in excitable cells. This second line of research, under the leadership of Peter Mitchell postulated a mechanism for the transfer of oxide/reductive power of organic molecules oxidation through electron transfer as the key for the energetic transfer mechanism required for ATP synthesis.
This diverted the attention from high energy (~P) phosphate bond to the transfer of electrons. During most of the time the harsh period of the two confronting points of view, Paul Boyer and followers attempted to act as a conciliatory third party, without getting good results, according to personal accounts (in L. A. or Latin America) heard from those few of our scientists who were able to follow the major scientific events held in USA, and who could present to us later. Paul  Boyer could present how the energy was transduced by a molecular machine that changes in conformation in a series of 3 steps while rotating in one direction in order to produce ATP and in opposite direction in order to produce ADP plus Pi from ATP (reversibility).

However, earlier, a victorious Peter Mitchell obtained the result in the conceptual dispute, over the Britton Chance point of view, after he used E. Coli mutants to show H+ gradients in the cell membrane and its use as energy source, for which he received a Nobel Prize. Somehow, this outcome represents such a blow to Chance’s previous work that somehow it seems to have cast a shadow over very important findings obtained during his earlier career that should not be affected by one or another form of energy transfer mechanism.  For instance, Britton Chance got the simple and rapid polarographic assay method of oxidative phosphorylation and the idea of control of energy metabolism that brings us back to Pasteur.

This metabolic alternative result seems to have been neglected in the recent years of obesity epidemics, which led to a search for a single molecular mechanism required for the understanding of the accumulation of chemical (adipose tissue) reserve in our body. It does not mean that here the role of central nervous system is neglected. In short, in respiring mitochondria the rate of electron transport linked to the rate of ATP production is determined primarily by the relative concentrations of ADP, ATP and phosphate in the external media (cytosol) and not by the concentration of respiratory substrate as pyruvate. Therefore, when the yield of ATP is high as it is in aerobiosis and the cellular use of ATP is not changed, the oxidation of pyruvate and therefore of glycolysis is quickly (without change in gene expression), throttled down to the resting state. The dependence of respiratory rate on ADP concentration is also seen in intact cells. A muscle at rest and using no ATP has a very low respiratory rate.   [When skeletal muscle is stressed by high exertion, lactic acid produced is released into the circulation and is metabolized aerobically by the heart at the end of the activity].

This respiratory control of metabolism will lead to preservation of body carbon reserves and in case of high caloric intake in a diet, also shows increase in fat reserves essential for our biological ancestors survival (Today for our obesity epidemics). No matter how important this observation is, it is only one focal point of metabolic control. We cannot reduce the problem of obesity to the existence of metabolic control. There are numerous other factors but on the other hand, we cannot neglect or remove this vital process in order to correct obesity. However, we cannot explain obesity ignoring this metabolic control. This topic is so neglected in modern times that we cannot follow major research lines of the past that were interrupted by the emerging molecular biology techniques and the vain belief that a dogmatic vision of biology could replace all previous knowledge by a new one based upon ATGC readings. For instance, in order to display bad consequences derived from the ignorance of these old scientific facts, we can take into account, for instance, how ion movements across membranes affects membrane protein conformation and therefore contradicts the wrong central dogma of molecular biology. This change in protein conformation (with unchanged amino acid sequence) and/or the lack of change in protein conformation is linked to the factors that affect vital processes as the heart beats. This modern ignorance could also explain some major pitfalls seen in new drugs clinical trials and in a small scale on bad medical practices.

The work of Britton Chance and of Peter Mitchell have deep and sound scientific roots that were made with excellent scientific techniques, supported by excellent scientific reasoning and that were produced in a large series of very important intermediary scientific results. Their sole difference was to aim at very different scientific explanations as their goals (They have different Teleology in their minds made by their previous experiences). When, with the use of mutants obtained in microorganisms P Mitchell´s goal was found to survive and B Chance to succumb to the experimental evidence, all those excellent findings of B Chance and followers were directed to the dustbin of scientific history as an example of lack of scientific consideration.  [On the one hand, the Mitchell model used a unicellular organism; on the other, Chance’s work was with eukaryotic cells, quite relevant to the discussion.]

