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Posts Tagged ‘Insulin resistance’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Obesity is a global concern that is associated with many chronic complications such as type 2 diabetes, insulin resistance (IR), cardiovascular diseases, and cancer. Growing evidence has implicated the digestive system, including its microbiota, gut-derived incretin hormones, and gut-associated lymphoid tissue in obesity and IR. During high fat diet (HFD) feeding and obesity, a significant shift occurs in the microbial populations within the gut, known as dysbiosis, which interacts with the intestinal immune system. Similar to other metabolic organs, including visceral adipose tissue (VAT) and liver, altered immune homeostasis has also been observed in the small and large intestines during obesity.

 

A link between the gut microbiota and the intestinal immune system is the immune-derived molecule immunoglobulin A (IgA). IgA is a B cell antibody primarily produced in dimeric form by plasma cells residing in the gut lamina propria (LP). Given the importance of IgA on intestinal–gut microbe immunoregulation, which is directly influenced by dietary changes, scientists hypothesized that IgA may be a key player in the pathogenesis of obesity and IR. Here, in this study it was demonstrate that IgA levels are reduced during obesity and the loss of IgA in mice worsens IR and increases intestinal permeability, microbiota encroachment, and downstream inflammation in metabolic tissues, including inside the VAT.

 

IgA deficiency alters the obese gut microbiota and its metabolic phenotype can be recapitulated into microbiota-depleted mice upon fecal matter transplantation. In addition, the researchers also demonstrated that commonly used therapies for diabetes such as metformin and bariatric surgery can alter cellular and stool IgA levels, respectively. These findings suggested a critical function for IgA in regulating metabolic disease and support the emerging role for intestinal immunity as an important modulator of systemic glucose metabolism.

 

Overall, the researchers demonstrated a critical role for IgA in regulating intestinal homeostasis, metabolic inflammation, and obesity-related IR. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease. This research further emphasized the importance of the intestinal adaptive immune system and its interactions with the gut microbiota and innate immune system within the larger network of organs involved in the manifestation of metabolic disease.

 

Future investigation is required to determine the impact of IgA deficiency during obesity in humans and the role of metabolic disease in human populations with selective IgA deficiency, especially since human IgA deficiency is associated with an altered gut microbiota that cannot be fully compensated with IgM. However, the research identified IgA as a critical immunological molecule in the intestine that impacts systemic glucose homeostasis, and treatments targeting IgA-producing immune populations and SIgA may have therapeutic potential for metabolic disease.

 

References:

 

https://www.nature.com/articles/s41467-019-11370-y?elqTrackId=dc86e0c60f574542b033227afd0fdc8e

 

https://www.jci.org/articles/view/88879

 

https://www.nature.com/articles/nm.2353

 

https://diabetes.diabetesjournals.org/content/57/6/1470

 

https://www.sciencedirect.com/science/article/pii/S1550413115001047?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1550413115002326?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1931312814004636?via%3Dihub

 

https://www.nature.com/articles/nature15766

 

https://www.sciencedirect.com/science/article/pii/S1550413116000371?via%3Dihub

 

https://www.nature.com/articles/nm.2001

 

https://www.sciencedirect.com/science/article/abs/pii/S1550413118305047?via%3Dihub

 

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Diabetes Mellitus

Author & Curator: Larry H. Bernstein, MD, FCAP

 

Diabetes mellitus (DM) is a group of metabolic diseases defined by high blood glucose levels, which, depending on the fasting blood glucose, may be pre-diabetes or overt diabetes (110 mg/dl. 124 mg/dl). This blood glucose level reflects a disorder of control of glucose metabolism, which is mediated through the pituitary growth hormone acting on the liver, which produces insulin growth factor 1 (IGF1).  Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. That said, there is much to be understood about the long term systemic effects of this disorder, a multisystem disease. The presence of pre-diabetes glucose levels is sufficient to proactively take measures to reduce the circulating glucose.

Globally, as of 2013, an estimated 382 million people have diabetes worldwide, with type 2 diabetes making up about 90% of the cases. This is equal to 8.3% of the adults population, with equal rates in both women and men. Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million deaths per year, making it the 8th leading cause of death. Diabetes overall at least doubles the risk of death. The number of people with diabetes is expected to rise to 592 million by 2035. The economic costs of diabetes globally was estimated in 2013 at $548 billion and in the United States in 2012 $245 billion.

The observation of symptoms of frequent urination, increased thirst, and increased hunger is symptomatic of overt DM, and is seen with diabetic ketoacidosis, with very high hyperglycemia and glucosuria, particularly in Type 1 DM. Untreated, diabetes leads to serious complications. Acute complications include diabetic ketoacidosis. Serious long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.

There are three main types of diabetes mellitus:

  • Type 1 DM results from the body’s failure to produce enough insulin. This form was previously referred to as “insulin-dependent diabetes mellitus” (IDDM) or “juvenile diabetes”. The cause is unknown.
  • Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as “non insulin-dependent diabetes mellitus” (NIDDM) or “adult-onset diabetes”. The primary cause is excessive body weight and not enough exercise.
  • Gestational diabetes, the third, occurs when pregnant women without a previous history of diabetes develop a high blood glucose level.

Type 1 DM, which presents suddenly in children or young adults, is possibly an as yet unidentified post-translational or epigenetic form, unrelated to Type 2, which is becoming more common in children.  It results in the destruction of islet beta cells that then have no capacity to produce insulin.  A family history of the disease would be a signal to raise a child with great care to not stress the pancreas.  Even though I raised the possibility of an epigenetic factor, it is important to keep in mind that the regulation of glucose is responsive to a number of stresses, even in a healthy person.  These are:

  • Corticosteroids
  • Glucagon
  • Growth hormone
  • Catecholamines
  • Proinflammatory cytokines
  • Anxiety disorder
  • Eating disorder

Gestational diabetes is perhaps Type 2 diabetes in a pregnant woman initiated by the condition of pregnancy. Whether these women were not diabetic, with a glucose level between 100-110 prior to pregnancy, is an open question. However, the pregnant state is accompanied by large effects by hormone levels.

Type 2 diabetes has been increasing worldwide, not only in western nations.  However, in non-western countries that have large populations of underserved, there is still a major problem with protein energy malnutrition (PEM). Globally, as of 2013, an estimated 382 million people have diabetes worldwide, with type 2 diabetes making up about 90% of the cases. This is equal to 8.3% of the adults population, with equal rates in both women and men. Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million deaths per year, making it the 8th leading cause of death. Diabetes overall at least doubles the risk of death. The number of people with diabetes is expected to rise to 592 million by 2035. The economic costs of diabetes globally was estimated in 2013 at $548 billion and in the United States in 2012 $245 billion.

The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease. Other “macrovascular” diseases are stroke, and peripheral vascular disease. The primary microvascular complications of diabetes include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and potentially blindness. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes.

