Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options.

Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.     

Crucial role of insulin receptor substrate-2 in compensatory beta-cell hyperplasia in response to high fat diet-induced insulin resistance

In type 2 diabetes, there is a defect in the regulation of functional beta-cell mass to overcome high-fat (HF) diet-induced insulin resistance. Many signals and pathways have been implicated in beta-cell function, proliferation and apoptosis. The co-ordinated regulation of functional beta-cell mass by insulin signalling and glucose metabolism under HF diet-induced insulin-resistant conditions is discussed in this article. Insulin receptor substrate (IRS)-2 is one of the two major substrates for the insulin signalling. Interestingly, IRS-2 is involved in the regulation of beta-cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased beta-cell proliferation was observed in mice with beta-cell-specific glucokinase haploinsufficiency (Gck(+/) (-)) fed a HF diet without upregulation of IRS-2 in beta-cells, which was reversed by overexpression of IRS-2 in beta-cells. As to the mechanism underlying the upregulation of IRS-2 in beta-cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element-binding protein triggered by calcium-dependent signalling is the critical pathway. Downstream from insulin signalling via IRS-2 in beta-cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of beta-cells to insulin resistance. These findings suggest that IRS-2 is critical for beta-cell hyperplasia in response to HF diet-induced insulin resistance.     

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology. Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Insulin Resistance: a Multifaceted Metabolic Syndrome. Insights Gained Using a Low-dose Insulin Infusion Technique

The term ‘insulin resistance’, when applied to human disease, is often equated with impaired whole-body insulin-mediated glucose disposal as determined using techniques such as the hyperinsulinaemic glucose ‘clamp’ technique. Insulin resistance may be defined in more generic terms as ‘a state in which normal concentrations of insulin produce an attenuated biological response’—a definition which does not restrict consideration of insulin action to a solitary aspect of metabolism and emphasizes the importance of examining the effects of insulin at concentrations which are relevant to normal physiology. While a number of useful investigative techniques have been developed for the assessment of insulin action in man, most focus narrowly on glucose metabolism; other key aspects of metabolism have received far less attention. Moreover, the pharmacological hyperinsulinaemia usually attained during euglycaemic clamp studies is unsuitable for assessing processes such as adipocyte lipolysis which are maximally inhibited by insulin concentrations within the low-physiological range. In this article we present a summary of our investigations of insulin action in vivo using a low-dose incremental insulin infusion technique. This technique permits examination of circulating insulin/metabolite dose–response relationships within the lower physiological range of plasma insulin concentrations. Using this approach, we have identified multiple abnormalities in the regulation of carbohydrate and lipid metabolism in subjects with a diverse array of insulin-resistant states characterized by variable degrees of glucose intolerance. Of note are the consistent observations of defective regulation of non-esterified fatty acid and glycerol metabolism, being apparent even in patients in whom glucose tolerance was either normal or only marginally impaired. Our studies indicate that defective insulin action is not confined to impaired glucose disposal in insulin-resistant disorders and is usually evident in other aspects of intermediary metabolism. We suggest that the concept of insulin resistance as a pathological entity would be usefully enhanced by greater recognition of the multiple defects in insulin action which may be encountered in insulin-resistant states.     

Insulin resistance in hypertension and cardiovascular disease

Insulin resistance is not simply a problem of decreased glucose uptake in response to insulin, but a multifaceted syndrome that significantly increases the risk for cardiovascular disease. Insulin resistance is strongly associated with arterial hypertension and a pathogenetic role in the development of arterial hypertension has been suggested. One question that remains open concerns the clinical approach to insulin-resistant patients. Observational and clinical trial data suggest that lifestyle changes including weight reduction and regular physical activity can improve insulin sensitivity and reduce the incidence and mortality of cardiovascular disease. Daily physical activity of moderate intensity for 30 min has a cardioprotective effect and reduces insulin resistance, independent of the effect on body weight. A pharmacological therapy for insulin resistance reducing cardiovascular disease remains to be defined. Concerning the antihypertensive therapy of insulin-resistant hypertensive patients, most hypertensive guidelines fail to provide specific advice.     

Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin's effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-L-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.     

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.     

Insulin resistance,hypertension and cellular ion transport systems

Much epidemiological, physiological and biochemical evidence links insulin resistance and hyperinsulinaemia to the pathogenesis of hypertension in some metabolic diseases such as obesity and type 2 (non-insulin-depedent) diabetes mellitus. Insulin resistance per se, by altering the energy needs of the cell, by causing a shift from glucose to lipid metabolism, or by some other incompletely defined mechanisms, could be responsible for the development of hypertension. It is also possible that hyperinsulinaemia, by acting on the vascular tree, leads to an increase in blood pressure. Moreover, insulin has been shown to augment renal sodium reabsorption, to stimulate the sympathetic nervous system, to influence atrial natriuretic peptide release and the renin-angiotensin-aldosterone system and to activate a number of sodium pumps which are present in all cell membranes, including vascular smooth muscle cells. Insulin can also directly stimulate cell growth. All these mechanisms, in various combinations, with the concurrence of some genetic factors, could lead to the development of the association between hypertension and abnormalities in glucose metabolism.     