We can resume the challenge faced by these two great scientists in the following form: The first conceptual unification in bioenergetics, achieved in the 1940s, is inextricably bound up with the name of Fritz Lipmann. Its central feature was the recognition that adenosine triphosphate, ATP, serves as a universal energy  “currency” much as money serves as economic currency. In a nutshell, the purpose of metabolism is to support the synthesis of ATP. In microorganisms, this is perfect! In humans or mammals, or vertebrates, by the same reason that we cannot consider that gene expression is equivalent to protein function (an acceptable error in the case of microorganisms) this oversimplifies the metabolic requirement with a huge error. However, in case our concern is ATP chemistry only, the metabolism produces ATP and the hydrolysis of ATP pays for the performance of almost, all kinds of works. It is possible to presume that to find out how the flow of metabolism (carbon flow) led to ATP production must be considered a major focal point of research of the two contenders. Consequently, what could be a minor fall of one of the contenders, in case we take into account all that was found during their entire life of research, the real failure in B Chance’s final goal was amplified far beyond what may be considered by reason!

Another aspect that must be taken into account: Both contenders have in the scientific past a very sound root. Metabolism may produce two forms of energy currency (I personally don´t like this expression*) and I use it here because it was used by both groups in order to express their findings. Together with simplistic thermodynamics, this expression conveys wrong ideas): The second kind of energy currency is the current of ions passing from one side of a membrane to the other. The P. Mitchell scientific root undoubtedly have the work of Hodgkin & Huxley, Huxley &  Huxley, Huxley & Simmons

*ATP is produced under the guidance of cell needs and not by its yield. When glucose yields only 2 ATPs per molecule it is oxidized at very high speed (anaerobiosis) as is required to match cellular needs. On the other hand, when it may yield (thermodynamic terms) 38 ATP the same molecule is oxidized at low speed. It would be similar to an investor choice its least money yield form for its investment (1940s to 1972) as a solid support. B. Chance had the enzymologists involved in clarifying how ATP could be produced directly from NADH + H+ oxidative reductive metabolic reactions or from the hydrolysis of an enolpyruvate intermediary. Both competitors had their work supported by different but, sound scientific roots and have produced very important scientific results while trying to present their hypothetical point of view.

Before the winning results of P. Mitchell were displayed, one line of defense used by B. Chance followers was to create a conflict between what would be expected by a restrictive role of proteins through its specificity ionic interactions and the general ability of ionic asymmetries that could be associated with mitochondrial ATP production. Chemical catalyzed protein activities do not have perfect specificity but an outstanding degree of selective interaction was presented by the lock and key model of enzyme interaction. A large group of outstanding “mitochondriologists” were able to show ATP synthesis associated with Na+, K+, Ca2+… asymmetries on mitochondrial membranes and any time they did this, P. Mitchell have to display the existence of antiporters that exchange X for hydrogen as the final common source of chemiosmotic energy used by mitochondria for ATP synthesis.

This conceptual battle has generated an enormous knowledge that was laid to rest, somehow discontinued in the form of scientific research, when the final E. Coli mutant studies presented the convincing final evidence in favor of P. Mitchell point of view.

Not surprisingly, a “wise anonymous” later, pointed out: “No matter what you are doing, you will always be better off in case you have a mutant”

(Principles of Medical Genetics T D Gelehrter & F.S. Collins chapter 7, 1990).

However, let’s take the example of a mechanical wristwatch. It clearly indicates when the watch is working in an acceptable way, that its normal functioning condition is not the result of one of its isolated components – or something that can be shown by a reductionist molecular view.  Usually it will be considered that it is working in an acceptable way, in case it is found that its accuracy falls inside a normal functional range, for instance, one or two standard deviations bellow or above the mean value for normal function, what depends upon the rigor wisely adopted. While, only when it has a faulty component (a genetic inborn error) we can indicate a single isolated piece as the cause of its failure (a reductionist molecular view).

We need to teach in medicine, first the major reasons why the watch works fine (not saying it is “automatic”). The functions may cross the reversible to irreversible regulatory limit change, faster than what we can imagine. Latter, when these ideas about normal are held very clear in the mind set of medical doctors (not medical technicians) we may address the inborn errors and what we may have learn from it. A modern medical technician may cause admiration when he uses an “innocent” virus to correct for a faulty gene (a rather impressive technological advance). However, in case the virus, later shows signals that indicate that it was not so innocent, a real medical doctor will be called upon to put things in correct place again.

