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

Insulin Resistance And Atherosclerosis: Convergence Between Metabolic Pathways And Inflammatory Nodes

Insulin Resistance And Atherosclerosis: Convergence Between Metabolic Pathways And Inflammatory Nodes

For some time now it has been known that diabetes and atherosclerosis are chronic inflammatory diseases that are closely associated with one another and often develop together. In both there is an increase in tissue-wide inflammation that is exhibited by the infiltration of immune cells into the adipose tissue and the vascular walls respectively. The monocyte/macrophage populations that are recruited in these seemingly different settings also display a high similarity by exhibiting similar phenotypes in both conditions. In the insulin resistant as well as the atherosclerotic setting there is a distinct switch in the macrophage populations present from an anti-inflammatory (M2) population to an inflammatory (M1) population, which releases cytokines and chemotactic factors with the ability to worsen the local environment and thus aggravate the situation by creating a vicious circle. However, although some discoveries suggest that preventing the development of M1 macrophages reduces inflammation and thereby aggravation of these diseases, there are currently no clear-cut opinions on how to achieve a switch from M2 to M1. Abbreviations: ADAM17, a disintegrin and metalloproteinase 17; ApoE, apolipoprotein E; Arg, arginase; ATM, adipose tissue macrophage; eNOS, endothelial nitric oxide synthase; FFA, non-esterified (‘free’) fatty acid; FoxO, Forkhead box O; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; IFNγ, interferon γ; Insr, insulin receptor; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LDL, low-density lipoprotein; LDLRKO, LDL receptor knockout; LXR, liver X receptor; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; MR, mannose receptor; NF-κB, nuclear factor κB; PGC1β, peroxisome-proliferator-activated rece 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 >>

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 >>

Non-alcoholic Fatty Liver Disease

Non-alcoholic Fatty Liver Disease

About non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. There is normally a small amount of fat in liver cells but when a significant amount builds up liver disease can follow. Non-alcoholic fatty liver disease has been increasing in both adults and children over recent decades and has now become the most common form of chronic liver disease in children. Health professionals are still learning about non-alcoholic fatty liver disease but believe that early recognition and treatment is important, as serious liver problems can develop in early adulthood including cirrhosis and liver cancer. What causes non-alcoholic fatty liver disease? Insulin is a hormone released by the pancreas which acts on muscle as well as fat cells. It has an important role in controlling sugar levels and food and energy balance in the body. In some people muscle and fat cells stop responding to insulin and the pancreas releases increasing amounts of insulin. The liver is then bombarded by insulin, allowing more fat into the liver cell and decreasing the amount of fat processed and released from the liver cell. People who are prone to insulin resistance and NAFLD tend to deposit fat around their abdomens and around the organs within the abdominal cavity, thus worsening the amount of fat in and around the liver. In some children and adults with fatty liver disease, for reasons that we do not yet understand, the liver can become irritated and fat can cause inflammation and lead to liver scarring. Why might non-alcoholic fatty liver disease be suspected in a young person? Children and young people often present to their GP with abdominal pain and undergo routine liver function tests (blood tests) and an ultrasound scan which 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 >>

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 >>

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 >>

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 >>

Consumption Of A Mango Fruit Powder Protects Mice From High-fat Induced Insulin Resistance And Hepatic Fat Accumulation

Consumption Of A Mango Fruit Powder Protects Mice From High-fat Induced Insulin Resistance And Hepatic Fat Accumulation

