RxPG News : Insulin Resistance

PAI-1 is the link between diabetes and cardiovascular disease

Wed, 25 Feb 2009 00:30:03 PST

( from http://www.rxpgnews.com ) Researchers at the University of Vermont Cardiovascular Research Institute, Colchester, Vermont have found that increased expression in the heart of plasminogen activator inhibitor type-1 (PAI-1) is profibrotic. The results, which appear in the March 2009 issue of Experimental Biology and Medicine, implicate PAI-1 overexpression, known to accompany insulin resistance and type 2 diabetes, as a factor contributing to the high incidence of heart failure after myocardial infarction in people with diabetes. The research team, Dr. A.K.M. Tarikuz Zaman, a research associate, Mr. Christopher J. French, medical and graduate student, Dr. David J. Schneider, Professor of Medicine and Director of the Cardiology and Vascular Biology Units, and Dr. Burton E. Sobel, Professor of Medicine and Director of the Cardiovascular Research Institute, performed studies in 10 week old mice subjected to coronary occlusion. Controls and PAI-1 overexpressing mice congenic on a C57BL6 background had comparable PAI-1 content in left ventricular myocardium despite a marked elevation of PAI-1 in plasma in the latter. 6 weeks after coronary occlusion the PAI-1 overexpressing mice exhibited a 2-fold increase in left ventricular (LV) PAI-1 content. Histochemical analysis demonstrated 33% more LV fibrosis as well. The increased fibrosis associated with increased PAI-1 was accompanied by functional derangements including diminished LV wall thickness in both diastole and systole, increased end systolic LV dimensions, depressed fractional shortening, a greater impairment of LV segmental function, and greater transmitral E-wave amplitude.

In summary, overexpression of PAI-1 in the heart altered the response of the left ventricle to myocardial infarction. It led to increased expression of PAI-1 late after coronary occlusion accompanied by increased fibrosis and functional derangements indicative of both systolic and diastolic dysfunction. Dr. Sobel said that "in concert with our previously reported findings demonstrating increased expression of PAI-1 in the heart in transgenic mice rendered insulin resistant, these results suggest that the markedly increased incidence and severity of heart failure following myocardial infarction in patients with insulin resistance and type 2 diabetes may reflect in part adverse consequences of increased PAI-1 expression in the heart predisposing to fibrosis and impairment performance of the left ventricle."

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "these elegant studies by Dr. Sobel and colleagues provide substantial insight into the mechanisms by which type 2 diabetes, with the resulting increase in PAI-1 in the heart, can lead to increased incidence and severity of heart failure following myocardial infarction. This is a major step forward in our understanding of the linkage between diabetes and cardiovascular disease".

Insulin inhibits resistin expression and secretion

Wed, 16 Jan 2008 14:07:06 PST

( from http://www.rxpgnews.com ) Obesity is a worldwide health problem directly linked to several diseases such as hypertension and type 2 diabetes. Resistin is a cysteine-rich hormone mainly secreted by adipose tissues and may form a biochemical link between obesity and type 2 diabetes.

It has been reported insulin inhibits resistin mRNA level in 3T3-L1, which does not support a role for resistin in insulin resistance. Does resistin play a role in insulin resistance? Is insulin the major regulator of resistin?

A research article to be published on January 7, 2008 in the World Journal of Gastroenterology (volume 14, issue 1) addresses these questions. The research team led by Dr. Guo Xi-Rong studied the resistin action in vitro and resistin secretion. In addition to this, diet-induced obese rats were used to study the relationship between insulin, resistin and insulin resistance.

One result reported by the investigators was resistin expression and secretion was enhanced during 3T3-L1 pre-adipocytes differentiation, insulin inhibits resistin expression and secretion. Insulin does not support a role for resistin in insulin resistance.

The result showed resistin induces cellular insulin resistance in H4IIE hepatocytes and L6 rat myoblasts. Serum resistin negatively correlates to insulin sensitivity, not to serum insulin in diet-induced obesity rats.

The results of this study suggest insulin inhibits resistin secretion and resistin induces insulin sensitivity. In vivo study shows serum resistin correlated to rat insulin sensitivity, so insulin is not the major regulator of resistin. Resistin induced hepatocytes insulin resistance takes part in diet induced insulin resistance.

