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The Liver, Muscle, And Fat Tissue Are All Prone To Insulin Resistance Due To Fat Build-up

High-fat Diet-induced Insulin Resistance In Single Skeletal Muscle Fibers Is Fiber Type Selective

High-fat Diet-induced Insulin Resistance In Single Skeletal Muscle Fibers Is Fiber Type Selective

Skeletal muscle is the major site for insulin-stimulated glucose disposal, and muscle insulin resistance confers many negative health outcomes. Muscle is composed of multiple fiber types, and conventional analysis of whole muscles cannot elucidate fiber type differences at the cellular level. Previous research demonstrated that a brief (two weeks) high fat diet (HFD) caused insulin resistance in rat skeletal muscle. The primary aim of this study was to determine in rat skeletal muscle the influence of a brief (two weeks) HFD on glucose uptake (GU) ± insulin in single fibers that were also characterized for fiber type. Epitrochlearis muscles were incubated with [3H]-2-deoxyglucose (2DG) ± 100 µU/ml insulin. Fiber type (myosin heavy chain expression) and 2DG accumulation were measured in whole muscles and single fibers. Although fiber type composition of whole muscles did not differ between diet groups, GU of insulin-stimulated whole muscles from LFD rats significantly exceeded HFD values (P < 0.005). For HFD versus LFD rats, GU of insulin-stimulated single fibers was significantly (P < 0.05) lower for IIA, IIAX, IIBX, IIB, and approached significance for IIX (P = 0.100), but not type I (P = 0.776) fibers. These results revealed HFD-induced insulin resistance was attributable to fiber type selective insulin resistance and independent of altered fiber type composition. Skeletal muscle is the major site for insulin-stimulated glucose disposal1, and skeletal muscle insulin resistance is a primary and essential event in the progression to type 2 diabetes2. Even in the absence of type 2 diabetes, insulin resistance confers negative health outcomes3. It is important to understand the processes responsible for insulin resistance of the skeletal muscle to develop interventions Continue reading >>

Insulin Resistance: A Vicious Circle Of Excess Fat

Insulin Resistance: A Vicious Circle Of Excess Fat

Every day I see patients I talk about insulin resistance and how it leads to diabetes. I have based my conversations, on what I thought was the best data. Now that I read Insulin Resistance: A Vicious Circle Of Excess Fat, by Phil Wood DVM, MS, PhD I realize that I am going to have to change a few of my statements as there are some facts you won’t want to miss. Insulin Resistance: A Vicious Circle Of Excess Fat Phillip Wood DVM, MS, PhD Insulin resistance is a common feature in patients who are obese or who have metabolic syndrome or type 2 diabetes. Insulin-resistant patients require higher than normal amounts of insulin to maintain normal blood glucose concentrations. The development of insulin resistance is complex, and many of its mechanisms are poorly understood. However, a common denominator in insulin-resistant patients is excess fatty acids (1), and insulin sensitivity is increased by any activity that reduces fatty acids in the tissues of the body. Such activities include increasing exercise with or without weight loss, reducing visceral adiposity with weight loss, or taking drugs that reduce fatty acids (thiazolidinediones, commonly known as “glitazones,” fibrates or metformin). The bottom line is that clearing the body of excess fat increases insulin sensitivity and, thus, decreases symptoms associated with insulin resistance. Often, insulin resistance is thought of as a focal process restricting the uptake of glucose as accomplished by muscle and mediated by insulin. It is true that muscle is a major location for insulin-mediated glucose uptake; however, uptake of glucose by muscle is only one of many metabolic processes that are disrupted by insulin resistance. I want to focus on three of those processes to demonstrate the vicious circle of insulin re Continue reading >>

Whole-body Insulin Resistance In The Absence Of Obesity In Fvb Mice With Overexpression Of Dgat1 In Adipose Tissue

Whole-body Insulin Resistance In The Absence Of Obesity In Fvb Mice With Overexpression Of Dgat1 In Adipose Tissue

