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Archive for the ‘Lipidomics’ Category


 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 1/15/2019

In the patent fight over PCSK9 inhibitors, the Supreme Court refused to hear Amgen’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling alirocumab (Praluent). Amgen still has a new patent trial starting in Delaware federal court next month, FiercePharma reports.

Amgen’s Repatha hits wall at SCOTUS but presses ahead—new price breaks included

Amgen has been trying since 2015 to protect its PCSK9 cholesterol drug Repatha by keeping Sanofi and Regeneron’s rival Praluent off the market, even going as far as to ask the U.S. Supreme Court to review an ongoing patent fight.

But that attempt fell short this week as SCOTUS refused to hear the company’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling its head-to-head rival.

Amgen isn’t giving up the fight, though. The company is prepping for a new patent trial starting in Delaware federal court next month. And it’s responding to long-standing criticism of the high cost of PCSK9 drugs, which hit the market in 2015 at list prices of about $14,000 a year.

Amgen had already brought the price of the biweekly version of Repatha down to $5,850 per year before discounts and rebates, and late Monday it said it would lower cost of the monthly injectable dose to that same level.

SOURCE

UPDATED on 11/13/2018

ODYSSEY OUTCOMES: Alirocumab Cost-effective at $6000 a Year

Marlene Busko

November 11, 2018

CHICAGO — Treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) is cost-effective at $6319 a year when the willingness-to-pay threshold is the generally accepted $100,000 per quality-adjusted life-year (QALY), new research reports.

Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, presented these cost-effectiveness findings for alirocumab, based on data from the ODYSSEY OUTCOMES trial, here at the American Heart Association (AHA) 2018 Scientific Sessions

As previously reported, results from ODYSSEY OUTCOMES were presented at American College of Cardiology (ACC) 2018 Annual Scientific Session in March and the study was published November 7 in the New England Journal of Medicine.

Strengths of the current cost analysis include that it used actual trial data as opposed to modeling estimates, Bhatt pointed out to theheart.org | Medscape Cardiology.

SOURCE

https://www.medscape.com/viewarticle/904744?nlid=126063_3866&src=WNL_mdplsfeat_181113_mscpedit_card&uac=93761AJ&spon=2&impID=1799507&faf=1

 

Did Amgen’s Repatha cut CV risks enough to make it cost-effective? Analysts say no

Sanofi, Regeneron’s Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients
SEE our curations on PCSK9 drugs:

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ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10.

Reporter: Aviva Lev-Ari, PhD, RN

 

For PCSK9 inhibitors, the effect on major adverse cardiovascular events has always fallen short of expectations based on cholesterol lowering.

But cardiovascular risk reduction is complicated. There is more to the puzzle than cholesterol. Some drugs lower both cholesterol and prevent cardiovascular events, but some people think that the two effects are actually not that closely related.

Milton Packer MD

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

In a previous trial (FOURIER), another PCSK9 inhibitor had only a modest benefit on its primary endpoint, and it did not reduce cardiovascular death, although the magnitude of cholesterol lowering was striking.

In another trial (SPIRE), a third PCSK9 inhibitor, the clinical trial was terminated prematurely by Pfizer because of reduction of the effect of the drug (a humanized but not fully humanized antibody) due to development of neutralizing antibodies in some of the patients. Actually, in patients treated for more than a year who did not develop neutralizing antibodies, a beneficial effect was seen.

The ODYSSEY Outcomes trial is evaluating the effects of a PCSK9 inhibitor,alirocumab, on major cardiovascular events in patients with an acute coronary syndrome within the prior year. The drug lowers serum cholesterol dramatically, and some are hopeful that that effect will translate into an important reduction in the risk of major adverse cardiovascular events. If you believe that cholesterol reduction inevitably leads to the prevention of cardiovascular death, myocardial infarction and stroke, then you would have high expectations for the ODYSSEY trial.

ODYSSEY. The trial uses a somewhat more aggressive treatment strategy and has a longer follow-up period than its predecessors. So maybe the benefit will be large. Maybe the drug will even reduce cardiovascular death or all-cause mortality.

In order to enrich the population for cardiovascular events, the trial enrolled patients with an acute coronary syndrome within the prior year. These patients are at high risk of having a recurrence. The problem is that risk is not necessarily related to changes in cholesterol, especially the events occurring early in the trial. And in this type of trial, the analysis tends to give extra weight to early events.

Trials like ODYSSEY are often designed to stop early if the results are unbelievably impressive. The ODYSSEY trial wasn’t stopped early.

the patients entering the ODYSSEY trial are starting out with a serum LDL <100 mg/dL or even <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with noncholesterol factors?

SOURCE

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

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  1. Lungs can supply blood stem cells and also produce platelets: Lungs, known primarily for breathing, play a previously unrecognized role in blood production, with more than half of the platelets in a mouse’s circulation produced there. Furthermore, a previously unknown pool of blood stem cells has been identified that is capable of restoring blood production when bone marrow stem cells are depleted.

 

  1. A new drug for multiple sclerosis: A new multiple sclerosis (MS) drug, which grew out of the work of UCSF (University of California, San Francisco) neurologist was approved by the FDA. Ocrelizumab, the first drug to reflect current scientific understanding of MS, was approved to treat both relapsing-remitting MS and primary progressive MS.

 

  1. Marijuana legalized – research needed on therapeutic possibilities and negative effects: Recreational marijuana will be legal in California starting in January, and that has brought a renewed urgency to seek out more information on the drug’s health effects, both positive and negative. UCSF scientists recognize marijuana’s contradictory status: the drug has proven therapeutic uses, but it can also lead to tremendous public health problems.

 

  1. Source of autism discovered: In a finding that could help unlock the fundamental mysteries about how events early in brain development lead to autism, researchers traced how distinct sets of genetic defects in a single neuronal protein can lead to either epilepsy in infancy or to autism spectrum disorders in predictable ways.

 

  1. Protein found in diet responsible for inflammation in brain: Ketogenic diets, characterized by extreme low-carbohydrate, high-fat regimens are known to benefit people with epilepsy and other neurological illnesses by lowering inflammation in the brain. UCSF researchers discovered the previously undiscovered mechanism by which a low-carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

 

  1. Learning and memory failure due to brain injury is now restorable by drug: In a finding that holds promise for treating people with traumatic brain injury, an experimental drug, ISRIB (integrated stress response inhibitor), completely reversed severe learning and memory impairments caused by traumatic brain injury in mice. The groundbreaking finding revealed that the drug fully restored the ability to learn and remember in the brain-injured mice even when the animals were initially treated as long as a month after injury.

 

  1. Regulatory T cells induce stem cells for promoting hair growth: In a finding that could impact baldness, researchers found that regulatory T cells, a type of immune cell generally associated with controlling inflammation, directly trigger stem cells in the skin to promote healthy hair growth. An experiment with mice revealed that without these immune cells as partners, stem cells cannot regenerate hair follicles, leading to baldness.

 

  1. More intake of good fat is also bad: Liberal consumption of good fat (monounsaturated fat) – found in olive oil and avocados – may lead to fatty liver disease, a risk factor for metabolic disorders like type 2 diabetes and hypertension. Eating the fat in combination with high starch content was found to cause the most severe fatty liver disease in mice.

 

  1. Chemical toxicity in almost every daily use products: Unregulated chemicals are increasingly prevalent in products people use every day, and that rise matches a concurrent rise in health conditions like cancers and childhood diseases, Thus, researcher in UCSF is working to understand the environment’s role – including exposure to chemicals – in health conditions.