Prevention and treatment involves a healthy diet, physical exercise, not using tobacco and being a normal body weight. Blood pressure control and proper foot care are also important for people with the disease. Type 1 diabetes must be managed with insulin injections. Type 2 diabetes may be treated with medications with or without insulin. Insulin and some oral medications can cause low blood sugar. Weight loss surgery in those with obesity is an effective measure in those with type 2 DM. Gestational diabetes usually resolves after the birth of the baby.

A number of articles in http://pharmaceuticalintelligence,com (this journal) have presented the relationship of DM to heart and vascular disease. The complexity of the disease is not to be underestimated, and there havr been serious controversies with adverse consequences over the use of the class of drugs that includes rosiglitazone and piaglitazone, which has opened serious issues about how clinical trials are conducted, and how the data obtained in studies may be compromised.

Pharmaceutical Insights

Management of Diabetes Mellitus: Could Simultaneous Targeting of Hyperglycemia and Oxidative Stress Be a Better Panacea?

Omotayo O. Erejuwa
Int. J. Mol. Sci. 2012, 13, 2965-2972; http://www.mdpi.com/journal/ijms http://dx.doi.org:/10.3390/ijms13032965

The primary aim of the current management of diabetes mellitus is to achieve and/or maintain a glycated hemoglobin level of ≤6.5%. However, recent evidence indicates that intensive treatment of hyperglycemia is characterized by increased weight gain, severe hypoglycemia and higher mortality. Besides, evidence suggests that it is difficult to achieve and/or maintain optimal glycemic control in many diabetic patients; and that the benefits of intensively-treated hyperglycemia are restricted to microvascular complications only. Evidence also indicates that multiple drugs are required to achieve optimal glycemic target in many diabetic patients. In fact, in many diabetic patients in whom optimal glycemic goal is achieved, glycemic control deteriorates even with optimal drug therapy. It does suggest that with the current hypoglycemic or antidiabetic drugs, it is difficult to achieve and/or maintain tight glycemic control in diabetic patients. In many developing countries, the vast majority of diabetic patients have limited or lack access to quality healthcare providers and good therapeutic monitoring.

While increased weight gain could be due to some component drugs (such as sulphonylureas or insulin) of the intensive therapy regimens, hypoglycemia could be drug-induced or comorbidity-induced. Considering the evidence that associates hypoglycemia with increased mortality, higher incidence of mortality in intensive therapy group could be due to hypoglycemia or too low levels of glycosylated hemoglobin. However, it is difficult to contend that increased mortality was entirely due to hypoglycemia. The possibility of drug-induced or drug-associated toxicities could not be ruled out. For instance, rosiglitazone, which has been prohibited and withdrawn from the market in Europe, was one of the hypoglycemic drugs used to achieve intensive therapy of hyperglycemia in Action to Control Cardiovascular Risk in Diabetes (ACCORD). If these findings are anything to go by, does it not suggest that targeting hyperglycemia as the only therapeutic goal in the management of diabetes mellitus could be detrimental to diabetic patients? In addition, the current hypoglycemic drugs are characterized by limitations and adverse effects. Together with the limitations of intensive glycemic treatment (only beneficial in reducing the risk of microvascular complications, but not macrovascular disease complications), does it not imply that targeting hyperglycemia alone is not only deleterious but also limited and ineffective?

The latest figures predict that the global incidence of diabetes mellitus, which was estimated to be 366 million in 2011, will rise to 522 million by 2030. In view of these frightening statistics on the prevalence of diabetes mellitus and on the lack of adequate healthcare, together with the associated diabetic complications, morbidity and mortality, does it not suggest that there is an urgent need for a better therapeutic management of this disorder? Taken together, with these findings and statistics, it can be contended that it is high time alternative and/or complementary therapies to the currently available hypoglycemic agents (which target primarily hyperglycemia only) were sought.

All these may contribute to the unabated increase in global prevalence of diabetes mellitus and its complications In view of these adverse effects and limitations of intensive treatment of hyperglycemia in preventing diabetic complications, which is linked to oxidative stress,

  • this commentary proposes a hypothesis that “simultaneous targeting of hyperglycemia and oxidative stress” could be more effective than “intensive treatment of hyperglycemia” in the management of diabetes mellitus.

Oxidative stress is defined as

  • an “imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage”.

It is implicated in the pathogenesis and complications of diabetes mellitus. The role of oxidative stress is more definite in the pathogenesis of type 2 diabetes mellitus than in type 1 diabetes mellitus. In regard to diabetic complications, there is compelling evidence in support of the role of oxidative stress in both types of diabetes mellitus. Evidence suggests that elevated reactive oxygen species (ROS), which causes factor of increased ROS production, causes tissue damage or diabetic complications have been identified. These include:

  • hyperglycemia-enhanced polyol pathway;
  • hyperglycemia-enhanced formation of advanced glycation endproducts (AGEs);
  • hyperglycemia-activated protein kinase C (PKC) pathway;
  • hyperglycemia-enhanced hexosamine pathway; and
  • hyperglycemia-activated Poly-ADP ribose polymerase (PARP) pathway.

These pathways are activated or enhanced by hyperglycemia-driven mitochondrial superoxide overproduction.

Even though oxidative stress plays an important role in its pathogenesis and complications,

  • unlike other diseases characterized by oxidative stress, diabetes mellitus is unique.

Its cure (restoration of euglycemia, e.g., via pancreas transplants) does not prevent oxidative stress and diabetic complications. This is very important because hyperglycemia exacerbates oxidative stress which is linked to diabetic complications. Theoretically, restoration of euglycemia should prevent oxidative stress and diabetic complications. However, this is not the case. At present, it remains unclear why restoration of euglycemia does not automatically prevent oxidative stress and diabetic complications. The development of diabetes-related complications (both microvascular and macrovascular) may occur in diabetic patients after normoglycemia has been restored. It is a phenomenon whereby previous hyperglycemic milieu is remembered in many target organs such as heart, eyes, kidneys and nerves. This phenomenon is also documented in diabetic animals. Compelling evidence implicates the role of oxidative stress as an important mechanism by which glycemic memory causes tissue damage and diabetic complications. In view of higher incidence of diabetic complications (of which oxidative stress plays an important role) in conventionally-treated diabetic patients, targeting oxidative stress in these patients might be beneficial. In other words, it is possible that the combination of a conventional therapy of hyperglycemia and antioxidant therapy might be more effective and beneficial than intensive therapy of hyperglycemia alone, which is the gold standard at the moment.

Loss of ACE 2 Exaggerates High-Calorie Diet-Induced Insulin Resistance by Reduction of GLUT4 in Mice

M Takeda, K Yamamoto, Y Takemura, H Takeshita, K Hongyo, et al.  Diabetes 61:1–11, 2012

ACE type 2 (ACE2) functions as

  • a negative regulator of the renin angiotensin system
  • by cleaving angiotensin II (AII) into angiotensin 1–7 (A1–7).

This study assessed the role of

  • endogenous ACE2 in maintaining insulin sensitivity.

Twelve-week-old male ACE2 knockout (ACE2KO) mice had normal insulin sensitivities when fed a standard diet. AII infusion or a high-fat high-sucrose (HFHS) diet impaired glucose tolerance and insulin sensitivity more severely

  • in ACE2KO mice than in their wild-type (WT) littermates.