Insulin resistance is often associated with obesity. We tested whether augmentation of triglyceride synthesis in adipose tissue by transgenic overexpression of the diacylglycerol aclytransferase-1 (Dgat1) gene causes obesity and/or alters insulin sensitivity. Male FVB mice expressing the aP2-Dgat1 had threefold more Dgat1 mRNA and twofold greater DGAT activity levels in adipose tissue. After 30 weeks of age, these mice had hyperglycemia, hyperinsulinemia, and glucose intolerance on a high-fat diet but were not more obese than wild-type littermates. Compared with control littermates, Dgat1 transgenic mice were both insulin and leptin resistant and had markedly elevated plasma free fatty acid levels. Adipocytes from Dgat1 transgenic mice displayed increased basal and isoproterenol-stimulated lipolysis rates and decreased gene expression for fatty acid uptake. Muscle triglyceride content was unaffected, but liver mass and triglyceride content were increased by 20 and 300%, respectively. Hepatic insulin signaling was suppressed, as evidenced by decreased phosphorylation of insulin receptor-β (Tyr1,131/Tyr1,146) and protein kinase B (Ser473). Gene expression data suggest that the gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were upregulated. Thus, adipose overexpression of Dgat1 gene in FVB mice leads to diet-inducible insulin resistance, which is secondary to redistribution of fat from adipose tissue to the liver in the absence of obesity. Obesity and insulin resistance are complex polygenic disorders that are manifest in a permissive environment where increased energy intake is prevalent. However, increased energy storage by itself, when confined in adipose tissue, is not a sufficient cause of tissue/organ dysfunction and insulin res Continue reading >>

The Role Of Fatty Acids In Insulin Resistance

The Role Of Fatty Acids In Insulin Resistance

Abstract Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin resistance appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs. Keywords Insulin resistanceInflammationFatty acidsPalmitic acidOmega-3 fatty acidsHypothalamusAdipose tissueLiverMuscleEndotoxemia Introduction The human body has developed an extraordinary number of systems to maintain stable blood glucose and to avoid broad swings in its level. These systems include hormones that are directly or indirectly generated by the diet. These hormones sense dietary nutrients and send appropriate neural signals to the brain (specifically the hypothalamus) to orchestrate fuel usage for either oxidation into energy or long-term storage. The central hormone involved in this metabolic communication system is insulin. However, increased inflammation can disturb these complex communication systems eventually leading to metabolic defects (obesity, metabolic syndrome, and diabetes). Insulin is the primary regulator of carbohydrate, fat, and protein metabolism [1–3]. It inhibits lipolysis of stored fat in the adipose tissue and gluconeogenesis in the liver, it stimulates the translocation of the GLUT-4 protein to bring glucose into the muscle cells along with gene expression of proteins required for the optimal cellular function, cellular repair, and growth, and it indicates the metabolic availability of various fuels to the brain. Continue reading >>

Review Article Regulation Of Obesity And Insulin Resistance By Nitric Oxide

Review Article Regulation Of Obesity And Insulin Resistance By Nitric Oxide

Highlights • Obesity is a major pandemic of the 21st century. • Decreased eNOS (NOS3) activity and abundance are commonly observed in obesity. • eNOS-derived NO has an antiobesogenic effect. • iNOS (NOS2) promotes insulin resistance. • NO derived from nNOS (NOS1) appears to regulate appetite. Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease. Graphical abstract Download high-res image (324KB) Download full-size image 3-NT 3-nitrotyrosine ADMA asymmetric dimethyl arginine Akt protein kinase B AMPK AMP-activated protein kinase BAT brown adipose tissue BH2 dihydrobiopterin BH4 tetrahydrobi Continue reading >>

What Causes The Insulin Resistance Underlying Obesity?

What Causes The Insulin Resistance Underlying Obesity?