 

  1. Cytomegalovirus found as common factor for diabetes and heart disease in young women: Cytomegalovirus is associated with risk factors for type 2 diabetes and heart disease in women younger than 50. Women of normal weight who were infected with the typically asymptomatic cytomegalovirus, or CMV, were more likely to have metabolic syndrome. Surprisingly, the reverse was found in those with extreme obesity.

 

References:

 

https://www.ucsf.edu/news/2017/12/409241/most-popular-science-stories-2017

 

https://www.ucsf.edu/news/2017/03/406111/surprising-new-role-lungs-making-blood

 

https://www.ucsf.edu/news/2017/03/406296/new-multiple-sclerosis-drug-ocrelizumab-could-halt-disease

 

https://www.ucsf.edu/news/2017/06/407351/dazed-and-confused-marijuana-legalization-raises-need-more-research

 

https://www.ucsf.edu/news/2017/01/405631/autism-researchers-discover-genetic-rosetta-stone

 

https://www.ucsf.edu/news/2017/09/408366/how-ketogenic-diets-curb-inflammation-brain

 

https://www.ucsf.edu/news/2017/07/407656/drug-reverses-memory-failure-caused-traumatic-brain-injury

 

https://www.ucsf.edu/news/2017/05/407121/new-hair-growth-mechanism-discovered

 

https://www.ucsf.edu/news/2017/06/407536/go-easy-avocado-toast-good-fat-can-still-be-bad-you-research-shows

 

https://www.ucsf.edu/news/2017/06/407416/toxic-exposure-chemicals-are-our-water-food-air-and-furniture

 

https://www.ucsf.edu/news/2017/02/405871/common-virus-tied-diabetes-heart-disease-women-under-50

 

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LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

#BostonDOT16

@BostonDOT

 

Nonalcoholic Steatohepatitis (NASH)

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

 

Wednesday, September 21

7:30 am Registration Open and Morning Coffee

8:00 Chairperson’s Opening Remarks

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

  • Epidemic of NASH,
  • approaches to treating NASH – Fibrosis
  • NASH is a metabolic Disease of the Liver
  • Treating the HCV will treat the Fibrosis

8:10 FEATURED PRESENTATION: The Epidemic of Fatty Liver Disease: Silent, Serious and Still Growing?

Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

  • Silent, Serious and Growing
  • Obesity the Disease = BMI>30: Medical Complicastions for BMI >%) – On ANti-Obisity and Bariatric SUrgery, Type 2 Diabetis .. NAFLD .. NASH .. Cirrhosis .. HCC
  • Parkinson’s Disease
  • HIV/AIDS
  1. Medical Complications of Obisity =197 :
  2. NAFLD – Nonalcoholic Fatty Liver Disease >>> Liver transplantation replacing HCV
  3. Associated with obesity and type 2 diabetes
  4. NAFLD is UP 90% wiht Severe Obesity
  5. Viral hepatitis and Hemochromatosis
  6. NAFLD: Steatosis, Inflamamtion, Hepatocellular Necrosis, Fibrosis, Cirrhosis
  7. NASH: insulin resistence .. metabolic syndrom .. interaction
  8. Alternative Model: Metabolis Syndrom.. Steatosis .. NASH … FIbrosis
  9. Genetics of Liver DIsease
  10. PNPLA3 Associated with NAFLD – Not Weight Gain
  11. Other genes: A Partial List:
  12. Diagnosis of NASH: Liver biopsy macrovescicular fatty change: InflammationMollery bodies
  13. 75% Patients with Cirrhousis have obisity
  14. Alcoholoc hepatisis >> Progression to Cirrhousis
  15. Macrovesicular Steatosis
  16. NASH – inflammation
  17. Sinusoidal Pericellular Fibrosis –
  18. LAB Features of NAFLD
  • Transaminase elevation
  • Akaline phosphate
  1. Biomarkers – NASH – associated cirrhousis with lower rate 30% of elevation
  2. Fibrosure
  • Clinical Features of NASH: none presentation, Bright, Echo Fibroscan FibroscanScreen for HCC, Varices if Gray zone: Biopsy
  • Treatment of NASH
  • Treat liver disease: Treat steatosis then Inflamamtion and fibrosis
  1. NAFLD Treatment Strategy: Stepwise Approach
  • Treat the steatosis Piodlitazone
  • PPARalpha, delta,
  • Treat Inflammation: ANtioxidant
  • CCR2/CCR% inhibitors
  • Metabolic SUrgery
  • Weigh-independent for bariatric
  • Bariatic: improvrment of steatosis,effect on inflammationless clear
  • dramatic on weigh loss
  • NO clear is surgery improved cirhousis
  • If NASH developed >>>> progression s the rule
  • No great treatment of NASH

Medication-assciated NASH: Glucocorti

 

8:40 Non-Alcoholic Steatohepatitis and Cardiovascular Disease: Modulation by Novel PPAR Agonists

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. In this presentation, we will review recent findings on the pathophysiological role of PPARs in the different stages of non-alcoholic fatty liver disease (NAFLD), from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidences for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis towards irreversible, more advanced lesions. Large controlled trials of long duration to assess the long-term clinical benefits of PPAR agonists in humans are ongoing.

Non-Alcoholic Steatohepatisis and CVD – Meta inflammatory disease

  • NAFL — abnormal Lipid accumulation
  • NASH >> Balooning, FIbrosis inflamation
  • Resolution of NASH is associated with reduction of Fibrosis (Golden – 505 trial)

CVD is linked to NAFLD: Lipids elevated and therosclerosis

  • TG – elevated, APO B elevated, VLDL – elevated HDL decrease
  • PPAR Alpha
  • Gamma
  • PPAR Beta/Delta agonist: GENFIT – Elafibranor
  • SPPARM

Trans-activation: Lipid and Glucose homeostasis: Trans-repression – anti-inflammatory properties

  • Hapatic mitochondrial activity deseases upon progression from NAFL to NASH: Obese NAFL and NASH
  1. Upregulated hepatic respiratory in obese humans with or without NAFL
  2. Impaired
  3. Hepatic PPARalpha Expression Decreases upon Progression of Nash and Fibrosis
  4. hepatic PPARalpha expression – target genes increase in patients with improved NASH histology after 1 year
  5. Metabolic Regualtion by thehepatic JNK Signaling Pathway
  6. Target gene transcription – miR-21 expression increases in human
  7. PPAR Delta: Elafibbranor: – effect on plasma lipids: A Dual PPAR alpha/Delts (GFT505): 80mg vs placebo and 120mg vs placebo, improves plasma apolipolipids and glucose HbA1C – insulin sensitivity
  8. efficacy in NASH acting on: Steatosis, fibrosis and cirrhosis
  9. inflammatory markers: RESOLVE-IT Phase 3 Study Desing: NASH ressolution without adverse on FIbrosis and Cirrhosis

GOLDEN505 Trial: Improves plasma lipid levels: Triglycerides

Inclusion Criteria:

ALT, AST, GGT, ALP

Improve atherogenic dyslipidemia

  • APOC3 – associated with CVD

9:10 PANEL DISCUSSION: Liver Fibrosis and NASH Targets

Moderator: H. James Harwood, Ph.D., Delphi BioMedical Consultants, LLC

Panelists:

Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

Weilin Xie, Ph.D., Senior Principal Scientist, Biotherapeutics, Celgene Corp.