肉桂油对胰岛素抵抗小鼠糖脂代谢的影响

目的:研究肉桂油对胰岛素抵抗小鼠糖脂代谢的影响,探讨其作用机制.方法:采用高脂饲料喂养建立小鼠胰岛素抵抗模型,经肉桂油治疗后测定口服糖耐量及胰岛素耐受,观察体质量、血糖、血清胰岛素、甘油三酯、总胆固醇、瘦素、抵抗素、脂联素的变化.结果:肉桂油能降低胰岛素抵抗小鼠的体质量(30.3±3.6vs34.6±3.1,P<0.05)、血糖(7.6±2.2vs9.2±1.3,P<0.05)、血清胰岛素(1.3±0.1vs1.7±0.2,P<0.05)、甘油三酯(70.1±10.9vs65.4±19.5,P<0.05)、总胆固醇(93.2±13.8vs102.3±21.5,P<0.05)、瘦素、抵抗素水平,同时改善口服糖耐量,降低胰岛素抵抗.结论:肉桂油能有效改善胰岛素抵抗小鼠糖脂代谢,其作用与降低血清瘦素、抵抗素水平,增加胰岛素敏感性有关.     

Mitochondrial dysfunction,insulin resistance,and type 2 diabetes mellitus

Insulin resistance is a characteristic feature of type 2 diabetes mellitus, obesity, and the metabolic syndrome. Increased intracellular fat content in skeletal muscle and liver associated with insulin resistance has led to the hypothesis that a mitochondrial defect in substrate oxidation exists in disorders of insulin resistance. In vivo measurements of metabolic fluxes through the tricarboxylic acid and oxidative phosphorylation with magnetic resonance spectroscopy have demonstrated multiple defects in mitochondrial function in skeletal muscle. A decrease in mitochondrial density and mitochondrial copy number has been reported in insulin-resistant individuals. However, these findings have not been a consistent observation in all studies. Similarly, an intrinsic functional defect in mitochondrial adenosine triphosphate production synthesis has been reported in some but not all studies. This review summarizes evidence that implicates a defect in mitochondrial oxidative phosphorylation and its relationship to insulin resistance in common metabolic diseases characterized by impaired insulin action.     

Insulin resistance predicts future deterioration of glucose tolerance in nondiabetic young African Americans

Insulin resistance has been linked to the development of type 2 diabetes mellitus and increased cardiovascular risk in several high-risk populations. The purpose of this study was to determine if insulin resistance measured by insulin clamp can predict deterioration of glucose metabolism and increased cardiovascular risk in nondiabetic young adult African Americans. Nondiabetic young African American men (n = 60) and women (n = 114) were enrolled. Measurements obtained included blood pressure, anthropometrics, plasma lipids, oral glucose tolerance test, and insulin sensitivity by insulin clamp. Participants were reexamined 8 years later. The relationship between insulin sensitivity and glucose metabolism was analyzed using a 2-way analysis of variance with body mass index at the initial examination as a covariate. After adjusting for the significant difference of body mass index between the insulin-resistant and insulin-sensitive groups, insulin resistance predicted statistically significant worsening glucose metabolism, developing diabetes, and increasing risk factors for cardiovascular disease.     

Androgens, insulin resistance and vascular disease in men

Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short-term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin-resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men.     

Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis

BACKGROUND & AIMS: The increasing prevalence of nonalcoholic steatohepatitis (NASH) is due to the epidemic of obesity and type 2 diabetes, both of which are associated with insulin resistance. METHODS: To clarify the causal relationship between insulin resistance and the development of NASH, steatohepatitis was induced in obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats by feeding them a methionine and choline-deficient (MCD) diet. Insulin sensitivity of the rats was altered by adding a high-fat (HF) diet or the peroxisomal-proliferator activated receptor-gamma agonist pioglitazone to the MCD diet. RESULTS: The MCD diet-induced steatohepatitis was accelerated in OLETF rats after 8 weeks. Steatosis preceded inflammation, which led to fibrosis and the development of steatohepatitis. The hepatic gene expression for transforming growth factor-beta, alpha1 procollagen and plasminogen activator inhibitor-1 was up-regulated in OLETF rats compared with LETO rats. The MCD + HF diet further enhanced insulin resistance and led to rapid development of pre-cirrhosis in OLETF rats by increasing the triglyceride pool, activating stellate cells, and up-regulating gene expression for sterol regulatory element-binding protein-1c and fatty acid synthase in the liver. In contrast, pioglitazone attenuated the MCD diet-induced steatohepatitis in OLETF rats but not in LETO rats by reversing the underlying pathogenesis involved in this model through improvement of insulin resistance. These results confirm a link between insulin resistance and the development/progression of steatohepatitis, at least partly via up-regulation of genes for lipogenesis, inflammation, and fibrogenesis, in animal models. CONCLUSIONS: Insulin resistance and/or diabetes may accelerate the entire pathologic spectrum of NASH.     

