Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle

Lipotoxicity in skeletal muscle plays a critical role in the aetiology of insulin resistance and type 2 diabetes mellitus by interference of lipid metabolites with insulin signalling and action. The dynamics of lipid oxidation and fine tuning with fatty acid uptake and intramyocellular triacylglycerol turnover may be very important to limit the accumulation of lipid intermediates. The use of metabolic inflexibility, defined as the impaired capacity to increase fat oxidation upon increased fatty acid availability and to switch between fat and glucose as the primary fuel source after a meal, does more justice to the complexity of changes in fuel oxidation during the day. Fatty acid availability, uptake and oxidation all play a role in metabolic flexibility and insulin resistance. During high fatty acid availability, fatty acid transporters may limit cellular and mitochondrial fatty acid uptake and thus limit fat oxidation. After a meal, when the demand for fatty acids as fuel is low, an increased fractional extraction of lipids from plasma may promote intramyocellular lipid accumulation and insulin resistance. Furthermore, defects in fuel switching cluster together with impaired mitochondrial content and/or function. Lifestyle changes in dietary fat intake, physical activity and weight loss may improve metabolic flexibility in skeletal muscle, and thereby contribute to the prevention of type 2 diabetes.     

Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance

High plasminogen activator inhibitor 1 (PAI-1) levels are associated with an increased cardiovascular risk of atherothrombosis. Furthermore, increased plasma PAI-1 levels are associated with dyslipidemia, hyperinsulinemia and hypertension. This association between PAI-1 and metabolic components of the Metabolic Syndrome could explain the predisposition of insulin resistant patients to atherothrombosis. Recent studies have suggested that visceral adipose tissue might be the link between elevated plasma PAI-1 and insulin resistance in the Metabolic Syndrome. Indeed, visceral adipose tissue was proposed as a potentially important source of PAI-1 in humans. However, in light of recent studies, visceral adipose tissue appears to be involved in the increase of plasma PAI-1 via the metabolic disorders usually associated with central obesity, rather than directly. High plasma PAI-1 levels are undoubtedly related to insulin resistance, and the mechanisms which could explain such an increase in the Metabolic Syndrome appear to be multi-factorial and remain to be elucidated. These mechanisms may involve several metabolic disorders such as hyperinsulinemia, dyslipidemia, impaired glucose tolerance and hypertension, which would favor PAI-1 synthesis and release from different cell types.     

Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms

Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.     

Probiotics and Pregnancy

Polycystic ovary syndrome is a frequent disorder in women of reproductive age that consists of a heterogeneous combination of hyperandrogenism, chronic anovulation, and polycystic ovaries. Hyperandrogenism and anovulation are clearly linked to insulin resistance and compensatory hyperinsulinism, with an ovarian androgenic hyperresponsiveness to circulating insulin. Evidence is increasing that suggests that lipotoxicity, which is a key mechanism in the development of insulin resistance and type 2 diabetes, could also explain the androgen overproduction. During adolescence, diagnosis of polycystic ovarian syndrome (PCOS) may be difficult but is of importance because PCOS increases future risk of type 2 diabetes and metabolic complications. Metabolic perturbations begin early in adolescence and also exist in adolescent relatives of women with PCOS, even before clinical signs of PCOS. Screening for impaired glucose tolerance or type 2 diabetes is also important in this population, and treatment should focus on PCOS clinical manifestations as well as long-term metabolic risk.     

Neuroendocrine mechanisms in insulin resistance

Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes.     

Role of mitochondrial dysfunction in insulin resistance

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.     

Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women

Adipose tissue plays a central role in determining whole body insulin sensitivity. Several aspects of adipose cell function are regulated by androgens. Given that high androgen levels and insulin resistance are linked in women, we proposed that androgens may influence insulin-mediated glucose metabolism in adipose cells. Preadipocytes harvested from s.c. adipose tissue of healthy women aged 37 +/- 5 years were differentiated in vitro, then treated with testosterone (T) and/or androgen receptor (AR) antagonists (cyproterone acetate, flutamide) for 48 h. Maximal insulin-stimulated glucose uptake (insulin 10 nM) and increment following insulin stimulation were significantly impaired in cells treated with T 10 and 100 nmol/l. This defect was abolished by cyproterone acetate and partially reversed by flutamide. The effect of T could not be accounted for by altered differentiation status of the adipocytes. In the glucose metabolic pathway of insulin signaling, treatment of cells with T 10 nmol/l did not alter insulin-stimulated phosphorylation of insulin receptor substrate-1 or Akt, but insulin-stimulated phosphorylation of protein kinase C (PKC) zeta was impaired. Insulin signaling via the mitogenic/gene regulatory pathway, as assessed by extracellular signal-regulated kinase phosphorylation, was unchanged. We conclude that (1) T, or an androgenic metabolite of T, induces insulin resistance in adipocytes of women, selective for metabolic signaling pathways; (2) this defect is via AR; and (3) the defect in signaling is independent of phosphatidylinositol 3-kinase activation and involves impaired phosphorylation of PKCzeta. These findings are relevant to understanding the pathogenesis of insulin resistance in hyperandrogenic women.     

Addressing the insulin resistance syndrome: a role for the thiazolidinediones

The global epidemic of type 2 diabetes and cardiovascular disease (CVD) is mirrored by increasing prevalence of the Insulin Resistance Syndrome (IRS) or Metabolic Syndrome. Accumulating data indicate that insulin resistance is the common denominator underlying this cluster of related CVD risk factors. Therapeutic interventions that address insulin resistance and other components of the IRS may be of benefit in reducing the significant health and socioeconomic burden presented by diabetes and CVD. Evidence is discussed that the thiazolidinediones, which improve glycemic control by directly targeting insulin resistance, have the additional benefit of improving many of the CVD risk factors in the IRS, and thus have the potential to reduce CVD in patients with type 2 diabetes. (Trends in Cardiovasc Med 2002; 12:354–362).     

Cellular mechanism of insulin resistance: potential links with inflammation

Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.     

Vascular insulin resistance: A potential link between cardiovascular and metabolic diseases

The physiologic actions of insulin in the vasculature serve to couple regulation of metabolic and hemodynamic homeostasis. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes glucose uptake in insulin-responsive tissues and nitric oxide (NO) production in the endothelium. NO induces vasodilation and inhibits platelet aggregation and vascular smooth muscle cell growth. In contrast, insulin activation of the mitogen-activated protein kinase (MAPK) leads to vasoconstriction and pathologic vascular cellular growth. In states of insulin resistance, insulin activation of PI3K is selectively impaired, whereas the MAPK pathway is spared and activated normally. In the endothelium, selective impairment of insulin-mediated NO production may contribute to the development of hypertension, endothelial dysfunction, atherogenesis, and insulin resistance. This article reviews experimental and clinical data elucidating the physiologic and pathophysiologic role of insulin in the vasculature and the mechanisms contributing to the development of vascular and metabolic diseases.     

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.     

Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism

In recent years, the central nervous system (CNS) has emerged as a principal site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focuses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.     

Vascular, metabolic, and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus

Endothelial dysfunction, insulin resistance, and elevated levels of circulating proinflammatory markers are among the earliest detectable abnormalities in people at risk for atherosclerosis. Accelerated atherosclerosis is a leading contributor to morbidity and mortality in type 2 diabetes mellitus, a complex genetic disorder. Therefore, we hypothesized that normoglycemic offspring of patients with type 2 diabetes mellitus (NOPD) may have impaired vascular and metabolic function related to an enhanced proinflammatory state. We compared NOPD (n = 51) with matched healthy control subjects without family history of diabetes (n = 35). Flow- and nitroglycerin-mediated brachial artery vasodilation were assessed by ultrasound to evaluate endothelium-dependent and -independent vascular function. Each subject also underwent an oral glucose tolerance test to evaluate metabolic function. Fasting levels of plasma adiponectin and circulating markers of inflammation (high-sensitivity C-reactive protein, CD40 ligand, interleukin 1beta, tumor necrosis factor alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule) were measured. Both NOPD and the control group had fasting glucose and insulin levels well within the reference range. However, results from oral glucose tolerance test and quantitative insulin sensitivity check index revealed that NOPD were insulin resistant with significantly impaired flow- and nitroglycerin-mediated dilation compared with the control group. Adiponectin levels were lower, whereas many circulating markers of inflammation were higher, in NOPD compared with the control group. Normoglycemic offspring of patients with type 2 diabetes mellitus have impaired vascular and metabolic function accompanied by an enhanced proinflammatory state that may contribute to their increased risk of diabetes and its vascular complications.     