  • FDA’s view on surrogate endpoints
  • Biomarkers of NASH
  • Regulatory challenges
  1. Liver biopsy: gold standard, invasive direct measure of endpoints pros/cons
  2. non-invasive functional tests – plasma bioamrkers
  3. non-invasisve liver imaging techniques: MRI to assess hepatic fat content MRE to assess hepatic fibrosis, Fibroscan,
  4. Endpoints acceptable by FDA: Current vs Future
  • Pre clinical Translational animal models

Discussion by Panel members

Progression from NAFLD to NASH: Oxidative stress and toxic lipids

NASH and Steatosis are different populations

Alcoholoc Steatosis vs Non-Alcoholic Steatosis

  • Obesity cause of Fatty liver
  • NASH in Diabetes
  • NASH progresses
  • Steatosis is associated with NASH
  • Different types of NASH: HTN, Dislipedemia,
  • GENETICS underlining factors, more genes are discovered
  • Limitations of Animal Studies for inference on Humans – careful in over generalizing results
  • Metabolic SYndrom -not all progresses to NASH
  • Nonalcoholic Steatohepatitis (NASH) depend on Steatosis

 

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Targeting Fibroblast Activation Protein (FAP) and FGF21 to Treat Fatty Liver Disease

Diana Ronai Dunshee, Ph.D., Department of Molecular Biology, Senior Scientific Researcher, Genentech, Inc.

FGF21 is a hormone with anti-obesity and hepatoprotective properties. However, the beneficial effects of FGF21 are limited by a relatively short half-life in circulation. We discovered that fibroblast activation protein (FAP), an endopeptidase overexpressed in liver with cirrhosis, cleaves and inactivates FGF21. Pharmacological inhibition of FAP increases endogenous levels of active FGF21, thus making FAP a promising target for the treatment of non-alcoholic-steatohepatitis (NASH).

  • Medical complications of obisity: NASH and DM-2
  • energy consumption
  • white adipose tissue – energy storage
  • brown adipose tissue matochondia’s energy
  • FGF21 – Human activation of protein cleavage: A Homone beneficial on metabolic health circulation, weigh loss
  • it suppreses hepatic Steatohepatitis
  • One singleinjection in mice — leads to energy expenditure induced weigh loss and metabolic improvement in Obese Humans
  • Negative FGF21 is Rapidly Eliminated from the body – renal degradation and Inactivation of FGF21 Endopeptidase Cleavage Site – Fibroblast Activation Protein Matched FAP Endopeptidease Specificity
  • Closest relative of DPP4 upregulted during tissue injury in NASH
  • FAP is SUfficient to Cleave FGF21
  • Recombinant FGF21 with Recombinant FAP in Serum or Plasma
  • FAP Protease – Serum Immunodepleted Ablates FGF21 Cleavage Activity: Peptide IgG vs anti-FAP
  • FAP Cleavage Inactivates Human FGF21 dependent on KLB-FGFR1c placed on the site
  • hFGF21 in Not Cleaved in FAP KO Mice
  • Fc-hFGF21 is more stable in FAP KO mice
  • FAR cleaves Endogenously Produced FGF21 In Vivo in monkeys and in dogs
  • The FAP Cleavage Consensus GLY-Pro is COnserved in most mammalian FGF21
  • FAP Does not Cleave the C-Terminal Residues of Mouse FGF21
  • Human: FAP, DPPIV
  • Mouse: FAP, DPP4
  • FAP INhibition
  • FAP is Overexpressed in Liver with Steatohepatitis: Early NASH vs Late NASH
  • Proposal: FAP Inhibition for FGF21 Stabilization in NASH
  1. Fatty hepatocytes – e.g. NASH
  2. Activated stellate cells, e.g. NASH

 

10:55 Thyroid Hormone Receptor Beta (THR-ß) Agonist for NASH: Correcting a Primary Deficiency in NASH Livers

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

NASH patients typically have metabolic syndrome including diabetes, dyslipidemia, obesity, and primarily die of cardiovascular disease. Hypothyroidism at the level of the thyroid gland and liver-specific hypothyroidism are common in NASH. Based on clinical and preclinical data, Thyroid receptor beta agonists decrease insulin resistance, reduce LDL-C, triglycerides fatty liver, inflammation and fibrosis in NASH. The target will also provide CV benefit to patients with NASH. MGL-3196 is a highly THR-ß selective liver-directed once daily oral medication that has shown excellent safety and lipid-lowering efficacy in humans; unlike prior thyroid receptor agonist(s), no cartilage findings in chronic toxicology or ALT increases in human studies. MGL-3196 is being advanced in Phase II studies in patients with genetic dyslipidemia or NASH.

Madrigal Portfolio of drugs:

  • MGL-3196: First-in-Class THR-Beta Agonist – discovered first at ROCHE – THR-beta selective targeted to the Liver – regulated by THR-Alpha  – in Phase II – no side effects on bone
  • Large & underserved Markets in NASH
  • Phase 2 HeFH Patients
  1. Hypothyroidism common in NASH patients
  2. Liver-specific Hypothyroidism present in human NASH degradation of thyroid hormone increases deiodised 9DIO) 3 produced by Stelllate cells in NASH liver
  3. Treating NASHrather than fibrosis is key in addressing the disease – approvable endpoint
  4. THR – Thyroid hormone reduces Cholesterol
  5. Thyroid hormone T3 thyroxine – treatment amy cause osteoporosis
  6. MGL 0 3196: Liver size, Live Triglycerides, Improve Insulin tolerance, decrease ALT
  7. Reduction of key NASH, Fibrosis Pathway Genes at Human Comparable Drug levels
  8. THR-beta: Decreased Liver Fibrosis, Apoptosis in mice:

HUMAN DATA

  • Single ascending dose study
  • Multiple – ascending studies: LDL and TG decrease
  • decrease Non-HDL CHolesterol
  • Decrease Apolipoprotein B
  • Pleiotropic Pioglitazone Effect in NASH at 6 month treatment and biopsy of liver – dramatic effect in NASH – ten years ago study
  • PPAR gamma agonist – NEGATIVE SIDE EFFECTS: weight gain, CHF, Bone osteoporosis
  • Anti-inflammatory: well tolerated

No Single NASH Therapeutics – Conbination agents

MGL – 3196 Phase 2 – Study: Proposed Phase 2 Proof of COncepts NASH Protocol

  • Unmet needs in FH, a severeGenetic Dyslipedemia
  • Weight loss in 6 weeksreduction in cholesterol and TG
  • Likelihood of Success
  • second study after 9 months
  • is different on NASH Patients in 12 weeks using MRI on Liver
  • prevalence
  • HeFH, PCSK9 inhibitors plus standard care
  • Unique and Complementary Lipid Lowering Profile
  1. Lowers Lp(a) and severely atherogenic practice
  2. Proposed Phase 2 HeFH Patients

 

11:25 Enjoy Lunch on Your Own

 

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Hybrid lipid bioelectronic membranes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Hybrid solid-state chips and biological cells integrated at molecular level

Biological ion channels combine with solid-state transistors to create a new kind of hybrid bioelectronics. Imagine chips with dog-like capability to taste and smell, or even recognize specific molecules.
http://www.kurzweilai.net/hybrid-solid-state-chips-and-biological-cells-integrated-at-molecular-level
Illustration depicting a biocell attached to a CMOS integrated circuit with a membrane containing sodium-potassium pumps in pores. Energy is stored chemically in ATP molecules. When the energy is released as charged ions (which are then converted to electrons to power the chip at the bottom of the experimental device), the ATP is converted to ADP + inorganic phosphate. (credit: Trevor Finney and Jared Roseman/Columbia Engineering)

Columbia Engineering researchers have combined biological and solid-state components for the first time, opening the door to creating entirely new artificial biosystems.

In this experiment, they used a biological cell to power a conventional solid-state complementary metal-oxide-semiconductor (CMOS) integrated circuit. An artificial lipid bilayer membrane containing adenosine triphosphate (ATP)-powered ion pumps (which provide energy for cells) was used as a source of ions (which were converted to electrons to power the chip).