The strain difference in glucose tolerance

  • was not eliminated by an AII receptor type 1 (AT1) blocker
  • but was eradicated by A1–7 or an AT1 blocker combined with the A1–7 inhibitor (A779).

The expression of GLUT4 and a transcriptional factor, myocyte enhancer factor (MEF) 2A,

  • was dramatically reduced in the skeletal muscles of the standard diet–fed ACE2KO mice.

The expression of GLUT4 and MEF2A was increased

  • by A1–7 in ACE2KO mice and
  • decreased by A779 in WT mice.

A1–7 enhanced upregulation of MEF2A and GLUT4 during differentiation of myoblast cells. In conclusion,

  • ACE2 protects against high calorie diet-induced insulin resistance in mice.

This mechanism may involve the transcriptional regulation of GLUT4 via an A1–7-dependent pathway.
Modulation of the action of insulin by angiotensin-(1–7)
FP. Dominici, V Burghi, MC. Munoz, JF. Giani

Clinical Science (2014) 126, 613–630 http://dx.doi.org:/10.1042/CS20130333

The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as

  1. obesity,
  2. systemic hypertension and
  3. dyslipidaemia,
  • defined as the metabolic syndrome.

Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between

  • AngII (angiotensin II) and the insulin signalling pathway

has been the focus of great interest in the last decade. Indeed,

substantial evidence has shown that

  • anti-hypertensive drugs that block the RAS (renin–angiotensin system) may also act to prevent diabetes.

Despite its long history, new components within the RAS continue to be discovered.

Among them, Ang-(1–7) [angiotensin-(1–7)] has gained special attention as a counter-regulatory hormone

  • opposing many of the AngII-related deleterious effects.

Specifically, we and others have demonstrated that Ang-(1–7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that

  • insulin and Ang-(1–7) share a common intracellular signalling pathway.

We also address the molecular mechanisms behind the beneficial effects of Ang-(1–7) on

  • AngII-mediated insulin resistance.

Finally, we discuss potential therapeutic approaches leading to modulation of the

  • ACE2 (angiotensin-converting enzyme 2)/Ang-(1–7)/Mas receptor axis

as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.

Increased Skeletal Muscle Capillarization After Aerobic Exercise Training and Weight Loss Improves Insulin Sensitivity in Adults With IGT

Prior, JB. Blumenthal, LI. Katzel, AP. Goldberg, AS. Ryan. Diabetes Care 2014;37:1469–1475
http://dx.doi.org:/10.2337/dc13-2358

Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus,

  • a reduction in capillary density (CD) may worsen insulin sensitivity.

Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and

  • may be modifiable through aerobic exercise training and weight loss (AEX+WL).

Insulin sensitivity (M) and 120-min postprandial glucose (G120) correlated with CD at baseline (r = 0.58 and r = 20.60, respectively, P < 0.05).

AEX+WL increased maximal oxygen consumption (VO2max) 18%(P = 0.02) and reduced weight and fat mass 8% (P < 0.02).

Regression analyses showed that the AEX+WL-induced increase in CD

  • independently predicted the increase in M (r = 0.74, P < 0.01)
  • as well as the decrease in G120 (r = 20.55, P < 0.05).

AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.

Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials.

K Esposito, P Chiodini, MI Maiorino, G Bellastella, A Capuano, D Giugliano. BMJ Open 2014;4:e005442.
http://dx.doi.org:/10.1136/bmjopen-2014-005442

A systematic review and meta-analysis of longterm randomised trials of DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin). on haemoglobin A1c (HbA1c) was conducted. The difference between final and intermediate HbA1c assessment was the primary outcome. All trials were of 76 weeks duration at least. The difference in HbA1c changes between final and intermediate points averaged 0.22% (95% CI 0.15% to 0.29%), with high heterogeneity (I2=91%, p<0.0001). Estimates
of differences were not affected by the analysis of six extension trials (0.24%, 0.02 to 0.46), or five trials in which a DPP-4 inhibitor was added to metformin (0.24%, 0.16 to 0.32).

  • The effect of DPP-4 inhibitors on HbA1c in type 2 diabetes significantly declines during the second year of treatment.

Overcoming Diabetes Mellitus & Borderline Diabetes
By Max Stanley Chartrand, Ph.D. (Behavioral Medicine)

The over-arching biomarker that has more to do with the ability to restore normal metabolic processes is in achieving a cellular pH 7.45 (via the Kreb’s Cycle). To say the least, getting one’s cellular pH to 7.45 and A1C score below 6.0 can be a daunting task!

SIRCLE®: Naturally Achieved Targets

 Cellular pH 7.35-7.45

 Oxygen 99-100% @55-65 bpm

 Resting Blood Pressure: 110-135/ 65-80

mmHg (differs male vs female)

 Fasting blood sugar consistently <70-99

mg/dL or 3.5-5.5 mmol/L

 HgA1C score: .04-5.8

 HDL: 40-60 mg/dL; LDL: 100 -140 mg/dL;

triglycerides: <85 mg/dL

 C-Reactive Protein (CRP) Score <.5

 Galectin-3 Assay <17.8 ng/mL

Antidiabetic Activity of Hydroalcoholic Extracts of Nardostachys jatamansi in Alloxan-induced Diabetic Rats

M.A. Aleem, B.S. Asad, T Mohammed, R.A. Khan, M.F. Ahmed, A. Anjum, M. Ibrahim. Brit J Med & Medical Res 4(28): 4665-4673, 2014. http://www.sciencedomain.org/review-history.php?iid=579&id=12&aid=5024

The antidiabetic study was carried out to estimate the anti hyperglycemic potential of Nardostachys Jatamansi rhizome’s hydroalcoholic extracts in alloxan induced diabetic rats over a period of two weeks. The hydroalcoholic extract HAE1 at a dose (500mg/kg) exhibited significantly greater antihyperglycemic activity than extract HAE2 at a dose (500mg/kg) in diabetic rats. The hydroalcoholic extracts showed improvement in different parameters associated with diabetes, like body weight, lipid
profile and biochemical parameters. Extracts also showed improvement in

  • regeneration of β-cells of pancreas in diabetic rats.

Histopathological studies support the healing of pancreas by hydro alcoholic extracts (HAE1& HAE2) of Nardostachys Jatamansi, as a probable mechanism of their antidiabetic activity.

Antidiabetic and Antihyperlipidemic Effect of Parmelia Perlata. Ach. in Alloxan Induced Diabetic Rats.
Jothi G and Brindha P
Internat J of Pharmacy and Pharmaceut Sciences 2014; 6(suppl 1)

The aqueous extract of the selected plant was administered at dose levels of 200mg and 400mg/kg body weight for 60 days. After the experimental period the blood and tissue samples were collected and subjected to various biochemical and enzymic parameters. There were profound alteration in

  • fasting blood glucose,
  • serum insulin,
  • glycosylated hemoglobin (HbA1C) and
  • liver glycogen levels in alloxanized rats.
  1. Glucose-6-phosphatase,
  2. glucokinase, and
  3. fructose 1-6 bisphosphatase activity
  • were also altered in diabetic rats.