Among the missing parts of normal evolution in biochemistry a lot about ion fluxes can be found. Even those oscillatory changes in Ca2+ that were shown to affect gene expression (C. De Duve) were laid to rest since, they clearly indicate a source of biological information that despite the fact that it does not change nucleotides order in the DNA, it shows an opposing flux of biological information against the dogma (DNA to RNA to proteins). Another, line has shown a hierarchy, on the use of mitochondrial membrane potential: First the potential is used for Ca2+ uptake and only afterwards, the potential is used for ADP conversion into ATP (A. L. Lehninger). In fact, the real idea of A. L. Lehninger was by far, more complex since according to him, mitochondria works like a buffer for intracellular calcium releasing it to outside in case of a deep decrease in cytosol levels or capturing it from cytosol when facing transient increase in Ca2+ load. As some of Krebs cycle dehydrogenases were activated by Ca2+, this finding was used to propose a new control factor in addition to the one of ADP (B. Chance). All this was discontinued with the wrong use of calculus (today we could indicate bioinformatics in a similar role) in biochemistry that has established less importance to a mitochondrial role after comparative kinetics that today are seen as faulty.

It is important to combat dogmatic reasoning and restore sound scientific foundations in basic medical courses that must urgently reverse the faulty trend that tries to impose a view that goes from the detail towards generalization instead of the correct form that goes from the general finding well understood towards its molecular details. The view that led to curious subjects as bioinformatics in medical courses as training in sequence finding activities can only be explained by its commercial value. The usual form of scientific thinking respects the limits of our ability to grasp new knowledge and relies on reproducibility of scientific results as a form to surpass lack of mathematical equation that defines relationship of variables and the determination of its functional domains. It also uses old scientific roots, as its sound support never replaces existing knowledge by dogmatic and/or wishful thinking. When the sequence of DNA was found as a technical advance to find amino acid sequence in proteins it was just a technical advance. This technical advance by no means could be considered a scientific result presented as an indication that DNA sequences alone have replaced the need to study protein chemistry, its responses to microenvironmental changes in order to understand its multiple conformations, changes in activities and function. As E. Schrodinger correctly describes the chemical structure responsible for the coded form stored of genetic information must have minimal interaction with its microenvironment in order to endure hundreds and hundreds years as seen in Hapsburg’s lips. Only magical reasoning assumes that it is possible to find out in non-reactive chemical structures the properties of the reactive ones.

For instance, knowledge of the reactions of the Krebs cycle clearly indicate a role for solvent that no longer could be considered to be an inert bath for catalytic activity of the enzymes when the transfer of energy include a role for hydrogen transport. The great increase in understanding this change on chemical reaction arrived from conformational energy.

Again, even a rather simplistic view of this atomic property (Conformational energy) is enough to confirm once more, one of the most important contribution of E. Schrodinger in his What is Life:

“This little book arose from a course of public lectures, delivered by a theoretical physicist to an audience of about four hundred which did not substantially dwindle, though warned at the outset that the subject matter was a difficult one and that the lectures could not be termed popular, even though the physicist’s most dreaded weapon, mathematical deduction, would hardly be utilized. The reason for this was not that the subject was simple enough to be explained without mathematics, but rather that it was much too involved to be fully accessible to mathematics.”

In a very simplistic view, while energy manifests itself by the ability to perform work conformational energy as a property derived from our atomic structure can be neutral, positive or negative (no effect, increased or decreased reactivity upon any chemistry reactivity measured as work)

Also:

“I mean the fact that we, whose total being is entirely based on a marvelous interplay of this very kind, yet if all possess the power of acquiring considerable knowledge about it. I think it possible that this knowledge may advance to little just a short of a complete understanding -of the first marvel. The second may well be beyond human understanding.”

In fact, scientific knowledge allows us to understand how biological evolution may have occurred or have not occurred and yet does not present a proof about how it would have being occurred. It will be always be an indication of possible against highly unlike and never a scientific proven fact about the real form of its occurrence.

As was the case of B. Chance in its bioenergetics findings, we may get very important findings that indicates wrong directions in the future as was his case, or directed toward our past.