The study, led by Ken Shepard, Lau Family Professor of Electrical Engineering and professor of biomedical engineering at Columbia Engineering, was published online today (Dec. 7, 2015) in an open-access paper in Nature Communications.

How to build a hybrid biochip

Living systems achieve this functionality with their own version of electronics based on lipid membranes and ion channels and pumps, which act as a kind of “biological transistor.” Charge in the form of ions carry energy and information, and ion channels control the flow of ions across cell membranes.

Solid-state systems, such as those in computers and communication devices, use electrons; their electronic signaling and power are controlled by field-effect transistors.

To build a prototype of their hybrid system, Shepard’s team packaged a CMOS integrated circuit (IC) with an ATP-harvesting “biocell.” In the presence of ATP, the system pumped ions across the membrane, producing an electrical potential (voltage)* that was harvested by the integrated circuit.

“We made a macroscale version of this system, at the scale of several millimeters, to see if it worked,” Shepard notes. “Our results provide new insight into a generalized circuit model, enabling us to determine the conditions to maximize the efficiency of harnessing chemical energy through the action of these ion pumps. We will now be looking at how to scale the system down.”

While other groups have harvested energy from living systems, Shepard and his team are exploring how to do this at the molecular level, isolating just the desired function and interfacing this with electronics. “We don’t need the whole cell,” he explains. “We just grab the component of the cell that’s doing what we want. For this project, we isolated the ATPases because they were the proteins that allowed us to extract energy from ATP.”

The capability of a bomb-sniffing dog, no Alpo required

Next, the researchers plan to go much further, such as recognizing specific molecules and giving chips the potential to taste and smell.

The ability to build a system that combines the power of solid-state electronics with the capabilities of biological components has great promise, they believe. “You need a bomb-sniffing dog now, but if you can take just the part of the dog that is useful — the molecules that are doing the sensing — we wouldn’t need the whole animal,” says Shepard.

The technology could also provide a power source for implanted electronic devices in ATP-rich environments such as inside living cells, the researchers suggest.

*  “In general, integrated circuits, even when operated at the point of minimum energy in subthreshold, consume on the order of 10−2 W mm−2 (or assuming a typical silicon chip thickness of 250 μm, 4 × 10−2 W mm−3). Typical cells, in contrast, consume on the order of 4 × 10−6 W mm−3. In the experiment, a typical active power dissipation for the IC circuit was 92.3 nW, and the active average harvesting power was 71.4 fW for the biocell (the discrepancy is managed through duty-cycled operation of the IC).” — Jared M. Roseman et al./Nature Communications

 

Hybrid integrated biological–solid-state system powered with adenosine triphosphate

Jared M. RosemanJianxun LinSiddharth RamakrishnanJacob K. Rosenstein & Kenneth L. Shepard
Nature Communications 7 Dec 2015; 6(10070)
     http://dx.doi.org:/10.1038/ncomms10070

There is enormous potential in combining the capabilities of the biological and the solid state to create hybrid engineered systems. While there have been recent efforts to harness power from naturally occurring potentials in living systems in plants and animals to power complementary metal-oxide-semiconductor integrated circuits, here we report the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitro environment to power such an artificial system. An integrated circuit is powered by adenosine triphosphate through the action of Na+/K+ adenosine triphosphatases in an integrated in vitro lipid bilayer membrane. The ion pumps (active in the membrane at numbers exceeding 2 × 106mm−2) are able to sustain a short-circuit current of 32.6pAmm−2 and an open-circuit voltage of 78mV, providing for a maximum power transfer of 1.27pWmm−2 from a single bilayer. Two series-stacked bilayers provide a voltage sufficient to operate an integrated circuit with a conversion efficiency of chemical to electrical energy of 14.9%.

 

Figure 1: Fully hybrid biological–solid-state system.

 

 

Fully hybrid biological-solid-state system.

http://www.nature.com/ncomms/2015/151207/ncomms10070/images/ncomms10070-f1.jpg

(a) Illustration depicting biocell attached to CMOS integrated circuit. (b) Illustration of membrane in pore containing sodium–potassium pumps. (c) Circuit model of equivalent stacked membranes, =2.1pA, =98.6G, =575G and =75pF, Ag/AgCl electrode equivalent resistance RWE+RCE<20k, energy-harvesting capacitor CSTOR=100nF combined with switch as an impedance transformation network (only one switch necessary due to small duty cycle), and CMOS IC voltage doubler and resistor representing digital switching load. RL represents the four independent ring oscillator loads. (d) Equivalent circuit detail of stacked biocell. (e) Switched-capacitor voltage doubler circuit schematic.

 

The energetics of living systems are based on electrochemical membrane potentials that are present in cell plasma membranes, the inner membrane of mitochondria, or the thylakoid membrane of chloroplasts1. In the latter two cases, the specific membrane potential is known as the proton-motive force and is used by proton adenosine triphosphate (ATP) synthases to produce ATP. In the former case, Na+/K+-ATPases hydrolyse ATP to maintain the resting potential in most cells.

While there have been recent efforts to harness power from some naturally occurring potentials in living systems that are the result of ion pump action both in plants2 and animals3, 4 to power complementary metal-oxide semiconductor (CMOS) integrated circuits (ICs), this work is the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitroenvironment to power such an artificial system. Prior efforts to harness power from in vitromembrane systems incorporating ion-pumping ATPases5, 6, 7, 8, 9 and light-activated bacteriorhodopsin9, 10, 11 have been limited by difficulty in incorporating these proteins in sufficient quantity to attain measurable current and in achieving sufficiently large membrane resistances to harness these currents. Both problems are solved in this effort to power an IC from ATP in an in vitro environment. The resulting measurements provide new insight into a generalized circuit model, which allows us to determine the conditions to maximize the efficiency of harnessing chemical energy through the action of electrogenic ion pumps.

 

ATP-powered IC

Figure 1a shows the complete hybrid integrated system, consisting of a CMOS IC packaged with an ATP-harvesting ‘biocell’. The biocell consists of two series-stacked ATPase bearing suspended lipid bilayers with a fluid chamber directly on top of the IC. Series stacking of two membranes is necessary to provide the required start-up voltage for IC and eliminates the need for an external energy source, which is typically required to start circuits from low-voltage supplies2, 3. As shown inFig. 1c, a matching network in the form of a switched capacitor allows the load resistance of the IC to be matched to that presented by the biocell. In principle, the switch S can be implicit. The biocell charges CSTOR until the self start-up voltage, Vstart, is reached. The chip then operates until the biocell voltage drops below the minimum supply voltage for operation, Vmin. Active current draw from the IC stops at this point, allowing the charge to build up again on CSTOR. In our case, however, the IC leakage current exceeds 13.5nA at Vstart, more than can be provided by the biocell. As a result, an explicit transistor switch and comparator (outside of the IC) are used for this function in the experimental results presented here, which are not powered by the biocell and not included in energy efficiency calculations (see Supplementary Discussion for additional details). The energy from the biocell is used to operate a voltage converter (voltage doubler) and some simple inverter-based ring oscillators in the IC, which receive power from no other sources.