Go to: NOT ALL FORMS OF OBESITY RESULT IN INSULIN RESISTANCE Obesity is the excessive growth of adipose tissue depots arising from the chronic consumption of calories in excess of the energetic needs of the individual. In humans, the expansion of adipose depots results from increased numbers of individual adipocytes (hyperplasia), and from the hypertrophy of adipocytes, in a depot-dependent fashion [3]. Importantly, there is a large individual variation in the size and expandability of different adipose tissue depots in humans. This factor is critically important in understanding the relationship between obesity and insulin resistance, as expansion of some depots is associated with increased risk, whereas expansion of others is associated with decreased risk [4]. Each standard deviation (SD) increase in subcutaneous adipose tissue mass decreases the odds of insulin resistance by 48%, whereas a SD increase in visceral adipose tissue mass increases the odds of insulin resistance by 80% [5▪]. These findings can explain the existence of ‘benign’ and ‘malign’ obesity wherein insulin resistance is not observed in all individuals with high BMIs. They may also explain the very high incidence of insulin resistance and diabetes in ethnic populations that display relatively low BMIs associated with high waist circumferences or waist-to-hip ratios, reflecting elevated visceral obesity [6]. In this context, the mechanisms that control the expandability of subcutaneous adipose tissue, including its high capacity for adipocyte differentiation and lipid storage may be key factors in determining diabetes risk in obesity [7]. The enhanced capacity for formation of adipocytes, inferred by the presence of hyperplasia in subcutaneous adipose tissue [8], correlates with decreased r Continue reading >>

Are Your Weight Issues Tied To Insulin Resistance?

Are Your Weight Issues Tied To Insulin Resistance?

Frequently, a new client will walk into my office knowing he or she needs to lose weight, get in shape and improve their health. Perhaps they feel sluggish and are hungry a good part of the day, and nothing they do makes a difference. Multiple diet regimes, exercise programs, lose-weight-quick gimmicks — they’ve tried them all and are just fed up. With no visible results, many are still searching for the root of the problem, which could actually be insulin resistance. Not until the last 10 years did many health care professionals really understand what it is and its impact on the body. It affects metabolism, hunger levels and zeal for life, and if untreated, can turn into diabetes. A Key That Won’t Turn Simply put, insulin is the key that unlocks the cell for sugar to get in, which in turn enables your body to use the food you consume. However, somewhere along the line, the key either gets stuck or has difficulty getting into the lock. Or, if it does get in, it can’t turn the lock, hence the term “resistant.” If your body develops a resistance to insulin, you are not able to utilize the food you take in, which can increase your fatigue and your cravings for ever-increasing amounts of carbohydrates. Why is this a problem? Well, if your insulin is not working properly, it sets up a cascade of effects which are not in your favor. This includes the ability to store fat more easily, as well as increases in blood pressure and cholesterol or triglycerides, which can lead to fatty liver. Lifestyle or Lifelong? Is insulin resistance a lifestyle issue? The answer is yes, but ... Insulin resistance is associated with a sedentary lifestyle — a diet high in processed carbohydrates and calories beyond one’s metabolism — but it can be present at birth. Research now s Continue reading >>

Menopause & Metabolic Syndrome – The Facts!

Menopause & Metabolic Syndrome – The Facts!

Have you put on belly fat with peri-menopause? Have you always had a pre-disposition to put on weight no matter how much exercise you do? Do you feel excessively tired after a meal? As menopause has hit, have you developed facial hair or lost your eyebrows? Do you have intermittent aches and pains in your feet? Are you bloated and retaining water? Have you lost muscle tissue? Are you feeling depressed? If any of these symptoms sound familiar, then read our FAQ’s about insulin and why controlling surges of insulin through optimal blood sugar regulation is critical to your Menopause Transformation. It’s tough, but with the support and guidance from MyMT™, you can reduce your risk of the cocktail of health problems that weight gain in menopause might lead to. Here at MyMT™ we believe in empowering women through education. With this knowledge you are better armed to change your lifestyle habits now, before you have to. What does Insulin do in the body? Insulin carries sugar. It is your energy storage hormone. When you eat something such as bread or rice, or a cookie, your blood glucose (sugar) rises. This signals the pancreas to release an amount of insulin necessary to carry the available glucose to the brain, the liver and muscles. There is no energy storage without insulin. It is a hormone which holds the key to unlocking the door to glucose being stored in the liver, muscles and in fat cells. In normal situations, insulin moves glucose into muscle and liver cells ready to supply energy for activity and metabolism. Sometimes however, we eat the wrong types of food, or we eat too much food, we don’t do enough exercise, our liver becomes impaired due to inflammation and in menopause, hormonal disturbance, can cause insulin to be released over and over again from Continue reading >>