Abstract Background/Aims: The aim of this study was to gain more insight into the beneficial effects of mango fruit powder on the early metabolic adverse effects of a high-fat diet. Methods: The progressive dose-response effects of mango fruit powder on body composition, circulating parameters, and the expression of genes related to fatty acid oxidation and insulin sensitivity in key tissues were studied in mice fed a moderate (45%) high-fat diet. Results: Findings suggest that mango fruit powder exerts physiological protective effects in the initial steps of insulin resistance and hepatic lipid accumulation induced by a high-fat diet in mice. Moreover, AMPK and SIRT1 appear as key regulators of the observed improvement in fatty acid oxidation capacity, as well as of the improved insulin sensitivity and the increased glucose uptake and metabolism through the glycolytic pathway capacity in liver and skeletal muscle. Conclusion: In summary, this study provides evidence that the functional food ingredient (CarelessTM) from mango fruit prevents early metabolic alterations caused by a high-fat diet in the initial stages of the metabolic syndrome. © 2017 The Author(s). Published by S. Karger AG, Basel Introduction Dysregulated glucose and lipid metabolism and, thus, energy homeostasis are early events in the development of insulin resistance, which in turn may lead to obesity and diabetes mellitus type 2. The overall prevalence of insulin resistance in developed societies is high, with 11.5-14.0% of the European population [1], 20% of adults in Japan [2], and nearly 30% of adult Americans [3] being afflicted. The insensitivity of peripheral tissues to the effects of insulin starts when the nutrient storage metabolic pathways are exposed to persistent energy excess, surpassin Continue reading >>

Fatty Liver Disease: 10 Common Symptoms

Fatty Liver Disease: 10 Common Symptoms

According to doctors, a fatty liver isn’t damaging to the body on its own accord. However, the accumulation of excessive fatty tissue can lead to severe liver damage—including inflammation and scarring. A fatty liver occurs when you take in more fat and calories than your liver can process. As a result, simple fats build up in the liver cells, making the liver prone to damage. The most common reason for the development of fatty liver disease is obesity—with obese individuals increasing their chances of developing the condition by about 75-percent. Although a fatty diet and weight gain is the main culprit, diabetes (or insulin resistance), hyperlipidemia (or elevated lipids in the blood), and alcohol abuse (with 90 to 100-percent of binge drinkers contracting fatty livers) will also increase the chances. Here are the ten most common symptoms of fatty liver disease… 1. Fatigue If any organ in our bodies becomes dysfunctional, in this case the liver, the body will try to protect itself and compensate by pumping excess blood to the organ, which often leads to unexplained weakness, confusion, impaired judgment, or trouble concentrating, severe energy loss, and a sudden inability to participate in social activities that were once enjoyed. Researchers also speculate that changes in brain chemistry and hormone production contribute to feelings of fatigue and exhaustion. The pathophysiology of liver disease-related fatigue often presents with additional neuropsychiatric symptoms, which typically develop over a compressed period of time. These symptoms can include problems like depression and anxiety, which may be worsened by changes in your body’s ability to produce serotonin, an important mood regulator. Serotonin production can diminish in patients with fatty liver d 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 >>

Adipose-specific Peroxisome Proliferator-activated Receptor Γ Knockout Causes Insulin Resistance In Fat And Liver But Not In Muscle

Adipose-specific Peroxisome Proliferator-activated Receptor Γ Knockout Causes Insulin Resistance In Fat And Liver But Not In Muscle

Abstract Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) γ, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPARγ in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased levels of plasma leptin and ACRP30. In addition, increased hepatic glucogenesis and IR were observed. Despite these defects, blood glucose, glucose and insulin tolerance, and insulin-stimulated muscle glucose uptake were all comparable to those of control mice. However, targeted mice were significantly more susceptible to high-fat diet-induced steatosis, hyperinsulinemia, and IR. Surprisingly, TZD treatment effectively reversed liver IR, whereas it failed to lower plasma free fatty acids. These results suggest that syndrome X may be comprised of separable PPARγ-dependent components whose origins and therapeutic sites may reside in distinct tissues. Continue reading >>