Figure 1: Fully hybrid biological–solid-state system.

http://www.nature.com/ncomms/2015/151207/ncomms10070/images/ncomms10070-f1.jpg

 

……..   Prior to the addition of ATP, the membrane produces no electrical power and has an Rm of 280G. A 1.7-pA short-circuit (SC) current (Fig. 2b) through the membrane is observed upon the addition of ATP (final concentration 3mM) to the cis chamber where functional, properly oriented enzymes generate a net electrogenic pump current. To perform these measurements, currents through each membrane of the biocell are measured using a voltage-clamp amplifier (inset of Fig. 2b) with a gain of 500G with special efforts taken to compensate amplifier leakage currents. Each ATPase transports three Na+ ions from the cis chamber to the trans chamber and two K+ ions from thetrans chamber to the cis chamber (a net charge movement of one cation) for every molecule of ATP hydrolysed. At a rate of 100 hydrolysis events per second under zero electrical (SC) bias13, this results in an electrogenic current of ~16aA. The observed SC current corresponds to about 105 active ATPases in the membrane or a concentration of about 2 × 106mm−2, about 5% of the density of channels occurring naturally in mammalian nerve fibres14. It is expected that half of the channels inserted are inactive because they are oriented incorrectly.

Figure 2: Single-cell biocell characterization.

http://www.nature.com/ncomms/2015/151207/ncomms10070/images_article/ncomms10070-f2.jpg

(a)…Pre-ATP data linear fit (black line) slope yield Rm=280G. Post ATP data fit to a Boltzmann curve, slope=0.02V (blue line). Post-ATP linear fit (red line) yields Ip=−1.8pA and Rp=61.6G, which corresponds to a per-ATP source resistance of 6.16 × 1015. The current due to membrane leakage through R_{m} is subtracted in the post-ATP curve…. (b)…

 

Current–voltage characteristics of the ATPases

Figure 2a shows the complete measured current–voltage (IV) characteristic of a single ATPase-bearing membrane in the presence of ATP. The current due to membrane leakage through Rm is subtracted in the post-ATP curve. The IV characteristic fits a Boltzmann sigmoid curve, consistent with sodium–potassium pump currents measured on membrane patches at similar buffer conditions13, 15, 16. This nonlinear behaviour reflects the fact that the full ATPase transport cycle (three Na+ ions from cis to trans and two K+ ions from trans to cis) time increases (the turn-over rate, kATP, decreases) as the membrane potential increases16. No effect on pump current is expected from any ion concentration gradients produced by the action of the ATPases (seeSupplementary Discussion). Using this Boltzmann fit, we can model the biocell as a nonlinear voltage-controlled current source IATPase (inset Fig. 2a), in which the current produced by this source varies as a function of Vm. In the fourth quadrant, where the cell is producing electrical power, this model can be linearized as a Norton equivalent circuit, consisting of a DC current source (Ip) in parallel with a current-limiting resistor (Rp), which acts to limit the current delivered to the load at increasing bias (IATPase~IpVm/Rp). Figure 2c shows the measured and simulated charging of Cm for a single membrane (open-circuited voltage). A custom amplifier with input resistance Rin>10T was required for this measurement (see Electrical Measurement Methods).

 

Reconciling operating voltage differences

The electrical characteristics of biological systems and solid-state systems are mismatched in their operating voltages. The minimum operating voltage of solid-state systems is determined by the need for transistors to modulate a Maxwell–Boltzmann (MB) distribution of carriers by several orders of magnitude through the application of a potential that is several multiples of kT/q (where kis Boltzmann’s constant, T is the temperature in degrees Kelvin and q is the elementary charge). Biological systems, while operating under the same MB statistics, have no such constraints for operating ion channels since they are controlled by mechanical (or other conformational) processes rather than through modulation of a potential barrier. To bridge this operating voltage mismatch, the circuit includes a switched-capacitor voltage doubler (Fig. 1d) that is capable of self-startup from voltages as low Vstart=145mV (~5.5kT/q) and can be operated continuously from input voltages from as low as Vmin=110mV (see Supplementary Discussion)…..

 

Maximizing the efficiency of harvesting energy from ATP

Solid-state systems and biological systems are also mismatched in their operating impedances. In our case, the biocell presents a source impedance, =84.2G, while the load impedance presented by the complete integrated circuit (including both the voltage converter and ring oscillator loads) is approximately RIC=200k. (The load impedance, RL, of the ring oscillators alone is 305k.) This mismatch in source and load impedance is manifest in large differences in power densities. In general, integrated circuits, even when operated at the point of minimum energy in subthreshold, consume on the order of 10−2Wmm−2 (or assuming a typical silicon chip thickness of 250μm, 4 × 10−2Wmm−3) (ref. 17). Typical cells, in contrast, consume on the order of 4 × 10−6Wmm−3 (ref. 18). In our case, a typical active power dissipation for our circuit is 92.3nW, and the active average harvesting power is 71.4fW for the biocell. This discrepancy is managed through duty-cycled operation of the IC in which the circuit is largely disabled for long periods of time (Tcharge), integrating up the power onto a storage capacitor (CSTOR), which is then expended in a very brief period of activity (Trun), as shown in Fig. 3a.

The overall efficiency of the system in converting chemical energy to the energy consumed in the load ring oscillator (η) is given by the product of the conversion efficiency of the voltage doubler (ηconverter) and the conversion efficiency of chemical energy to electrical energy in the biocell (ηbiocell), η=ηconverter × ηbiocell. ηconverter is relatively constant over the range of input voltages at ~59%, as determined by various loading test circuits included in the chip design (Supplementary Figs 1–6). ηbiocell, however, varies with transmembrane potential Vm. η is the efficiency in transferring power to the power ring oscillator loads from the ATP harvested by biocell.

…….

To first order, the energy made available to the Na+/K+-ATPase by the hydrolysis of ATP is independent of the chemical or electric potential of the membrane and is given by |ΔGATP|/(qNA), where ΔGATP is the Gibbs free energy change due to the ATP hydrolysis reaction per mole of ATP at given buffer conditions and NA is Avogadro’s number. Since every charge that passes through IATPase corresponds to a single hydrolysis event, we can use two voltage sources in series with IATPase to independently account for the energy expended by the pumps both in moving charge across the electric potential difference and in moving ions across the chemical potential difference. The dependent voltage source Vloss in this branch fixes the voltage across IATPase, and the total power produced by the pump current source is (|ΔGATP|/NA)(NkATP), which is the product of the energy released per molecule of ATP, the number of active ATPases and the ATP turnover rate. The power dissipated in voltage source Vchem models the work performed by the ATPases in transporting ions against a concentration gradient. In the case of the Na+/K+ ATPase,Vchem is given by . The power dissipated in this source is introduced back into the circuit in the power generated by the Nernst independent voltage sources, and . The power dissipated in the dependent voltage source Vloss models any additional power not used to perform chemical or electrical work. ……

 

Integration of ATP-harvesting ion pumps could provide a means to power future CMOS microsystems scaled to the level of individual cells22. In molecular diagnostics, the integration of pore-forming proteins such as alpha haemolysin23 or MspA porin24 with CMOS electronics is already finding application in DNA sequencing25. Exploiting the large diversity of function available in transmembrane proteins in these hybrid systems could, for example, lead to highly specific sensing platforms for airborne odorants or soluble molecular entities26, 27. Heavily multiplexed platforms could become high-throughput in vitro drug-screening platforms against this diversity of function. In addition, integration of transmembrane proteins with CMOS may become a convenient alternative to fluorescence for coupling to synthetic biological systems28.

 

Roseman, J. M. et al. Hybrid integrated biological–solid-state system powered with adenosine triphosphate. Nat. Commun. 6:10070      http://dx.doi.org:/10.1038/ncomms10070 (2015).