The Causes Of Insulin Resistance In Type 1 Diabetes, Type 2 Diabetes And Prediabetes (video)

The Causes Of Insulin Resistance In Type 1 Diabetes, Type 2 Diabetes And Prediabetes (video)

Most people believe that people with type 1 diabetes are not insulin resistant simply because they are not overweight. This could not be farther from the truth. While insulin resistance affects many overweight individuals, many people with type 1 diabetes remain skinny their entire lives despite a large degree of insulin resistance (1–3). Over the past decade, I have helped many people with type 1 diabetes measure, track and reverse insulin resistance. In practice, 100% of all my clients with type 1 diabetes suffer from insulin resistance despite the assumption that they were insulin sensitive. By measuring their baseline insulin resistance, we were able to identify an impaired ability to utilize glucose as a fuel, and through dedicated diet modification and frequent exercise, some of my clients have reduced their insulin usage by as much as 60%. If you have type 1 diabetes, do not be fooled into thinking that you are insulin sensitive simply because you are skinny. Insulin resistance is a hidden condition, and affects both normal weight and overweight individuals (1–3). What Causes Insulin Resistance? Insulin resistance underlies all forms of diabetes, and is a condition which primarily affects your muscles, liver and adipose tissue. Many people think that diabetes is caused by an excess intake of sugar and candy starting from a young age. While eating artificial sweeteners and drinking soda can certainly increase your risk for the development of insulin resistance and diabetes, in most cases diabetes is caused by excessive FAT intake. The most important thing you can do as a person with diabetes is understand the following: Diabetes is caused by a fat metabolism disorder, which results in a glucose metabolism disorder. At the heart of all forms of diabetes is insu Continue reading >>

Insulin Resistance: Risk Factor For Heart Disease And Diabetes

Insulin Resistance: Risk Factor For Heart Disease And Diabetes

MORE Insulin resistance is a metabolic disorder that occurs when the body's cells cannot properly intake insulin. Insulin, which is produced in the pancreas, is a hormone that helps the body use energy from blood glucose, or blood sugar from digested food, according to the National Institute of Diabetes and Digestive and Kidney Diseases. "Think of insulin as the key that unlocks the door to their cells. That door needs to be opened in order for glucose to exit the blood into the cell," said Kimber Stanhope, a nutrition research scientist at the University of California at Davis. When people are insulin resistant, their pancreas, which acts as the locksmith of sorts, is still making those "keys," but the locks — the receptors on cells that take in blood sugar — aren't working as well as they should, Stanhope said. That’s a problem because insulin doesn't just play a role in helping the body use blood sugar as fuel; it's critical for many other bodily processes as well. Being insulin resistant can put people on the path towards developing Type 2 diabetes, and is the single best predictor of who will develop diabetes 10 or 20 years down the line. Once someone is pre-diabetic or diabetic, the pancreas simply can't produce enough insulin to make the cells sufficiently take up glucose and blood sugar levels rise. Insulin resistance also raises the risk of other disorders, such as heart disease. More than 50 million Americans have metabolic disorders that include insulin resistance, according to the American Heart Association. The condition occurs in more than 50 percent of obese children, according to a 2006 study published in the journal Diabetes Care. Causes One of the primary causes of insulin resistance is excess body fat, Stanhope said. "Nearly everybody that is ov Continue reading >>