Insulin resistance in early teens may predict diabetes

Tue, 22 Aug 2006 20:25:37 PST

( from http://www.rxpgnews.com ) The body's decreased response to insulin beginning as early as age 13 may mean increased cardiovascular disease risk by age 19, according to research reported in Hypertension: Journal of the American Heart Association.

The finding indicates that the prevalence of atherosclerotic cardiovascular disease risk factors and type 2 diabetes (both of which are related to obesity and are increasing as today's children reach adulthood) also are related to insulin resistance independent from obesity, said Alan R. Sinaiko, M.D., lead author of the study and professor of pediatrics at the University of Minnesota Medical School in Minneapolis. After screening blood pressure, height and weight in more than 12,000 5th through 8th grade students in Minneapolis public schools, 357 students (average age 13) were recruited for the study. Two-hundred twenty-four participants completed the study. The participants were 58 percent male and 83 percent white.

At baseline the children underwent a complete physical examination including measurements of blood pressure, height, weight, percentage of body fat, high density lipoprotein cholesterol (HDL-C), triglycerides and fasting insulin levels. The students were also categorized by stage of sexual development. Sinaiko and colleagues tracked insulin resistance with a series of insulin clamp studies first at age 13, then 15 and again at 19.

"The insulin clamp is considered the gold standard to measure insulin resistance, a precursor to type 2 diabetes," Sinaiko said. "Insulin regulates sugars, starches, fats and proteins in the body. When cells become resistant to the effects of insulin, insulin levels increase to regulate metabolism." This clamp technique infuses insulin and glucose into the blood and measures the resulting glucose and insulin levels. Those who require lower amounts of glucose, indicating lower uptake of glucose into muscle cells, were considered insulin resistant, he said.

The insulin clamp tests were repeated at age 15 on 309 participants and again at age 19 on 224 participants. Occurring together, insulin resistance, high blood pressure, low HDL-C, high triglycerides and obesity are defined as the metabolic or insulin resistance syndrome, which Sinaiko and other researchers say may trigger type 2 diabetes and atherosclerosis. Sinaiko said the correlation between insulin resistance at age 13 and age 19 was highly significant. Insulin resistance at age 13 predicted high systolic blood pressure, which is associated with risk of stroke, and high triglycerides at age 19. For every unit increase in insulin resistance there was a 0.41 millimeters of mercury (mm Hg) increase in systolic blood pressure and 1.91 milligrams per deciliter (mg/dl) increase in triglycerides. "This is the first study to show insulin resistance by itself is a significant predictor of cardiovascular disease, beginning in childhood," Sinaiko said.

Race may be risk factor for insulin resistance

Tue, 27 Jun 2006 02:56:37 PST

( from http://www.rxpgnews.com ) Black women even if their weight is normal may be at increased risk for insulin resistance, a condition associated with diabetes, high blood pressure, and heart vessel disease, according to new research by Wake Forest University School of Medicine.

"It is well known that obesity is a contributor to insulin resistance," said senior researcher Jorge Calles-Escandon, M.D. "Our research suggests that race may also be an important factor. Almost half of lean, black women had insulin resistance double the rate in Hispanic or Caucasian women."

The goal of the study was to see how obesity relates to insulin resistance in three ethnic groups: black, Caucasian and Hispanic. Insulin resistance is when the body does not effectively use the hormone insulin to process glucose, forcing the pancreas to produce more insulin. Researchers analyzed data from the Insulin Resistance Atherosclerosis Study (IRAS), designed to assess relationships between insulin resistance and cardiovascular disease in a large multi-ethnic population.

For the study, the researchers divided data from female IRAS participants into different groups based on body mass index (BMI), a measure of body fat based on height and weight. A BMI of less than 25 is considered "normal." For example, a woman who weighs 148 and is 5 feet, 6 inches, has a BMI of 25.

The analysis revealed that 47 percent of black women of normal weight had insulin resistance, compared to less than 20 percent of the Hispanic or Caucasian women.

"Our research suggests that race, in addition to obesity, is an important contributor to the development of insulin resistance and possibly to type 2 diabetes," said Jennifer Wolfgang, D.O., an endocrinology fellow, who presented the results.

Both insulin resistance and the likelihood of developing type 2 diabetes increase as obesity increases, but it was not previously known that race alone may influence insulin resistance. Type 2 diabetes, the most common form, is when the body does not produce enough insulin or does not respond to even very high levels of insulin, which causes glucose to build up in the blood.