 

 

  • Rottenberg, H. The measurement of membrane potential and deltapH in cells, organelles, and vesicles. Methods Enzymol. 55, 547569 (1979).
  • Himes, C., Carlson, E., Ricchiuti, R. J., Otis, B. P. & Parviz, B. A. Ultralow voltage nanoelectronics powered directly, and solely, from a tree. IEEE Trans. Nanotechnol. 9, 25(2010).
  • Mercier, P. P., Lysaght, A. C., Bandyopadhyay, S., Chandrakasan, A. P. & Stankovic, K. M.Energy extraction from the biologic battery in the inner ear. Nat. Biotechnol. 30, 12401243(2012).
  • Halámková, L. et al. Implanted Biofuel Cell Operating in a Living Snail. J. Am. Chem. Soc.134, 50405043 (2012).

 

 

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brown adipocyte protein CIDEA promotes lipid droplet fusion

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

 

The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding

Parker, Nicholas T Ktistakis, Ann M Dixon, Judith Klein-Seetharaman, Susan Henry, Mark Christian Dirk Dormann, Gil-Soo Han, Stephen A Jesch, George M Carman, Valerian Kagan, et al.

eLife 2015;10.7554/eLife.07485     http://dx.doi.org/10.7554/eLife.07485

 

Maintenance of energy homeostasis depends on the highly regulated storage and release of triacylglycerol primarily in adipose tissue and excessive storage is a feature of common metabolic disorders. CIDEA is a lipid droplet (LD)-protein enriched in brown adipocytes promoting the enlargement of LDs which are dynamic, ubiquitous organelles specialized for storing neutral lipids. We demonstrate an essential role in this process for an amphipathic helix in CIDEA, which facilitates embedding in the LD phospholipid monolayer and binds phosphatidic acid (PA). LD pairs are docked by CIDEA trans-complexes through contributions of the N-terminal domain and a C-terminal dimerization region. These complexes, enriched at the LD-LD contact site, interact with the cone-shaped phospholipid PA and likely increase phospholipid barrier permeability, promoting LD fusion by transference of lipids. This physiological process is essential in adipocyte differentiation as well as serving to facilitate the tight coupling of lipolysis and lipogenesis in activated brown fat.

 

Evolutionary pressures for survival in fluctuating environments that expose organisms to times of both feast and famine have selected for the ability to efficiently store and release energy in the form of triacyclglycerol (TAG). However, excessive or defective lipid storage is a key feature of common diseases such as diabetes, atherosclerosis and the metabolic syndrome (1). The organelles that are essential for storing and mobilizing intracellular fat are lipid droplets (LDs) (2). They constitute a unique cellular structure where a core of neutral lipids is stabilized in the hydrophilic cytosol by a phospholipid monolayer embedding LD-proteins. While most mammalian 46 cells present small LDs (<1 Pm) (3), white (unilocular) adipocytes contain a single giant LD occupying most of their cell volume. In contrast, brown (multilocular) adipocytes hold multiple LDs of lesser size, increasing the LD surface/volume ratio which facilitates the rapid consumption of lipids for adaptive thermogenesis (4).

The exploration of new approaches for the treatment of metabolic disorders has been stimulated by the rediscovery of active brown adipose tissue (BAT) in adult humans (5, 6) and by the induction of multilocular brown-like cells in white adipose tissue (WAT) (7). The multilocular morphology of brown adipocytes is a defining characteristic of these cells along with expression of genes such as Ucp1. The acquisition of a unilocular or multilocular phenotype is likely to be controlled by the regulation of LD growth. Two related proteins, CIDEA and CIDEC promote LD enlargement in adipocytes (8-10), with CIDEA being specifically found in BAT. Together with CIDEB, they form the CIDE (cell death-inducing DFF45-like effector) family of LD-proteins, which have emerged as important metabolic regulators (11).

Different mechanisms have been proposed for LD enlargement, including in situ neutral lipid synthesis, lipid uptake and LD-LD coalescence (12-14). The study of CIDE 62 proteins has revealed a critical role in the LD fusion process in which a donor LD progressively transfers its content to an acceptor LD until it is completely absorbed (15). However, the underlying mechanism by which CIDEC and CIDEA facilitate the interchange of triacylglycerol (TAG) molecules between LDs is not understood. In the present study, we have obtained a detailed picture of the different steps driving this LD enlargement process, which involves the stabilization of LD pairs, phospholipid binding, and the permeabilization of the LD monolayer to allow the transference of lipids.

 

CIDEA expression mimics the LD dynamics observed during the differentiation of brown adipocytes

Phases of CIDEA activity: LD targeting, LD-LD docking and LD growth

A cationic amphipathic helix in C-term drives LD targeting

The amphipathic helix is essential for LD enlargement

LD-LD docking is induced by the formation of CIDEA complexes

CIDEC differs from CIDEA in its dependence on the N-term domain

CIDEA interacts with Phosphatidic Acid

PA is required for LD enlargement

 

The Cidea gene is highly expressed in BAT, induced in WAT following cold exposure (46), and is widely used by researchers as a defining marker to discriminate brown or brite adipocytes from white adipocytes (7, 28). As evidence indicated a key role in the LD biology (47) we have characterized the mechanism by which CIDEA promotes LD enlargement, which involves the targeting of LDs, the docking of LD pairs and the transference of lipids between them. The lipid transfer step requires the interaction of CIDEA and PA through a cationic amphipathic helix. Independently of PA-binding, this helix is also responsible for anchoring CIDEA in the LD membrane. Finally, we demonstrate that the docking of LD pairs is driven by the formation of CIDEA complexes involving the N-term domain and a C-term interaction site.

CIDE proteins appeared during vertebrate evolution by the combination of an ancestor N-term domain and a LD-binding C-term domain (35). In spite of this, the full process of LD enlargement can be induced in yeast by the sole exogenous expression of 395 CIDEA, indicating that in contrast to SNARE-triggered vesicle fusion, LD fusion by lipid transference does not require the coordination of multiple specific proteins (48). Whereas vesicle fusion implicates an intricate restructuring of the phospholipid bilayers, LD fusion is a spontaneous process that the cell has to prevent by tightly controlling their phospholipid composition (23). However, although phospholipid-modifying enzymes have been linked with the biogenesis of LDs (49, 50), the implication of phospholipids in physiologic LD fusion processes has not been previously described.

Complete LD fusion by lipid transfer can last several hours, during which the participating LDs remain in contact. Our results indicate that both the N-term domain and a C-term dimerization site (aa 126-155) independently participate in the docking of LD pairs by forming trans interactions (Fig. 7). Certain mutations in the dimerization sites that do not eliminate the interaction result in a decrease on the TAG transference efficiency, reflected on the presence of small LDs docked to enlarged LDs. This suggests that in addition to stabilizing the LD-LD interaction, the correct conformation of the 409 CIDEA complexes is necessary for optimal TAG transfer. Furthermore, the formation of stable LD pairs is not sufficient to trigger LD fusion by lipid transfer. In fact, although LDs can be tightly packed in cultured adipocytes, no TAG transference across neighbour LDs is observed in the absence of CIDE proteins (15), showing that the phospholipid monolayer acts as a barrier impermeable to TAG. Our CG-MD simulations indicate that certain TAG molecules can escape the neutral lipid core of the LD and be integrated within the aliphatic chains of the phospholipid monolayer. This could be a transition state 416 prior to the TAG transference and our data indicates that the docking of the amphipathic helix in the LD membrane could facilitate this process. However, the infiltrated TAGs in LD membranes in the presence of mutant helices, or even in the absence of docking, suggests that this is not enough to complete the TAG transference.