Administration of plant extract significantly (P<0.05)

  • reduced the fasting blood glucose and HbA1C level and increased the level of plasma insulin.

The activities of glucose metabolizing enzymes were also resumed to normal. There was a profound improvement in serum lipid profiles by

  • reducing serum triglyceride, cholesterol, LDL, VLDL, free fatty acids, phospholipids and increasing the HDL level in a dose dependent manner.

The effects of leaf extract were compared with standard drug glibenclamide (600μg/Kg bw). The results indicate that Parmelia perlata. Ach., Linn. could be a good natural source for developing an antidiabetic drug that can effectively maintained the blood glucose levels and lipid profile to near normal values.

Pathophysiological Insights
Diabetic glomerulosclerosis

Reviewers: Nikhil Sangle, M.D.
Revised: 21 February 2014,
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General

==================================================

  • Diffuse capillary basement membrane thickening, diffuse and nodular glomerulosclerosis
  • Causes glomerular disease, arteriolar sclerosis, pyelonephritis, papillary necrosis; similar between type I and II patients
  • Accounts for 30% of long term dialysis patients in US; causes 20% of deaths in patients with diabetes < age 40
  • Changes may be related to nephronectin, which functions in the assembly of extracellular matrix (Nephrol Dial Transplant 2012;27:1889)

Clinical features

==================================================

  • Proteinuria occurs in 50%, usually 12-22 years after onset of diabetes
  • End stage renal disease occurs in 30% of type I patients
  • Early increased GFR and microalbuminemia (30-300 mg/day) are predictive of future diabetic nephropathy
  • Renal disease reduced by tight diabetic control; may recur with renal allografts; ACE inhibitors may reduce progression

Micro description

==================================================

  • Basement membrane thickening and increased mesangial matrix in ALL patients
  • Diffuse glomerulosclerosis: increase in mesangial matrix associated with PAS+ basement membrane thickening, eventually obliterates mesangial cells
  • Nodular glomerulosclerosis: also called intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease; ovoid, spherical, laminated hyaline masses in peripheral of glomerulus, PAS+, eventually obliterates glomerular tuft; specific for diabetes and membranoproliferative glomerulonephritis, light-chain disease and amyloidosis (Hum Pathol 1993;24:77 (pathogenesis of Kimmelstiel-Wilson nodule))
  • Profound hyalinization of afferent arterioles (insudative lesion-intramural): specific for diabetes in afferent arterioles, but non-specific if in periphery of glomerular loop, Bowman’s capsule or mesangium; insudative material composed of proteins, lipids and mucopolysaccharides
  • Organizing fibroepithelial crescents: associated with aggressive clinical course
  • Diffuse thickening of tubular basement membrane, tubular atrophy and interstitial fibrosis
  • Isolated thickened glomerular basement membrane and proteinuria may be an early predictor of diabetic disease (Mod Pathol 2004;17:1506)

Nodular glomerulosclerosis, Kidney

 Glomeruli:

  1.     Acellular, homogeneous, eosinophilic, globular nodules in the mesangial orintercapillary region of a glomerular tuft with capillary displaced to the periphery.
  2.     Diffuse intercapillary glomerulosclerosis: increasing eosinophilic mesangial matrix materials.
  3.     Capsular drop: eosinophilic small nodules on Bowman’s capsule.
  4.     Fibrin cap: eosinophilic, waxy, fatty structure within the lumen of one or more capillary loops of glomerular tufts.
nodular glomeruloschlerosis

nodular glomeruloschlerosis

http://www.kidneypathology.com/Imagenes/Diabetes/Imagen.Hial.jul.w.jpg

Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.

Westermark P1, Andersson A, Westermark GT.
Physiol Rev. 2011 Jul;91(3):795-826.
http://dx.doi.org:/10.1152/physrev.00042.2009.

Islet amyloid polypeptide (IAPP), or amylin, was named for its tendency to

  • aggregate into insoluble amyloid fibrils, features typical of islets of most individuals with type 2 diabetes.

This pathological characteristic is most probably of

  • great importance for the development of the β-cell failure in this disease,
  • but the molecule also has regulatory properties in normal physiology.

In addition, it possibly contributes to the diabetic condition. This review deals with both these facets of IAPP.

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is

  • a regulatory peptide with putative function
  • both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets.

It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described.

IAPP was discovered through its ability to

  • aggregate into pancreatic islet amyloid deposits,

which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats.

Aggregated IAPP has cytotoxic properties and is believed to be

  • of critical importance for the loss of β-cells in type 2 diabetes

and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the

  • pathophysiological role of aggregated forms of IAPP,
  • including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

Islet amyloid, initially named “islet hyalinization,” was described in 1901 by two researchers independently and for a long time was considered an enigma. It was found to occur in association with diabetes mellitus, particularly in elderly individuals, but its possible pathogenetic importance was often denied. The similarity of the hyaline substance to amyloid was noted at an early date, and some researchers reported staining reactions typical of amyloid. It had been shown in 1959 that

  • amyloid of several types has a characteristic ultrastructure,
  • and islet deposits were found to share this appearance.

When biochemical analyses of amyloid fibrils from systemic primary and secondary amyloidoses showed that

  • these consisted of distinctive proteins,
  • it was suspected that the islet deposits might also be a polymerized protein.

The chemical composition of islet amyloid did not attract much attention even after the characteristics of other amyloid fibrils had been elucidated. The finding that the amyloid in C cell-derived medullary thyroid carcinoma is of polypeptide hormonal origin was an important indication that amyloid in other endocrine tissues also comes from the local secretory products, and it was believed that

  • insulin, or proinsulin, or split products thereof constitute the islet amyloid fibrils.

Immunological trials to characterize the amyloid yielded equivocal results. Only when concentrated formic acid was used on amyloid,

  • extracted from an amyloid-rich insulinoma, was it possible to purify the major fibril protein
  • and characterize it by NH2-terminal amino acid sequence analysis,

which very unexpectedly revealed a novel peptide,

  • not resembling any part of proinsulin
  • but with partial identity to the neuropeptide calcitonin gene-related peptide (CGRP).

Further characterization of the peptide purified from an insulinoma and from islet amyloid of human and feline origin proved it to be a 37-amino acid (aa) residue peptide. The peptide was initially named “insulinoma amyloid peptide” , later diabetes-associated peptide (DAP), and finally islet amyloid polypeptide (IAPP), or “amylin”.

IAPP is a 37-aa residue long peptide, but by the application of molecular biological methods it was quickly shown that IAPP is expressed initially as

  • part of an 89-aa residue preproprotein containing a 22-aa signal peptide and
  • two short flanking peptides, the latter cleaved off at double basic aa residues similar to proinsulin.

IAPP is expressed by one single-copy gene on the short arm of chromosome 12,

  • in contrast to insulin and the other members of the calcitonin family, including
  • CGRP,
  • adrenomedullin, and
  • calcitonin,

all of which are encoded by genes on the evolutionary related chromosome 11.