It is not know how many people with insulin resistance develop diabetes and cardiovascular disease, but it is assumed that treating insulin resistance with weight loss and exercise will help prevent those diseases.

Calles-Escandon, an associate professor of endocrinology, said that the results suggest that the definition of "obesity" may need to be redefined in black women. "If the results hold true, black women may need to be evaluated and treated for insulin resistance and cardiovascular disease even at weight not considered obese by current standards," he said.

He said additional research is needed to explore how obesity relates to insulin resistance in men, as well as whether the women with insulin resistance have a higher percentage of body fat, or body fat that is distributed differently, from the Caucasian or Hispanic women.

Other potential areas of research include determining if certain genes in blacks lead to insulin resistance, and whether the insulin resistance is accompanied by other changes that may promote diabetes, cardiovascular disease and diabetes, including reduced elasticity of vessels or deposits of calcium in the vessels leading to the heart.

IRAS involved 1,625 people from San Antonio, Texas, San Luis Valley, Colo., and Oakland and Los Angeles, Calif.

Elevation of fat-derived molecule RBP4 foretells early insulin resistance

Thu, 15 Jun 2006 16:38:37 PST

( from http://www.rxpgnews.com ) A study in the June 15 issue of The New England Journal of Medicine (NEJM) reveals that elevated levels of a molecule called RBP4 (retinol binding protein 4) can foretell early stages in the development of insulin resistance, a major cause of type 2 diabetes as well as cardiovascular disease.

The new findings, led by researchers at Beth Israel Deaconess Medical Center (BIDMC), offer a potential new target for the development of anti-diabetic therapies to lower serum RBP4 levels as well as an early means of identifying individuals who are at risk of developing diabetes before the onset of overt disease.

"Type 2 diabetes is a rapidly increasing epidemic in the Western world," explains senior author Barbara Kahn, MD, Chief of the Division of Diabetes, Endocrinology and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. "Since it is now occurring even in childhood, predictions indicate that it could shorten lifespan in the U.S. for the first time in more than a century."

Insulin resistance develops when the body's muscles, fat and liver cells lose the ability to respond to the hormone insulin. Because insulin is necessary to enable the body to take up sugar from blood and convert it into energy, this impairment results in a buildup of glucose in the bloodstream.

"Insulin resistance not only predisposes individuals to type 2 diabetes, it is also a major risk factor for cardiovascular disease," adds co-lead author Timothy Graham, MD, an investigator in the Kahn laboratory. "Unfortunately, in the clinical setting, it is often difficult to distinguish individuals with and without insulin resistance."

Last year, in a study conducted in animals, Kahn's laboratory made the discovery that RBP4, a protein secreted from fat, can cause insulin resistance. Prior to this, the molecule was recognized only for its role in the transport of vitamin A.

In this new research, Graham, together with co-lead author Qin Yang, MD, PhD, set out to determine whether levels of RBP4, as measured in blood, correlate with the presence or absence of insulin resistance. (Study subjects represented three separate cohorts from San Diego, California; Goteberg, Sweden; and Leipzig, Germany.)

They first studied individuals with either obesity, impaired glucose tolerance (a "pre-diabetic" state), or with type 2 diabetes, comparing the blood levels of RBP4 in these insulin-resistant subjects with levels found in non-obese healthy subjects. Their results showed that not only were RBP4 levels higher in all cases in which insulin resistance was high, but that elevated serum RBP4 was also closely associated with components of the metabolic syndrome, including increased body mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure, as well as decreased levels of high-density lipoprotein (HDL), or good, cholesterol.

The study was then extended to subjects with normal body weight and normal blood glucose, but with a strong family history of type 2 diabetes. "These are people who appear healthy, but have a high risk of developing diabetes due to their genetic background," explains Ulf Smith, MD, PhD, of Sahlgrenska Hospital, Goteberg, Sweden, where this group of subjects was based. As predicted, the investigators found elevated RBP4 levels among this group as well.

Finally, the authors tested whether a therapeutic intervention in this case, exercise could lower RBP4 levels and increase insulin sensitivity. They found that all of the people who improved their insulin sensitivity with exercise also lowered their serum RBP4 levels. Among the one-third of the subjects who did not improve their insulin sensitivity, neither did RBP4 levels go down.