The Skeleton of Physical Time – Quantum Energies in Relative Space of S-labs

By Radoslav S. Bozov  Independent Researcher

WSEAS, Biology and BioSystems of Biomedicine

Space does not equate to distance, displacement of an object by classically defined forces – electromagnetic, gravity or inertia. In perceiving quantum open systems, a quanta, a package of energy, displaces properties of wave interference and statistical outcomes of sums of paths of particles detected by a design of S-labs.

The notion of S-labs, space labs, deals with inherent problems of operational module, R(i+1), where an imagination number ‘struggles’ to work under roots of a negative sign, a reflection of an observable set of sums reaching out of the limits of the human being organ, an eye or other foundational signal processing system.

While heavenly bodies, planets, star systems, and other exotic forms of light reflecting and/or emitting objects, observable via naked eye have been deduced to operate under numerical systems that calculate a periodic displacement of one relative to another, atomic clocks of nanospace open our eyes to ever expanding energy spaces, where matrices of interactive variables point to the problem of infinity of variations in scalar spaces, however, defining properties of minute universes as a mirror image of an astronomical system. The first and furthermost problem is essentially the same as those mathematical methodologies deduced by Isaac Newton and Albert Einstein for processing a surface. I will introduce you to a surface interference method by describing undetermined objective space in terms of determined subjective time.

Therefore, the moment will be an outcome of statistical sums of a numerical system extending from near zero to near one. Three strings hold down a dual system entangled via interference of two waves, where a single wave is a product of three particles (today named accordingly to either weak or strong interactions) momentum.

The above described system emerges from duality into trinity the objective space value of physical realities. The triangle of physical observables – charge, gravity and electromagnetism, is an outcome of interference of particles, strings and waves, where particles are not particles, or are strings strings, or  are waves waves of an infinite character in an open system which we attempt to define to predict outcomes of tomorrow’s parameters, either dependent or independent as well as both subjective to time simulations.

We now know that aging of a biological organism cannot be defined within singularity. Thereafter, clocks are subjective to apparatuses measuring oscillation of defined parameters which enable us to calculate both amplitude and a period, which we know to be dependent on phase transitions.

The problem of phase was solved by the applicability of carbon relative systems. A piece of diamond does not get wet, yet it holds water’s light entangled property. Water is the dark force of light. To formulate such statement, we have been searching truth by examining cooling objects where the Maxwell demon is translated into information, a data complex system.

Modern perspectives in computing quantum based matrices, 0+1 =1 and/or 0+0=1, and/or 1+1 =0, will be reduced by applying a conceptual frame of Aladdin’s flying anti-gravity carpet, unwrapping both past and future by sending a photon to both, placing present always near zero. Thus, each parallel quantum computation of a natural system approaching the limit of a vibration of a string defining 0 does not equal 0, and 1 does not equal 1. In any case, if our method 1+1 = 1, yet, 1 is not 1 at time i+1. This will set the fundamentals of an operational module, called labris operator or in simplicity S-labs. Note, that 1 as a result is an event predictable to future, while interacting parameters of addition 1+1 may be both, 1 as an observable past, and 1 as an imaginary system, or 1+1 displaced interactive parameters of past observable events. This is the foundation of Future Quantum Relative Systems Interference (QRSI), taking analytical technologies of future as a result of data matrices compressing principle relative to carbon as a reference matter rational to water based properties.

Goedel’s concept of loops exist therefore only upon discrete relative space uniting to parallel absolute continuity of time ‘lags’. ( Goedel, Escher and Bach: An Eternal Golden Braid. A Metaphorical Fugue on Minds and Machines in the Spirit of Lewis Carroll. D Hofstadter.  Chapter XX: Strange Loops, Or Tangled Hierarchies. A grand windup of many of the ideas about hierarchical systems and self-reference. It is concerned with the snarls which arise when systems turn back on themselves-for example, science probing science, government investigating governmental wrongdoing, art violating the rules of art, and finally, humans thinking about their own brains and minds. Does Gödel’s Theorem have anything to say about this last “snarl”? Are free will and the sensation of consciousness connected to Gödel’s Theorem? The Chapter ends by tying Gödel, Escher, and Bach together once again.)  The fight struggle in-between time creates dark spaces within which strings manage to obey light properties – entangled bozons of information carrying future outcomes of a systems processing consciousness. Therefore, Albert Einstein was correct in his quantum time realities by rejecting a resolving cube of sugar within a cup of tea (Henri Bergson 19th century philosopher. Bergson’s concept of multiplicity attempts to unify in a consistent way two contradictory features: heterogeneity and continuity. Many philosophers today think that this concept of multiplicity, despite its difficulty, is revolutionary.) However, the unity of time and space could not be achieved by deducing time to charge, gravity and electromagnetic properties of energy and mass.