The preproIAPP gene contains three exons, of which

  • the last two encode the full prepromolecule.

The signal peptide is cleaved

  • off in the endoplasmic reticulum (ER), and
  • conversion of proIAPP to IAPP takes place in the secretory vesicles.

ProIAPP and proinsulin are both processed by the two endoproteases

  • prohormone convertase 2 (PC2) and
  • prohormone convertase 1/3 (PC1/3) and
  • by carboxypeptidase E (CPE) (Figure 1).
amylin

amylin

A: the amino acid sequence of human pro-islet amyloid polypeptide (proIAPP) with the cleavage site for PC2 at the NH2 terminus and the cleavage site for PC1/3 at the COOH terminus, indicated by arrows. The KR residues (blue) that remain at the COOH terminus after PC1/3 processing are removed by carboxypeptidase E. This event exposes the glycine residue that is used for COOH-terminal amidation.
Below is a cartoon of IAPP in blue with the intramolecular S-S bond between residues 2–7 and the amidated COOH terminus.

B: the amino acid sequence of human proinsulin with the basic residues at the B-chain/C-peptide junction and the A-chain/C-peptide/junction indicated in blue and the processing sites indicated by arrows. PC1/3 does almost exclusively process proinsulin at the B-chain/C-peptide junction while PC2 preferentially processes proinsulin at the A-chain/C-peptide junction. The basic residues (RR) (position 31, 32) that remain at the COOH terminus of the B-chain is removed by the carboxypeptidase CPE. Below is a cartoon of insulin A-chain and B-chain in red with intermolecular SS bonds between cystein residues 7 in the A and B chains, between cystein residues at position 19 in the B-chain and 20 in the A-chain and the intermolecular SS bond between cystein residues at position 6 and 11 of the A-chain.

http://physrev.physiology.org/content/physrev/91/3/795/F1.large.jpg

  1. IAPP and insulin genes contain similar promoter elements,
  2. and the transcription factor PDX1 regulates the effects of glucose on both genes.
  3. Glucose stimulated β-cells respond with a parallel expression pattern of IAPP and insulin in the rat.

However, this parallel secretion of IAPP and insulin is altered in experimental diabetes models in rodents. Perfused rat pancreas secreted relatively

  • more IAPP than insulin when exposed to dexamethasone, whereas
  • high doses of streptozotocin or alloxan reduced insulin secretion more than that of IAPP.

Oleat and palmitate increased the expression of IAPP but not of insulin in MIN6 cells. In mice fed a diet high in fat for 6 mo, plasma IAPP increased 4.5 times more than insulin compared with mice fed standard food containing 4% fat.

In human recipients who had become insulin-independent by intrahepatically transplanted islets, there was disproportionately

  • more IAPP than normal secreted during hyperglycemia.

These examples show that the strictly parallel expression of IAPP and insulin may be disturbed under certain conditions.

The crystalline structure of insulin in granules is well characterized.

  • Hexameric insulin, together with zinc, constitutes the core of the mature granules, while
  • IAPP, together with a large number of additional components, including the C peptide, is found in the halo region.

The highly fibrillogenic human IAPP has to be protected in some way from aggregation, which otherwise would take place spontaneously. The fact that very fibril-prone proteins can be kept in solution at high concentrations is known from studies of arthropod silk. The composition of the β-cell granule is extremely complex, and it has many components in addition to insulin and C peptide, in micromolar concentrations.

It is probable that IAPP is protected from aggregation by interaction with other components. Plausible candidates are

  • proinsulin, insulin, or their processing intermediates.

Insulin has been found to be

  • a strong inhibitor of IAPP fibril formation.

This finding has been verified in a number of subsequent studies, which have also shown the potency of the inhibition. The inhibition seems to depend

  • solely on the B-chain,
  • which binds specifically to a short segment of IAPP.

An insulin-to-IAPP ratio of between 1:5 and 1:100 had a strong inhibitory effect. The molar ratio between IAPP and insulin in the granule as a whole is ∼1–2:50.

Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study

Rita Peila, Beatriz L. Rodriguez and Lenore J. Launer
Diabetes Apr 2002; 51(4): 1256-1262
http://dx.doi.org:/10.2337/diabetes.51.4.1256

Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes

  • alone or combined with the apolipoprotein E (APOE) gene
  • with incident dementia and neuropathological outcomes

in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolulu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes.

Diabetes was associated with

  1. total dementia (RR 1.5 [95% CI 1.01–2.2]),
  2. Alzheimer’s disease (AD; 1.8 [1.1–2.9]), and
  3. vascular dementia (VsD; 2.3 [1.1–5.0]).

Individuals with both type 2 diabetes and the APOE ε4 allele

  • had an RR of 5.5 (CI 2.2–13.7) for AD compared with those with neither risk factor.

Participants with type 2 diabetes and the ε4 allele had

  • a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2–7.3]) and
  • neurofibrillary tangles in the cortex (IRR 3.5 [1.6–7.5]) and hippocampus (IRR 2.5 [1.5–3.7]), and
  • they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5–29.6).

Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE ε4 allele. The neuropathological data are consistent with the clinical results.

Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice

  1. Anderson, MR. King, L Delbruck, CG. Jolivalt
    Dis. Model. Mech. June 2014; 7(6): 625-633
    http://dx.doi.org:/10.1242/dmm.015750

One of the tissues or organs affected by diabetes is the nervous system,

  • predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy)
  • but also the central system with impaired learning, memory and mental flexibility.

The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but

  • only the C57BL6 mice showed statistically significant hyperglycemia.

STZ-diabetic C57BL6 mice

  • developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas
  • neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point.

By 6 months on HFD, Swiss Webster mice developed

  • learning and memory deficits in the Barnes maze test,
  • whereas their peripheral nervous system remained normal.

In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction,

  • as indicated by nerve conduction slowing and thermal hyperalgesia,
  • but showed normal learning and memory functions.

Our data indicate that STZ-induced diabetes or a HFD can damage

  • both peripheral and central nervous systems,
  • but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions
  • and only in Swiss Webster mice.

In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype.

Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin

S Srodulski, S Sharma, AB Bachstetter, JM Brelsfoard, et al.
Molecular Neurodegeneration  2014; 9(30):
http://dx.doi.org:/10.1186/1750-1326-9-30

Background: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment

  • contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells.

Amylin deposition is promoted by

  • chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance.

Human amylin oligomerizes quickly when oversecreted, which is toxic,

  • induces inflammation in pancreatic islets and
  • contributes to the development of T2D.

Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

Methods: In contrast to amylin from humans,

  • rodent amylin is neither amyloidogenic nor cytotoxic.

We exploited this fact by comparing

  • rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats

which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels.

Results: Compared to WT rats, HIP rats show

i) reduced exploratory drive,
ii) impaired recognition memory and
iii) no ability to improve the performance on the rotarod.

The development of neurological deficits is

  • associated with amylin accumulation in the brain.