Nutrient-induced insulin resistance.

Impaired function of the hormone insulin (insulin resistance) is a major feature of type 2 diabetes, a condition that is expected to afflict over 200 million people by early next century. Intensive investigation has failed to find a genetic basis for insulin resistance in the majority of cases. In this brief review the evidence that insulin resistance may be caused by excess nutrient supply will be presented. Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissue, while excess fat can cause impaired suppression of endogenous glucose production. Each nutrient may impair insulin action by several mechanisms, at least one of which may be common to both.     

Inflamed adipose tissue, insulin resistance and vascular injury

Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.     

NF-kappaB-inducing kinase (NIK) mediates skeletal muscle insulin resistance: blockade by adiponectin

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.     

Toward an improved diagnosis of the metabolic syndrome other clues to the presence of insulin resistance

A substantial portion of the population of the United States has the Metabolic Syndrome, a condition that greatly increases risk for cardiovascular disease and diabetes. Insulin resistance, and the resulting compensatory hyperinsulinemia, is the principal pathophysiologic abnormality underlying the majority of these cases. Based on the most recent recommendations of the National Cholesterol Education Panel, such patients can be identified by the presence of three or more of the following traits: impaired fasting glucose, abdominal obesity, hypertension, elevated levels of triglycerides, and low concentrations of HDL-cholesterol. However, a significant number of insulin resistant (and thus high risk) individuals will not be identified using these criteria. This discrepancy occurs because insulin resistance is a continuous variable, without an absolute cut-off between normal and abnormal, and those fitting the definition are the most insulin resistant. Moreover, easily applicable testing to diagnose insulin resistance accurately in the general population is currently not feasible. It is therefore necessary to broaden the criteria that define the metabolic syndrome to include other conditions associated with the presence of insulin resistance. Such conditions include the following: a family history of type 2 diabetes or coronary artery disease in first- or second-degree relatives, signs of an over active sympathetic nervous system, and elevated concentrations of uric acid. By recognizing these "other conditions," appropriate lifestyle changes and medication can be recommended to help prevent cardiovascular disease and diabetes from developing in these high-risk patients.     

Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes

The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.     

Congenital and environmental factors associated with adipocyte dysregulation as defects of insulin resistance

The metabolic syndrome refers to insulin resistance and its associated cluster of related cardiovascular metabolic risk factors including type 2 diabetes, hypertension, dyslipidemia and central obesity. Although many hypotheses and facts have been proposed to explain the interaction between genetic and environmental causes of this syndrome, the primary etiology of the metabolic syndrome is adipose tissue dysregulation. Firstly, the thrifty genotype and phenotype hypothesis may explain the endemic increase in type 2 diabetes and cardiovascular disease in developing countries and elucidates the congenital susceptibility and environmental triggering of the metabolic syndrome. Secondly, over-nutrition leads to fatty acid (FA) accumulation in adipocytes and to an overflow to ectopic fat storage organs. This causes functional changes in adipocytes shifting the intra-cellular metabolic pathway toward insulin resistance. Thirdly, obese subjects exhibit increased fat cell size and over-secretion of biologic adipocytokines. Fourthly, failure to adequately develop adipose tissue mass, as seen in lipodystrophy cases, causes severe insulin resistance and diabetes. Lastly, similar to human type 2 diabetes, Psammonys obesus, a desert rat which feeds mainly on low-calorie vegetation, develops the metabolic syndrome when given a diet of calorie rich food. The above evidence indicates adipocyte dysregulation and secretion of FA as well as certain molecules from overloaded adipocytes/adipokines contribute to the pathogenesis of impaired insulin secretion and insulin resistance, endothelial dysfunction, a pro-inflammatory state and promote progression of atherosclerosis. The metabolic syndrome is a modern disease resulting adipocyte dysmetabolism resulting from the paradox of the slow human evolution combined with rapid environmental changes.     

Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes.

Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority ( approximately 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.