"Collectively, these findings tell us that RBP4 is a useful marker for therapeutic improvement and that this protein could play a causal role in insulin resistance in humans, just as our lab previously showed in mice," says Kahn. Furthermore, she adds, because RBP4 levels consistently corresponded with insulin resistance -- even among lean subjects whose genetic risk for the development of diabetes might otherwise be overlooked -- this protein could be an important marker for type 2 diabetes among the general population.

"Being able to determine diabetes risk well before the onset of symptoms could provide an important opportunity for patients to take preventive measures," she adds. "For those who are overweight or sedentary, this could mean making changes to their diet and fitness routines. For those who are lean and fit, but have a family history of type 2 diabetes, this could mean taking antidiabetic medication. Either way, these findings could help clinicians to better manage this growing epidemic."

Insulin Resistance Linked to Pancreatic Cancer

Wed, 14 Dec 2005 17:02:38 PST

( from http://www.rxpgnews.com ) Higher insulin concentrations and insulin resistance are associated with an increased risk of pancreatic cancer in men, according to a study in the December 14 issue of JAMA.

Based on the findings from several retrospective and prospective observational studies, type 2 diabetes mellitus and glucose intolerance are fairly consistent, albeit somewhat controversial, risk factors for pancreatic cancer, according to background information in the article. This is because it has been unresolved whether diabetes mellitus is involved in pancreatic carcinogenesis or the result of subclinical malignancy. One biologically plausible mechanism whereby type 2 diabetes mellitus may be related to pancreatic carcinogenesis is through the growth-regulatory effects of insulin. Experimental studies show that insulin has growth promoting effects on pancreatic cancer cells and patients with type 2 diabetes mellitus are known to exhibit hyperinsulinemia, during the early stages of their disease.

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (1985-1988) of male smokers previously reported a significant 2-fold increased risk between self-reported diabetes mellitus and pancreatic cancer. Rachael Z. Stolzenberg-Solomon, Ph.D., of the National Cancer Institute, Department of Health and Human Services, Rockville, Md., and colleagues examined a cohort from the ATBC study to determine whether fasting serum insulin and glucose concentrations were associated with risk for incident pancreatic cancer. The study consisted of 29,133 male Finnish smokers ages 50 to 69 years. The study included 400 randomly sampled subcohort control participants and 169 incident pancreatic cancer cases that occurred after the 5th year of follow-up. All participants were followed up through December 2001 (up to 16.7 years of follow-up).

The researchers found that after adjustment for age, years smoked, and body mass index, higher concentrations of glucose, insulin, and insulin resistance tended to show positive dose-response associations with pancreatic cancer. Biochemically defined diabetes mellitus and insulin concentration in the highest quartile demonstrated significant 2-fold increased risks. There were significant interactions between quartile-categorized glucose, insulin, and insulin resistance and pancreatic cancer by follow-up time, such that risks were greater among the cases that occurred with longer follow-up time.

"In conclusion, our results support the hypothesis that higher insulin concentrations and insulin resistance may be a mechanism that explains the associations between diabetes mellitus, higher glucose concentration, and pancreatic cancer observed in previous studies. Although based solely on male smokers, our findings for glucose and biochemical-defined diabetes mellitus are consistent with previous studies conducted in diverse populations that have included women and nonsmokers," the authors write.

"The associations for insulin and insulin resistance reported herein require confirmation and along with observations of other studies could potentially have important implications for nutrition and treatment-related cancer preventive strategies that modify or interfere with the insulin resistance pathway to help decrease the burden from this devastating disease. Lifestyle changes to decrease glucose and insulin concentrations through weight reduction, increasing physical activity, and diet such as decreasing saturated fat intake, and identification of other modifiable factors that may contribute to higher glucose and insulin concentrations could possibly impact pancreatic cancer development, as well as other cancer and chronic disease," the researchers write.

Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of langerhans

Mon, 05 Sep 2005 13:42:38 PST

( from http://www.rxpgnews.com ) Insulin resistance is a fundamental factor in non-insulin-dependent diabetes. Prolonged activation of the insulin receptor, inflammation, and excessive insulin levels can induce insulin resistance by decreasing levels of insulin receptor substrate (IRS) proteins.

However, the mechanism(s) underlying the destruction of IRS proteins and subsequent resistance to insulin have not been well defined. Proteins of the SOCS family have been implicated in the negative regulation of insulin signaling and also regulate cytokine signaling by targeting proteins for degradation by the proteasome. In particular, the function for the SOCS-7 protein was previously unclear.