The Cell Biology Of Fat Expansion

The Cell Biology Of Fat Expansion

Abstract Adipose tissue is a complex, multicellular organ that profoundly influences the function of nearly all other organ systems through its diverse metabolite and adipokine secretome. Adipocytes are the primary cell type of adipose tissue and play a key role in maintaining energy homeostasis. The efficiency with which adipose tissue responds to whole-body energetic demands reflects the ability of adipocytes to adapt to an altered nutrient environment, and has profound systemic implications. Deciphering adipocyte cell biology is an important component of understanding how the aberrant physiology of expanding adipose tissue contributes to the metabolic dysregulation associated with obesity. Fat—properly defined as adipose tissue—is a biological caloric reservoir that expands in response to overnutrition and releases lipids in response to energy deficit. Adipocytes represent the primary cell type of adipose tissue and are responsible for storing excess calories as triglycerides in their cellular lipid droplets without the common lipotoxicity experienced by other cells under these conditions (Konige et al., 2014). This unparalleled capacity for lipid storage and release upon systemic metabolic demand links the cell biology of the adipocyte and adipose tissue physiology to whole body metabolism (Fig. 1). Figure 1. Benign and unhealthy adipose tissue. The overall health of adipose tissue can be visualized histologically. Benign murine subcutaneous adipose tissue (left; trichrome staining) is rich in unilocular white adipocytes with sparse ECM. On high-fat feeding (right), adipose tissue experiences hypoxia and inflammation, resulting in a dense, fibrous ECM. These histological tissue features are characteristic of insulin-resistant adipocytes. Adipocytes exist in a sp Continue reading >>

Insulin Resistance

Insulin Resistance

Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. The body produces insulin when glucose starts to be released into the bloodstream from the digestion of carbohydrates in the diet. Normally this insulin response triggers glucose being taken into body cells, to be used for energy, and inhibits the body from using fat for energy. The concentration of glucose in the blood decreases as a result, staying within the normal range even when a large amount of carbohydrates is consumed. When the body produces insulin under conditions of insulin resistance, the cells are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to the development of type 2 diabetes or latent autoimmune diabetes of adults.[1] Although this type of chronic insulin resistance is harmful, during acute illness it is actually a well-evolved protective mechanism. Recent investigations have revealed that insulin resistance helps to conserve the brain's glucose supply by preventing muscles from taking up excessive glucose.[2] In theory, insulin resistance should even be strengthened under harsh metabolic conditions such as pregnancy, during which the expanding fetal brain demands more glucose. People who develop type 2 diabetes usually pass through earlier stages of insulin resistance and prediabetes, although those often go undiagnosed. Insulin resistance is a syndrome (a set of signs and symptoms) resulting from reduced insulin activity; it is also part of a larger constellation of symptoms called the metabolic syndrome. Insuli Continue reading >>

The Role Of Hepatic Lipids In Hepatic Insulin Resistance And Type 2 Diabetes

The Role Of Hepatic Lipids In Hepatic Insulin Resistance And Type 2 Diabetes

Go to: Molecular mechanism of lipid-induced insulin resistance Insulin action requires a coordinated, intricate relay of intracellular signals, involving mostly phosphorylation and dephosphorylation events. In the canonical view of hepatic insulin signalling, insulin binds and activates the insulin receptor tyrosine kinase (IRTK), which in turn promotes tyrosine kinase phosphorylation of insulin receptor substrates (IRS), most importantly IRS2 in the liver (Fig. 1)17. Phosphorylation of IRS2 generates binding sites for Src homology 2 domain proteins, including phosphatidylinositol-3-OH kinase (PI(3)K)18. The binding of PI(3)K to IRS2 recruits phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), which in turn recruits Akt19. Under insulin-stimulated conditions, 3-phosphoinositide-dependent kinase-1 phosphorylates and activates Akt, which is thought to suppress hepatic glucose production through two key mechanisms: first, decreased expression of gluconeogenic enzymes by phosphorylation and nuclear exclusion of the fork-head box protein FOXO1 and its pro-gluconeogenic targets, and second, activation of glycogen synthase by phosphorylation and inactivation of glycogen synthase kinase-3β. Although this relatively linear construct is useful for interrogating insulin signalling in experimental models, it fails to capture the interwoven mechanisms that have evolved to regulate hepatic glucose and lipid metabolism. For example, although acute insulin signalling following a meal can decrease messenger RNA expression of gluconeogenic enzymes, it probably does not acutely alter the protein levels of these enzymes. Gluconeogenic enzymes are also conventionally thought to be subject to allosteric activation: acetyl coenzyme A (acetyl-CoA) activates pyruvate carboxylase20,21, Continue reading >>

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