Pathogenesis Of Insulin Resistance In Skeletal Muscle

Pathogenesis Of Insulin Resistance In Skeletal Muscle

Journal of Biomedicine and Biotechnology Volume 2010 (2010), Article ID 476279, 19 pages Division of Diabetes, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA Academic Editor: Guy M. Benian Copyright © 2010 Muhammad A. Abdul-Ghani and Ralph A. DeFronzo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle. 1. Introduction Skeletal muscle is the major site for disposal of ingested glucose in lean healthy normal glucose tolerance (NGT) individuals [1–4]. Following a meal, approximately one third of ingested glucose is taken up by the liver and the rest by peripheral tissues, primarily skeletal muscle via an insulin dependent mechanism [1–4]. The postprandial hyperglycemia stimulates insulin secretion from the pancreas and the Continue reading >>

Adipose Tissue

Adipose Tissue

From Lipid Storage Compartment to Endocrine Organ Abstract Adipose tissue, when carried around in excessive amounts, predisposes to a large number of diseases. Epidemiological data show that the prevalence of obesity has significantly increased over the past 20 years and continues to do so at an alarming rate. Here, some molecular aspects of the key constituent of adipose tissue, the adipocyte, are reviewed. While the adipocyte has been studied for many years and remarkable insights have been gained about some processes, many areas of the physiology of the fat cell remain unexplored. Our understanding of how cellular events in the adipocyte affect the local environment through paracrine interactions and how systemic effects are achieved through endocrine interactions is rudimentary. While storage and release of lipids are major functions of adipocytes, the adipocyte also uses specific lipid molecules for intracellular signaling and uses a host of protein factors to communicate with essentially every organ system in the body. The intensity and complexity of these signals are highly regulated, differ in each fat pad, and are dramatically affected by various disease states. We have appreciated for a long time that excess adipose tissue predisposes toward the development of insulin resistance. It is less well known, but equally important, that loss of selective fat pads (or absence of adipose tissue altogether) is also associated with severe forms of insulin resistance (1–3). This is in part due to the absence of the compartment that is specialized for the storage of lipids under normal conditions. This leads to a dysregulation of triglyceride and free fatty acid levels, as well as a dysregulation of specific adipocyte-derived secretory proteins, a group of proteins that Continue reading >>

What Causes Type 2 Diabetes?

What Causes Type 2 Diabetes?

Insulin resistance and high levels of insulin and lipids all precede the development of metabolic dysfunction. Which metabolic factor is to blame? Type 2 diabetes is a multifactorial metabolic disease.1 Obesity, elevated levels of lipids and insulin in the blood, and insulin resistance all accompany the elevated blood glucose that defines diabetes. (Diabetes is defined as fasting blood glucose concentrations above 7 millimolar (mM), or above 11 mM two hours after ingestion of 75 grams of glucose.) But while researchers have made much progress in understanding these components of the metabolic dysfunction, one major question remains: What serves as the primary driver of disease? Lifestyle choices characterized by inactivity have been postulated as one possible cause. Researchers have also pointed the finger at nutrition, postulating that poor food choices can contribute to metabolic disease. However, there is thus far weak support for these hypotheses. Changing to a healthy diet typically does not result in significant weight loss or the resolution of metabolic dysfunction, and it is rare to reverse obesity or diabetes through increased exercise. Furthermore, there does not appear to be a strong relationship between body-mass index (BMI) and activity level, though exercise clearly has many other health benefits. With such macroscale factors unable to explain most cases of obesity and diabetes, scientists have looked to molecular mechanisms for answers. There are at least 40 genetic mutations known to be associated with type 2 diabetes. These genes tend to be involved in the function of pancreatic β cells, which secrete insulin in response to elevated levels of the three types of cellular fuel: sugar, fat, and protein. In healthy young adults, circulating glucose concent Continue reading >>

When The Liver Gets Fatty

When The Liver Gets Fatty

As Americans have gotten fatter, so have their livers, and some hearts may suffer as a result. There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease. Fatty liver disease isn't confined to any one group, and there doesn't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible. Plumped-up liver cells The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood. Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not in Continue reading >>

Insulin And Insulin Resistance

Insulin And Insulin Resistance

Go to: Abstract As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the compl Continue reading >>

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