In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Paul Rothman and colleagues from the University of Iowa demonstrate that SOCS-7 regulates insulin signaling by associating with several components of the insulin-signaling cascade.

The researchers generate SOCS-7-deficient mice and show that cells lacking SOCS-7 have increased IRS protein levels and prolonged IRS activation. SOCS-7 deficient mice are more insulin sensitive as measured by a glucose tolerance test and an insulin tolerance test. In addition, SOCS-7-deficient mice exhibit increased growth of pancreatic islets with increased fasting insulin levels and hypoglycemia. As one of the only mouse knockout models featuring increased insulin sensitivity, these data suggest that SOCS-7 is a potent regulator of glucose homeostasis and insulin signaling.

Insulin Resistance May Be the Result of Mitochondrial Dysfunction

Tue, 16 Aug 2005 20:41:38 PST

( from http://www.rxpgnews.com ) The role of insulin resistance (IR) in type 2 diabetes, the most frequently encountered metabolic disorder in the world, has attracted much attention in recent years. Virtually all patients with type 2 diabetes have IR, which usually appears some 1020 years before the disease itself. Although the existence of the relationship between IR and type 2 diabetes is well recognized, the underlying mechanisms are poorly understood. A study by Kitt Falk Petersen and colleagues provides important new information on the underlying pathogenic mechanisms that lead to the development of IR.

Recent findings have suggested that inherited defects in mitochondrial oxidative phosphorylation activity might play a key role in the development of IR. Studies have demonstrated a relationship between dysregulated fatty acid metabolism, fat accumulation in muscle cells, and IR in skeletal muscle. This fat accumulation appears to interfere with insulin signaling, resulting in reduced insulin-stimulated muscle glucose transport activity and decreased muscle glycogen synthesis. Magnetic resonance spectroscopy (MRS) studies have found reduced basal rates of muscle mitochondrial ATP production, associated with increased intramyocellular lipid content. Consistent with these results, microarray studies have found a coordinated reduction in PGC-1á-responsive genes in patients with obesity and type 2 diabetes and their overweight first-degree relatives.

Building on these findings, Petersen and colleagues examined insulin-stimulated rates of muscle ATP synthesis and phosphate transport, to investigate whether mitochondrial function is affected not only in the fasting state but also during insulin stimulation and to determine whether inherited defects in mitochondrial oxidative phosphorylation activity might be responsible for IR.

Participants in the study were in their late 20s, lean, nonsmoking individuals with IR who were offspring of parents with type 2 diabetes. The participants were thus selected to be free of other risk factors for IR such as obesity and smoking. Such individuals are ideal for examining the earliest metabolic defects responsible for the pathogenesis of IR since they have none of the confounding factors that are likely to be present in patients with type 2 diabetes. A metabolic defect in this group is likely to be an early event of genetic origin and, therefore, is potentially a primary cause of the later development of diabetes. The individuals in the control group were healthy, nonsmoking, and matched for age and weight to the individuals in the IR group. Insulin was administered using a hyperinsulinemic-euglycemic clamp, and rates of mitochondrial phosphorylation activity (muscle ATP synthesis) were assessed by MRS.

Rates of insulin-stimulated glucose uptake were decreased by approximately 50% in the individuals with IR compared to the controls and were associated with an approximately 2-fold increase in intramyocellular lipid content. In the control individuals, rates of ATP synthesis increased by approximately 90% during the hyperinsulinemic-euglycemic clamp. In contrast, insulin-stimulated rates of muscle mitochondrial ATP synthesis increased by only 5% in the individuals with IR. This small increase in muscle mitochondrial ATP synthesis in the individuals with IR was associated with a severe reduction of insulin-stimulated increases in intramyocellular phosphorus concentrations.

The authors say their study provides further evidence that IR in skeletal muscle of individuals with IR who are offspring of parents with type 2 diabetes may be related to defects in mitochondrial dysfunction. Furthermore, there were also severe defects in insulin-stimulated phosphate transport into skeletal muscle in the individuals with IR, which may be part of the defect leading to impaired ATP synthesis in the muscle of these individuals.

The implications of the study are also discussed in a Perspective by Anton Wagenmakers (DOI: 10.1371/journal.pmed.0020289). Although he suggests that the defects underlying IR are likely also to involve organs other than muscle, he notes the clinical relevance of the main finding, which might explain the weight maintenance problems that individuals with obesity and IR have.