Charge is further deduced to interference of particles/strings/waves, contrary to the Hawking idea of irreducibility of chemical energy carrying ‘units’, and gravity is accounted for by intrinsic properties of   anti-gravity carbon systems processing light, an electromagnetic force, that I have deduced towards ever expanding discrete energy space-energies rational to compressing mass/time. The role of loops seems to operate to control formalities where boundaries of space fluctuate as a result of what we called above – dark time-spaces.

Indeed, the concept of horizon is a constant due to ever expanding observables. Thus, it fails to acquire a rational approach towards space-time issues.

Richard Feynman has touched on issues of touching of space, sums of paths of particle traveling through time. In a way he has resolved an important paradigm, storing information and possibly studying it by opening a black box. Schroedinger’s cat is alive again, but incapable of climbing a tree when chased by a dog. Every time a cat climbs a garden tree, a fruit falls on hedgehogs carried away parallel to living wormholes whose purpose of generating information lies upon carbon units resolving light.

In order to deal with such a paradigm, we will introduce i+1 under square root in relativity, therefore taking negative one ( -1 = sqrt (i+1), an operational module R dealing with Wheelers foam squeezed by light, releasing water – dark spaces. Thousand words down!

What is a number? Is that a name or some kind of language or both? Is the issue of number theory possibly accountable to the value of the concept of entropic timing? Light penetrating a pyramid holding bean seeds on a piece of paper and a piece of slice of bread, a triple set, where a church mouse has taken a drop of tear, but a blood drop. What an amazing physics! The magic of biology lies above egoism, above pride, and below Saints.

We will set up the twelve parameters seen through 3+1 in classic realities:

–              discrete absolute energies/forces – no contradiction for now between Newtonian and Albert Einstein mechanics

–              mass absolute continuity – conservational law of physics in accordance to weak and strong forces

–              quantum relative spaces – issuing a paradox of Albert Einstein’s space-time resolved by the uncertainty principle

–              parallel continuity of multiple time/universes – resolving uncertainty of united space and energy through evolving statistical concepts of scalar relative space expansion and vector quantum energies by compressing relative continuity of matter in it, ever compressing flat surfaces – finding the inverse link between deterministic mechanics of displacement and imaginary space, where spheres fit within surface of triangles as time unwraps past by pulling strings from future.

To us, common human beings, with an extra curiosity overloaded by real dreams, value happens to play in the intricate foundation of life – the garden of love, its carbon management in mind, collecting pieces of squeezed cooling time.

The infinite interference of each operational module to another composing ever emerging time constrains unified by the Solar system, objective to humanity, perhaps answers that a drop of blood and a drop of tear is united by a droplet of a substance separating negative entropy to time courses of a physical realities as defined by an open algorithm where chasing power subdue to space becomes an issue of time.

Jose Eduardo de Salles Roselino

Some small errors: For intance an increase i P leads to a decrease in V ( not an increase in V)..

 

Radoslav S. Bozov  Independent Researcher

If we were to use a preventative measures of medical science, instruments of medical science must predict future outcomes based on observable parameters of history….. There are several key issues arising: 1. Despite pinning a difference on genomic scale , say pieces of information, we do not know how to have changed that – that is shift methylome occupying genome surfaces , in a precise manner.. 2. Living systems operational quo DO NOT work as by vector gravity physics of ‘building blocks. That is projecting a delusional concept of a masonry trick, who has not worked by corner stones and ever shifting momenta … Assuming genomic assembling worked, that is dealing with inferences through data mining and annotation, we are not in a position to read future in real time, and we will never be, because of the rtPCR technology self restriction into data -time processing .. We know of existing post translational modalities… 3. We don’t know what we don’t know, and that foundational to future medicine – that is dealing with biological clocks, behavior, and various daily life inputs ranging from radiation to water systems, food quality, drugs…

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