To be transferred to the adjacent LD, the TAGs integrated in the hydrophobic region of the LD membrane should cross the energy barrier defined by the phospholipid polar heads, and the interaction of CIDEA with PA could play a role in this process, as suggested by the disruption of LD enlargement by the mutations preventing PA-binding (K167E/R171E/R175E) and the inhibition of CIDEA after PA depletion. The minor effects observed with more conservative substitutions in the helix, suggests that the presence of positive charges is sufficient to induce TAG transference by attracting anionic phospholipids present in the LD membrane. PA, which requirement is indicated by our PA-depletion experiments, is a cone-shaped anionic phospholipid which could locally destabilize the LD monolayer by favoring a negative membrane curvature incompatible with the spherical LD morphology (51). Interestingly, while the zwitterion PC, the main component of the monolayer, stabilizes the LD structure (23), the negatively charged PA promote their coalescence (29). This is supported by our CD-MD results which resulted in a deformation of the LD shape by the addition of PA. We propose a model in which the C-term amphipathic helix positions itself in the LD monolayer and interacts with PA molecules in its vicinity, which might include trans interactions with PA in the adjacent LD. The interaction with PA disturbs the integrity of the phospholipid barrier at the LD-LD interface, allowing the LD to LD transference of TAG molecules integrated in the LD membrane (Fig. 7). Additional alterations in the LD composition could be facilitating TAG transference, as differentiating adipocytes experience a reduction in saturated fatty acids in the LD phospholipids (52), and in their PC/PE ratio (53) which could increase the permeability of the LD membranes, and we previously observed that a change in the molecular structures of TAG results in an altered migration pattern to the LD surface (32).

During LD fusion by lipid transfer, the pressure gradient experienced by LDs favors TAG flux from small to large LDs (15). However, the implication of PA, a minor component of the LD membrane, could represent a control mechanism, as it is plausible that the cell could actively influence the TAG flux direction by differently regulating the levels of PA in large and small LDs, which could be controlled by the activity of enzymes such as AGPAT3 and LIPIN-1J (13, 30). This is a remarkable possibility, as a switch in the favored TAG flux direction could promote the acquisition of a multilocular phenotype and facilitate the browning of WAT (24). Interestingly, Cidea mRNA is the LD protein- encoding transcript that experiences the greatest increase during the cold-induced process by which multilocular BAT-like cells appear in WAT (24). Furthermore, in BAT, cold exposure instigates a profound increase in CIDEA protein levels that is independent of transcriptional regulation (54). The profound increase in CIDEA is coincident with elevated lipolysis and de novo lipogenesis that occurs in both brown and white adipose tissues after E-adrenergic receptor activation (55). It is likely that CIDEA has a central role in coupling these processes to package newly synthesized TAG in LDs for subsequent lipolysis and fatty acid oxidation. Importantly, BAT displays high levels of glycerol kinase activity (56, 57) that facilitates glycerol recycling rather than release into the blood stream, following induction of lipolysis (58), which occurs in WAT. Hence, the reported elevated glycerol released from cells depleted of CIDEA (28) is likely to be a result of decoupling lipolysis from the ability to efficiently store the products of lipogenesis in LDs and therefore producing a net increase in detected extracellular glycerol. This important role of CIDEA is supported by the marked depletion of TAG in the BAT of Cidea null mice following overnight exposure to 4 °C (28) and our findings that CIDEA-dependent LD enlargement is maintained in a lipase negative yeast strain.

Cidea and the genes that are required to facilitate high rates of lipolysis and lipogenesis are associated with the “browning” of white fat either following cold exposure (46) or in genetic models such as RIP140 knockout WAT (59). The induction of a brown- like phenotype in WAT has potential benefits in the treatment and prevention of metabolic disorders (60). Differences in the activity and regulation of CIDEC and CIDEA could also be responsible for the adoption of unilocular or multilocular phenotypes. In addition to their differential interaction with PLIN1 and 5, we have observed that CIDEC is more resilient to the deletion of the N-term than CIDEA, indicating that it may be less sensitive to regulatory posttranslational modifications of this domain. This robustness of CIDEC activity together with its potentiation by PLIN1, could facilitate the continuity of the LD enlargement in white adipocytes until the unilocular phenotype is achieved. In contrast, in brown adipocytes expressing CIDEA the process would be stopped at the multilocular stage for example due to post-translational modifications that modulate the function or stability of the protein or alteration of the PA levels in LDs.

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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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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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FDA Guidance Documents Update

Reporter: Stephen J. Williams, Ph.D.

You are subscribed to FDA Guidance Documents for U.S. Food & Drug Administration (FDA).

This information has recently been updated and is now available.

Recently posted guidance documents

10/14/15: General Considerations for Animal Studies for Medical Devices – Draft Guidance for Industry and Food and Drug Administration Staff

10/14/15: Recommendations for Microbial Vectors Used for Gene Therapy; Draft Guidance for Industry

10/15/15: Draft PDEs for Triethylamine and for Methylisobutylketone

10/15/15: ICH Q3C Maintenance Procedures for the Guidance for Industry Q3C Impurities: Residual Solvents

10/19/15: CVM GFI #229 – Evaluating the Effectiveness of New Animal Drugs for the Reduction of Pathogenic Shiga Toxin-Producing E. coli in Cattle

10/21/15: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use

10/21/15: Manufacturing Site Change Supplements: Content and Submission – Draft Guidance for Industry and Food and Drug Administration Staff

10/26/15: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry

10/26/15: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act

10/26/15: Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance

10/27/15: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

10/27/15: Product Development Under the Animal Rule

10/28/15: DSCSA Implementation: Product Tracing Requirements for Dispensers — Compliance Policy (Revised) Guidance for Industry

10/29/15: Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation

Guidance Document Search

•    Search all FDA official guidance documents and other regulatory guidance

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Liposomes, Lipidomics and Metabolism

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Building a Better Liposome

Computational models suggest new design for nanoparticles used in targeted drug delivery.

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=184147

Using computational modeling, researchers at Carnegie Mellon University, the Colorado School of Mines and the University of California, Davis have come up with a design for a better liposome. Their findings, while theoretical, could provide the basis for efficiently constructing new vehicles for nanodrug delivery.

Liposomes are small containers with shells made of lipids, the same material that makes up the cell membrane. In recent years, liposomes have been used for targeted drug delivery. In this process, the membrane of a drug-containing liposome is engineered to contain proteins that will recognize and interact with complementary proteins on the membrane of a diseased or dysfunctional cell. After the drug-containing liposomes are administered, they travel through the body, ideally connecting with targeted cells where they release the drug.

liposome_853x480-min.jpg

This packaging technique is often used with highly toxic nanodrugs, like chemotherapy drugs, in an attempt to prevent the free drug from damaging non-cancerous cells. However, studies of this model of delivery have shown that in many cases less than 10 percent of the drugs transported by liposomes end up in tumor cells. Often, the liposome breaks open before it reaches a tumor cell and the drug is absorbed into the body’s organs, including the liver and spleen, resulting in toxic side effects.

“Even with current forms of targeted drug delivery, treatments like chemotherapy are still very brutal. We wanted to see how we could make targeted drug delivery better,” said Markus Deserno, professor of physics at Carnegie Mellon and a member of the university’s Center for Membrane Biology and Biophysics.

Deserno and colleagues propose that targeted drug delivery can be improved by making more stable liposomes. Using three different types of computer modeling, they have shown that liposomes can be made sturdier by incorporating a nanoparticle core made of a material like gold or iron and connecting that core to the liposome’s membrane using polymer tethers. The core and tethers act as a hub-and-spoke-like scaffold and shock-absorber system that help the liposome to weather the stresses and strains it encounters as it travels through the body to its target.