The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates

  • is almost double in HIP rats compared with WT littermates (P < 0.05).

Large amylin deposits (>50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin

  • alters the brain structure at the molecular level.

Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which

  • are clustering in areas positive for amylin infiltration.

Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that

  • amylin deposition in the brain induces a neuroinflammatory response.

Conclusions:

  1. Hyperamylinemia promotes accumulation of oligomerized amylin in the brain
  2. leading to neurological deficits through an oligomerized amylin-mediated inflammatory response.

Additional studies are needed to determine

  • whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.

Keywords: Diabetes, Alzheimer’s Disease, Amylin, Pre-diabetes, Insulin Resistance, Inflammation, Behavior

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Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI

Reporter and Curator: Larry H Bernstein, MD, FCAP

Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabete

AK Gupta, E Ravussin, DL Johannsen, AJ Stull,WT.Cefalu and WD Johnson at Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA Brit J Med & Med Res 2012; 2(3):413-423 [www.ScienceDomain.org]

provides an exceedingly interesting insight into the relationship between type 2 diabetes mellitus, obesity and risk for cardiovascular disease in patients who are asymptomatic prediabetics, defined as a fasting blood glucose between 1000 and 1240 mg/L, or a Hb A1c (may not accurate for African Americans) between 5.6 and 6.5.  They would be expected to show an abnormal 5-hr GTT.

Obesity is associated with the release from adipocytes of adiponectin, which it has been reported is countered by resistin.  We might also have the effect of the insulin secreting beta cell, that releases insulin without a relationship to an anabolic function, through IGF-1 related to feedback to the pituitary GH, which takes a dominant catabolic role. Thus, insulin resistance. This is an oversimplification, and far greater depth is found elsewhere.

This study is consistent with another study on  Metabolism Influences Cancer

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

Recent development on Human Stem Cell Therapies for comorbidity and Cardiovascular disease

Human Stem Cell Therapies: UCSD New Discovery addressing the Limiting Factor and Providing the Solution

https://pharmaceuticalintelligence.com/2014/01/06/human-stem-cell-therapies-ucsd-new-discovery-addressing-the-limiting-factor-and-providing-the-solution/

This study reported a potential early marker of myocardial infarction by the release into the circulation of damaged endothelial cells that are to be measured in patients suspected of severe ischemia in a clinical trial.  The question that I raised in my comment was whether this would have to be a special immunochemical assay of tagged cells, and if that were the case, would it be measured on an automated flow-based hemocytometer, which can differentiate several populations of cells – granulocytes, lymphocytes, red cells, platelets, immature granuloytes, BLASTS.  That would be a very practical extension of the technology for labs worldwide.

Abstract

Aims: To elucidate if endothelial dysfunction is an early CV risk marker in obese men and women with prediabetes.
Study Design: Cross-sectional study.

Place and Duration of Study: Clinical Research Unit, Pennington Biomedical Research Center, Baton Rouge, LA. United States.

Background: Overweight and obese status denotes an increasing adipose tissue burden which spills over into ectopic locations, including the visceral compartment, muscle and liver. Associated co-morbidities enhance cardiovascular (CV) risk. Endothelium which is the largest receptor-effector end-organ in our bodies, while responding to numerous physical and chemical stimuli maintains vascular homeostasis. Endothelial dysfunction (ED) is the initial perturbation, which precedes fatty streak known to initiate atherosclerosis: insidious process which often culminates as sudden catastrophic CV adverse event.

Methodology:  Asymptomatic men and women; [n=42] coming in after an overnight fast had demographic, anthropometric, clinical chemistry and

  • resting endothelial function (EF)
  • increased test finger peripheral arterial tone (PAT) relative to control;
    • expressed as relative hyperemia index (RHI)] assessments.

Results: Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) µU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg].

Obese adults [n=22] had

  • prediabetes [FPG, 106.5(3.5) g/dL],
  • hyperinsulinemia [INS 18.0(5.2) µU/ml],
  • insulin resistance [HOMA-IR .59(2.3)],
  • prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and
  • endothelial dysfunction [ED;
  • reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05].

Age-adjusted RHI correlated with BMI [r=-0.53; p<0.001]; however,

    • BMI-adjusted RHI was not correlated with age [r=-0.01; p=0.89].

Conclusion: Endothelial dysfunction reflective of cardiometabolic changes in obese adults can be an early risk marker for catastrophic CV events.

Keywords: Fasting plasma glucose; healthy adults; reverse cholesterol transport pathway; insulin resistance; body weight; relative hyperemia index.

ABBREVIATIONS

ADA: American Diabetes association; BMI: body mass index; CVD: cardiovascular disease; CV: cardiovascular; DBP: diastolic blood pressure; ED: endothelial dysfunction; EF: resting endothelial function; FPG: fasting plasma glucose; HOMA-IR: homeostasis model assessment; INS: insulin; JNC 7: Joint National Commission 7; LDL-C/HDL-C: low density lipoprotein cholesterol to high density lipoprotein; NCEP ATP III: National Cholesterol Education Program Adult Treatment Panel III; PAT: peripheral arterial tone; PreDM: prediabetes; PreHTN: prehypertension; PBRC: Pennington Biomedical Research Center; RHI: relative hyperemia index; SBP: systolic blood pressure; Total-C/HDL-C: total cholesterol to high density lipoprotein cholestrol; TG/HDL-C: triglycerides to high density lipoprotein cholesterol; WC: waist circumference.

Introduction

Healthy adults with no chronic medical conditions, on no prescription medications (n=24) and with low cardiovascular risk, in a randomized-order, cross-over clinical trial, with a 2 week washout period, exhibitd improved endothelial function (measured with flow mediated dilatation) with a diet rich in antioxidants (Franzini et al., 2012). Healthy over weight and obese volunteers with normal glucose appear to attenuate flow mediated dilation after high
glycemic index carbohydrate meals (Suessenbacher et al., 2011). In matched (age, work place, physical activity, tobacco use, blood pressure, serum lipids and family history of premature coronary artery disease) male shift and no shift workers, peripheral endothelial function (peripheral arterial tone (PAT) index obtained with the EndoPAT technique) was impaired in shift workers, suggesting elevated cardiovascular risk (Lavi et al., 2009).

Endothelial function thus appears to be an exquisitely sensitive marker for a variety of populations, under various conditions. Although endothelial function has been evaluated in numerous disease conditions and perturbed with a variety of agents, there has, to our knowledge, not been a comparison of resting endothelial function in free living healthy lean, overweight and obese subjects. Using a noninvasive assessment for resting endothelial function (by measuring the peripheral arterial tone, Bonetti et al., 2004), we tested the hypothesis that fasting glucose escalation in otherwise asymptomatic obese men and women is functionally reflected as endothelial dysfunction.