Francesca Stanzione and Amadeu K. Sum of the Colorado School of Mines conducted a fine-grained simulation that looked at how the polymer tethers anchor the liposome’s membrane at an atomistic level. Roland Faller of UC Davis did a meso-scale simulation that looked how a number of tethers held on to a small patch of membrane. Each of these simulations allowed researchers to look at smaller components of the liposome, nanoparticle core and tethers, but not the entire structure.

To see the entire structure, Carnegie Mellon’s Deserno and Mingyang Hu developed a coarse-grained model that represents groupings of components rather than individual atoms. For example, one lipid in the cell membrane might have 100 atoms. In a fine-grain simulation, each atom would be represented. In Deserno’s coarse grain simulation, those atoms might be represented by only three pieces instead of 100.

“Its unfeasible to look at the complete construct at an atomistic level. There are too many atoms to consider, and the timescale is too long. Even with the most advanced supercomputer, we wouldn’t have the power to run an atom-level simulation,” Deserno said. “But the physics that matters isn’t locally specific. It’s more like soft matter physics, which can be described at a much coarser resolution.”

Deserno’s simulation allowed the researchers to see how the entire reinforced liposome construct responded to stress and strain. They proposed that if a liposome was given the right-sized hub and tethers, its membrane would be much more resilient, bending to absorb impact and pressure.

Additionally, they were able to simulate how to best assemble the liposome, hub and tether system. They found that if the hub and tether are attached and placed in a solution of lipids, and solvent conditions are suitably chosen, a correctly sized liposome would self-assemble around the hub and tethers.

The researchers hope that chemists and drug developers will one day be able to use their simulations to determine what size core and polymer tethers they would need to effectively secure a liposome designed to deliver a specific drug or other nanoparticle. Using such simulations could narrow down the design parameters, speed up the development process and reduce costs.

 

Lipotype GmbH and NIHS Collaborate

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=184363

NIHS to use the Lipotype Shotgun Lipidomics Technology for lipid analysis.

Lipotype GmbH and the Nestlé Institute of Health Sciences (NIHS) have collaborated to employ the innovative Lipotype Shotgun Lipidomics Technology to analyze lipids in blood for nutritional research. Recently, Lipotype and NIHS have jointly published results of the robustness of the Lipotype Technology. Lipotype envisions a future use of its technology in clinical diagnostics screens for establishing reliable lipid diagnostic biomarkers.

Innovative Lipotype Technology for lipid analysis
The purpose of this collaboration is to enable NIHS to use the Lipotype Shotgun Lipidomics Technology for lipid analysis. The mass spectrometry-based Lipotype technology covers a broad spectrum of lipid molecules and delivers quantitative results in high-throughput. The Nestlé Institute of Health Sciences uses this technology platform for nutritional research. NIHS is a specialized biomedical research institute and is part of Nestlé’s global Research & Development network.

Joint research project reveals robustness of Lipotype Technology
During the collaboration, Lipotype and NIHS conducted a joint research project and demonstrated that the Lipotype technology was robust enough to deliver data with high precision and negligible technical variation between different sites. In addition, important features are the high coverage and throughput, which were confirmed when applying the Lipotype technology.

Lipotype envisions these as important features, required for future use in clinical diagnostics screens, in order to establish and validate reliable lipid diagnostic biomarkers. The results have been published in October 2015, in the European Journal of Lipid Science and Technology (Surma et al. “An Automated Shotgun Lipidomics Platform for High Throughput, Comprehensive, and Quantitative Analysis of Blood Plasma Intact Lipids.”).

Lipids play an important role for health and disease
Lipotype is a spin-off company of the Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden, Germany. Prof. Kai Simons, CEO of Lipotype explains: “We developed a novel Shotgun-Lipidomics technology to analyze lipids in blood and other biological samples. Our analysis is quick and covers hundreds of lipid molecules at the same time. Our technology can be used to identify disease related lipid signatures.”

 

New Treatment for Obesity Developed

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=183998

Researchers at the University of Liverpool, working with a global healthcare company, have helped develop a new treatment for obesity.
The treatment, which is a once-daily injectable derivative of a metabolic hormone called GLP-1 conventionally used in the treatment of type 2 diabetes, has proved successful in helping non-diabetic obese patients lose weight.

Professor John Wilding, who leads Obesity and Endocrinology research in the Institute of Ageing and Chronic Disease, investigates the pathophysiology and treatment of both obesity and type 2 diabetes and is applying his expertise in this area to work with, and often act as a consultant for, a number of large pharmaceutical companies looking to develop new treatments for obesity and diabetes.

Exciting development

Professor Wilding, said: “The biology of GLP-1 has been a focus of my research for 20 years; in particular when I was working at Hammersmith Hospital in London, I was part of the team that demonstrated that it was involved in appetite regulation; work on GLP-1 has continued during my time in Liverpool. Being involved in the development of a treatment, from the basic research right through to clinical trials in patients is very exciting”.

“It is likely that the treatment will be used initially in very specific situations, such as helping patients who are severely obese. It differs from current treatments used for diabetes, as it has stronger appetite regulating effects but no greater effect on glucose control.”

In 2014 more than 1.9 billion adults worldwide were classed as obese by the World Health Organisation; in the UK numbers have more than tripled since 1980. This Obesity can lead to other serious health-related illnesses including type 2 diabetes, hypertension and obstructive sleep apnoea as well as increasing the risk for many common cancers.

The drug has been approved in the European Union, but has not yet launched in the UK.

Professor Wilding added: “Consultancy like this can help relationship and reputation building and informs my research keeping it at the forefront of developments. It also brings many other benefits such as publications and income generation, which can help support other research, for example by such as funding for pilot projects that can lead to grant applications and investigator-initiated trials funded by the company”.

 

Evidence of How Incurable Cancer Develops

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=184346

Researchers in the West Midlands have made a breakthrough in explaining how an incurable type of blood cancer develops from an often symptomless prior blood disorder.

The findings could lead to more effective treatments and ways to identify those most at risk of developing the cancer.

All patients diagnosed with myeloma, a cancer of the blood-producing bone marrow, first develop a relatively benign condition called ‘monoclonal gammopathy of undetermined significance’ or ‘MGUS’.

MGUS is fairly common in the older population and only progresses to cancer in approximately one in 100 cases. However, currently there is no way of accurately predicting which patients with MGUS are likely to go on to get myeloma.

Myeloma is diagnosed in around 4,000 people each year in the UK. It specifically affects antibody-producing white blood cells found in the bone marrow, called plasma cells. The researcher team from the University of Birmingham, New Cross and Heartlands Hospitals compared the cellular chemistry of bone marrow and blood samples taken from patients with myeloma, patients with MGUS and healthy volunteers.

Surprisingly, the researchers found that the metabolic activity of the bone marrow of patients with MGUS was significantly different to plasma from healthy volunteers, but there were very few differences at all between the MGUS and myeloma samples. The research was funded by the blood cancer charity Bloodwise, which changed its name from Leukaemia & Lymphoma in September.

The findings suggest that the biggest metabolic changes occur with the development of the symptomless condition MGUS and not with the later progression to myeloma.

Dr Daniel Tennant, who led the research at the University of Birmingham, said, “Our findings show that very few changes are required for a MGUS patient to progress to myeloma as we now know virtually all patients with myeloma evolve from MGUS. A drug that interferes with these specific initial metabolic changes could make a very effective treatment for myeloma, so this is a very exciting discovery.”

The research team found over 200 products of metabolism differed between the healthy volunteers and patients with MGUS or myeloma, compared to just 26 differences between MGUS patients and myeloma patients. The researchers believe that these small changes could drive the key shifts in the bone marrow required to support myeloma growth.

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