Endothelial Function

Assessment of resting endothelial function was done with the participant in fasting state, after having avoided stimulants (caffeine, tobacco, alcohol, exercise) for 12 hours, at the same fixed clock hour (range 8-10 AM), using the EndoPAT 2000 device manufactured by ITAMAR Medical®. This assessment technique has been previously validated (Bonetti et al., 2004), has been used in numerous (>250) peer reviewed publications (Carty et al., 2012; Kuvin et al., 2003) and has been in routine use in our clinical core. Briefly: subjects coming
in from home, after an overnight fast and having avoided stimulants for 12-hours, were placed in a supine position for 20 minutes in a quiet room before the test. A patented single use finger sleeve was then placed on the index finger of each hand to continuously measure peripheral arterial tone. A blood pressure cuff applied to the upper arm of the non-dominant arm (test arm) was then used to occlude the brachial artery for 5 minutes. This was followed by a rapid release. The dominant arm without any manipulation served as the control. The
built in, validated software integrated the data gathered from the finger sleeves of the control (undisturbed) and the test arms (during the baseline, occlusion and release phases), thus providing the relative hyperemia index (RHI) for the test arm. This flow mediated dilatation induced change in the test arm, relative to the control arm, served as the measure for endothelial function (RHI).

The subjects with desirable and overweight body weight were significantly younger [36.7(19.1) and 27.4(3.9) years, respectively], than those who were obese [53.2(11.6) years]. We performed correlations between the measure for endothelial function (RHI) and confounding factors like BMI, age and gender. Age-adjusted RHI correlated with BMI [r=- 0.53, p<0.001]; however, BMI-adjusted RHI was not associated with age [r=-0.01, p=0.89]. Fig. 1 depicts panels for the regression line for RHI as a function of age, (and BMI, glucose
and HOMA-IR, respectively) superimposed on a scatter plot. No correlation was observed between endothelial function and age (r²=0.07), while endothelial function was highly correlated with body mass index, glucose and insulin sensitivity (r²=0.3).

DISCUSSION

Asymptomatic obese adults with prediabetes (when compared to asymptomatic desirable weight and overweight adults with normal glucose), exhibit above the upper limits for desirable fasting plasma total cholesterol (>200mg/dL) and triglycerides (>150 mg/dL), but due to a relatively lower HDL-C display higher cardiac risk ratios (Total-C/HDL-C; p=0.05 and TG/HDL-C; p=0.02). A lower HDL-C and the elevated cardiac risk ratios are early clinical indicators for an impaired reverse cholesterol transport (RCT) pathway, a process by which cholesterol from the periphery is transported to the liver (Tall, 1998). The RCT pathway has been shown to be a sensitive indicator of the net flux (deposition vs. removal) of cholesterol homeostasis at the endothelium (Gupta et al., 1993; Tall et al., 2000). It is at the endothelium that the first fatty streaks, which over time deteriorate into atherosclerosis, have been shown to develop (Rosenfeld et al., 2000).

Impaired endothelial dysfunction is the first step in the process of atherosclerosis, even before the development of the fatty streak (Davignon, 2004; Ross 1999). These healthy obese men and women with prediabetes, prehypertension and impaired reverse cholesterol transport pathway were assessed to have impaired resting endothelial function, which is consistent with latent early onset cardiovascular disease.

We have demonstrated a high prevalence of isolated prediabetes or prehypertension and co-existing prediabetes and prehypertension, among the otherwise healthy US adults (Gupta et al., 2011). We have also elucidated that asymptomatic obese adults with overly heightened systemic inflammation, tend to have prediabetes and prehypertension (Gupta et al., 2010a). These individuals by various conventional measures (larger waist circumference, exacerbated systemic inflammation, higher insulin resistance, elevated triglycerides, lower high-density lipoprotein cholesterol, above average cardiac risk ratios and a significant co-existence of two or three concomitant metabolic risk factors) appear to be on an accelerated pathway towards early adverse cardiovascular events (Gupta et al., 2010a, 2010b). With this study we provide a dynamic, non-invasive, functional correlate: significant resting endothelial dysfunction, as an early biomarker for pre-atherosclerosis in obese adults with prediabetes.

Increased organ ectopic adipose burden especially in the muscle and liver appears to drive clinically recognizable adverse cardio metabolic changes (Hamdy et al., 2006). Increased inflammation (local and systemic) along with enhanced insulin resistance (liver, muscle) manifests as dysglycemia, dyslipidemia, excess reactive oxygen species, hyper-coagulablility and loss of blood pressure control (Gastaldelli et al., 2010).

We demonstrate an early impairment in the reverse cholesterol transport pathway, indicating a net deposition versus removal of cholesterol at the endothelium. In asymptomatic obese men and women with predisease  conditions (prediabetes and prehypertension) when contrasted with ideal bodyweight or overweight adults with normoglycemia and normal blood pressure, resting endothelial dysfunction can be an early warning sign for future catastrophic cardiovascular adverse events.

© 2012 Gupta et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

REFERENCES on circulating Endothelial Progenitor Cells as Biomarkers for Cardiovascular Disease and their Angiogenesis Potential.

Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964-967.

Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999;5:434-438.

Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430-436.

Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457-463.

Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.

Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001;103:2885-2890

Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004;109:220-226.

Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999-1007.

Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9:1370-1376.

Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-148.

Zhang H, Vakil V, Braunstein M, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005;105:3286-3294

Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194-1201.

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Effect of Dietary Magnesium Intake on Insulin Resistance

Reporter: Larry H. Bernstein, MD, FCAP

Dietary Magnesium Intake Improves Insulin Resistance among Non-Diabetic Individuals with Metabolic Syndrome Participating in a Dietary Trial

J Wang1,2,†, G Persuitte3,†, BC Olendzki2, NM Wedick2, …, and Yunsheng Ma 2,*
1 Department of Preventive Medicine, Medical School of Yangzhou University, Yangzhou 225001, China
2 Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
3 Division of Biostatistics and Health Services Research, Department of Quantitative Health Science, University of Massachusetts Medical School, Worcester, MA 01655, USA †

Nutrients 27 Sep 2013; 5(10):3910-3919; http://dx.doi.org/10.3390/nu5103910

Many cross-sectional studies show

  1. an inverse association between dietary magnesium and insulin resistance, but
  2. few longitudinal studies examine the ability to meet the Recommended Dietary Allowance (RDA)
  • for magnesium intake through food and
  • its effect on insulin resistance among participants with metabolic syndrome (MetS).

The dietary intervention study examined this question in 234 individuals with MetS. Magnesium intake was assessed using 24-h dietary recalls at baseline, 6, and 12 months.

  1. Fasting glucose and insulin levels were collected at each time point; and
  2. insulin resistance was estimated by the homeostasis model assessment (HOMA-IR).

The relation between magnesium intake and HOMA-IR was assessed using linear mixed models adjusted for covariates.

  • Baseline magnesium intake was 287 ± 93 mg/day (mean ± standard deviation), and
  • HOMA-IR, fasting glucose and fasting insulin were 3.7 ± 3.5, 99 ± 13 mg/dL, and 15 ± 13 μU/mL, respectively.

At baseline, 6-, and 12-months, 23.5%, 30.4%, and 27.7% met the RDA for magnesium. After multivariate adjustment,

    • magnesium intake was inversely associated with metabolic biomarkers of insulin resistance (P < 0.01).

Further, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower [odds ratio (OR): 0.29; 95% confidence interval (CI): 0.12, 0.72] in participants

  • in the highest quartile of magnesium intake than those in the lowest quartile.

For individuals meeting the RDA for magnesium,

  • the multivariate-adjusted OR for high HOMA-IR over time was 0.37 (95% CI: 0.18, 0.77).

These findings indicate that dietary magnesium intake is inadequate among non-diabetic individuals with MetS and suggest that

    • increasing dietary magnesium to meet the RDA has a protective effect on insulin resistance.

Keywords: magnesium; insulin resistance; metabolic syndrome; epidemiology

Cite This Article

Wang J, Persuitte G, Olendzki BC, Wedick NM, Zhang Z, Merriam PA, Fang H, Carmody J, Olendzki G-F, Ma Y. Dietary Magnesium Intake Improves Insulin Resistance among Non-Diabetic Individuals with Metabolic Syndrome Participating in a Dietary Trial. Nutrients. 2013; 5(10):3910-3919.

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Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker

Article Curator: Aviva Lev-Ari, PhD, RN

ClinicalTrials.gov identifier: NCT00005135

Other Study ID Numbers: 1005
Study First Received: May 25, 2000
Last Updated: April 13, 2009

Insulin Resistance Atherosclerosis Study (IRAS)

sponsored by National Heart, Lung, and Blood Institute (NHLBI)

Clinical Trial had the following purpose:  

To conduct a multicenter study of the relationship between insulin resistance and cardiovascular disease (CVD) and its risk factors in a tri-ethnic (African-American, Hispanic, and non-Hispanic white) population aged 40 to 69 years at baseline. Also, to identify the genetic determinants of insulin resistance and visceral adiposity.

Conditions

  • Cardiovascular Diseases
  • Atherosclerosis
  • Diabetes Mellitus
  • Heart Diseases
  • Obesity
  • Insulin Resistance

List of Investigators and Publications

http://www.clinicaltrials.gov/ct2/show/NCT00005135?term=Insulin+Resistance+Atherosclerosis+Study&rank=1

Results of the Completed Clinical Trial

were presented at European Association for the Study of Diabetes (EASD) 49th Annual Meeting

September 23 – 27, 2013; Barcelona, Spain

http://www.medscape.com/viewcollection/32906

by Dr Carlos Lorenzo (University of Texas Health Science Center, San Antonio) in an interview with Heartwire

http://www.medscape.com/viewarticle/811536

Study Parameters

#1

Patient population

IRAS enrolled 863 nondiabetic subjects (age 40–69) at four centers. Insulin sensitivity and acute insulin response were measured at baseline and at regular intervals over a five-year follow-up period. Diabetes and IGT were defined by

  • current fasting and
  • two-hour plasma glucose criteria
  • and/or use of glucose-lowering medications

Of the 863 subjects, the number of people in IRAS who fell into this high-calcium group was relatively small—about 15% to 17% of the study population.

Respectively, Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker for Diabetes-risk Forecasts is applicable for 15% -17% of the Patient population, thus, the prediction power of the new Biomarker is defined by this percentage.
#2
Comorbidities
Cardiovascular disease and diabetes share many of the same risk factors and that calcium has also been linked with

  • lower insulin sensitivity,
  • impaired glucose tolerance (IGT), and the
  • metabolic syndrome

#3

Tree Key factors involved in Calcium Regulation NOT studies by Insulin Resistance Atherosclerosis Study (IRAS)

The study did not address

  • vitamin D – involved in calcium regulation
  • parathyroid hormone levels – involved in calcium regulation
  • physical-activity levels, which are also known to have an impact on serum calcium

#4

Hypothesis was that serum calcium may also play some role in the development of diabetes
Dr. Lorenzo told heartwire:
Whether serum calcium plays a causative role in the development of diabetes or is a marker for other adverse processes remains unclear; “we can’t answer that question,”  “There is a relationship, but we can’t yet determine why this is happening.”

Study Results Highlights

  • High concentrations of serum calcium—but not necessarily calcium intake—are associated with an increased risk of developing type 2 diabetes, results from the Insulin Resistance Atherosclerosis Study (IRAS) show. Moreover, calcium concentration appears to act independently of glucose, insulin secretion, and insulin resistance
  • relationship between calcium concentration and incident diabetes was statistically significant but did not follow a linear relationship. Only subjects with the highest concentrations of calcium (>2.38 mmol/L) had a significantly increased risk of developing diabetes. After controlling for
    • age,
    • sex,
    • race/ethnicity,
    • family history of diabetes,
    • body-mass index (BMI),
    • plasma glucose levels,
    • insulin-sensitivity index,
    • acute insulin response,
    • estimated glomerular filtration rate (eGFR), and
    • diuretic drugs,

    researchers found that only patients at the highest levels of serum calcium (>2.5 mmol/L) showed a statistically significant increase in incident diabetes.

  • A similar, nonlinear relationship was seen between the highest category of serum calcium and impaired fasting glucose.
  • Of note, in models that looked at albumin-adjusted calcium concentration as well as total calcium intake, no statistically significant relationship with five-year diabetes risk was seen
  • In the past, explained Lorenzo, researchers have speculated that the link between calcium and diabetes is related to insulin resistance or insulin secretion. “Our study shows that people with serum calcium that is pretty much in the normal range, but in the upper-normal range—those people are at higher risk for diabetes. And that, most probably, is not related to their metabolic status defined by their obesity or their insulin resistance or their insulin secretion.”
  • Calcium Intake Not Linked With Diabetes IncidenceThe findings on calcium intake are also important, he noted, since it shows that high calcium intake, per se, is not problematic; rather, it is the body’s ability to regulate calcium that seems to be at issue.
  • Dr, Lorenzo suspect [serum calcium levels] won’t add much to their prediction equations, but “if you have someone in the clinic who has those levels of calcium, that person is going to be at higher risk for diabetes,” he concluded.

Other RELATED articles published on this Open Access Online Scientific Journal, include the following:

Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

MGH’s Largest-ever Genetic Study of Five Psychiatric Disorders: Variation in SNPs in Two Genes involved in Calcium-Channel Signaling

https://pharmaceuticalintelligence.com/2013/02/28/mghs-largest-ever-genetic-study-of-five-psychiatric-disorders-variation-in-snps-in-two-genes-involved-in-calcium-channel-signaling/

Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

https://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

Calcium Regulation Key Mechanism Discovered: New Potential for Neuro-degenerative Diseases Drug Development

https://pharmaceuticalintelligence.com/2013/01/17/calcium-regulation-key-mechanism-discovered-new-potential-for-neuro-degenerative-diseases-drug-development/

Calcium dependent NOS induction by sex hormones: Estrogen

https://pharmaceuticalintelligence.com/2012/10/03/calcium-dependent-nos-induction-by-sex-hormones/

List of TEN articles on Dysfunction of Calcium Release Mechanism and Cardiovascular Diseases

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmiasand Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

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