Differentiation of the metabolic and vascular effects of insulin in insulin resistance in patients with chronic heart failure

Chronic heart failure (HF) is associated with insulin resistance. Putative mechanisms of insulin resistance are abnormal skeletal muscle blood flow and antagonism of insulin action due to sympathetic nervous system activation. We measured insulin sensitivity, the vasoactive properties of insulin, and the association between insulin resistance and markers of neurohormonal activation in 10 patients with chronic HF and in 9 healthy controls. Noninvasive hemodynamic measurements and an hyperinsulinemic, euglycemic clamp were used. Patients were insulin resistant compared with the controls (p <0.05 for area under insulin dose-response curve). Insulin infusion led to a selective increase in forearm blood flow accompanied by a decrease in mean arterial pressure and superior mesenteric blood flow. Heart rate decreased in patients but not in controls; however, when baseline measurements were controlled for, there was no difference in the overall hemodynamic response to insulin infusion between the study groups. In univariate analysis, age, serum creatinine, fasting insulin, and triglyceride levels correlated inversely with insulin sensitivity (p <0.05 for all). Cardiac output had a significant correlation with insulin sensitivity (p <0.05). On stepwise multiple linear regression analysis, only age and fasting plasma insulin emerged as significant predictors of insulin sensitivity (R(2) 0.613, p = 0.001). In particular, we found no evidence of a relation between insulin sensitivity and plasma noradrenaline. Patients with chronic HF exhibit significant metabolic insulin resistance. Insulin resistance is not secondary to failure of insulin-mediated vasodilatation or sympathetic nervous system activation and is likely due to abnormalities at the level of the skeletal myocyte.     

Obesity, insulin resistance, and renal function

There is a growing body of evidence indicating that obesity and insulin resistance contribute to the progression of renal disease. A low-grade inflammatory response occurs in obesity and insulin resistance that causes an increase in macrophage infiltration into the adipose tissue and the kidney. The infiltration of macrophages gives rise to the production of an array of pro-inflammatory cytokines and downstream elements such as interleukin-6, NFkappaB, and cellular adhesion molecules. In addition, increased adiposity triggers the release of adipokines such as leptin that can cause vascular remodeling and disruption of renal function. Insulin resistance can alter the balance between endogenous vasoactive molecules such as nitric oxide and reactive oxygen species, resulting in altered renal endothelial function. Moreover, hyperinsulinemia has direct renal effects such as induced relaxation of the afferent arteriole, resulting in glomerular hyperfiltration and renal damage. High insulin levels also stimulate angiogenesis and mesangial cell proliferation, associated with the development of diabetic nephropathy. Current evidence indicates a direct link between increased adiposity and insulin resistance with renal vascular injury; however, further investigation into the renal microvascular effects of obesity and insulin resistance are required to better understand this disease process.     

Gene expression profiling in skeletal muscle of Zucker diabetic fatty rats: implications for a role of stearoyl-CoA desaturase 1 in insulin resistance

Aims/hypothesis Insulin resistance in skeletal muscle is a hallmark of type 2 diabetes. Therefore, we sought to identify and validate genes involved in the development of insulin resistance in skeletal muscle. Materials Differentially regulated genes in skeletal muscle of male obese insulin-resistant, and lean insulin-sensitive Zucker diabetic fatty (ZDF) rats were determined using Affymetrix microarrays. Based on these data, various aspects of glucose disposal, insulin signalling and fatty acid composition were analysed in a muscle cell line overexpressing stearoyl-CoA desaturase 1 (SCD1). Results Gene expression profiling in insulin-resistant skeletal muscle revealed the most pronounced changes in gene expression for genes involved in lipid metabolism. Among these, Scd1 showed increased expression in insulin-resistant animals, correlating with increased amounts of palmitoleoyl-CoA. This was further investigated in a muscle cell line that overexpressed SCD1 and accumulated lipids, revealing impairments of glucose uptake and of different steps of the insulin signalling cascade. We also observed differential effects of high-glucose and fatty acid treatment on glucose uptake and long-chain fatty acyl-CoA profiles, and in particular an accumulation of palmitoleoyl-CoA in cells overexpressing SCD1. Conclusions/interpretation Insulin-resistant skeletal muscle of ZDF rats is characterised by a specific gene expression profile with increased levels of Scd1. An insulin-resistant phenotype similar to that obtained by treatment with palmitate and high glucose can be induced in vitro by overexpression of SCD1 in muscle cells. This supports the hypothesis that elevated SCD1 expression is a possible cause of insulin resistance and type 2 diabetes. Electronic supplementary material Supplementary material is available for this article at and accessible for authorised users.     

Relationships between insulin secretion, insulin metabolism and insulin resistance in mild glucose intolerance

The aim of this study was to evaluate whether the correlation between insulin resistance and peripheral hyperinsulinaemia existing in mild glucose intolerance corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the possibility that insulin resistance is related to insulin metabolism was examined. Twenty five subjects with fasting normoglycaemia and an abnormal glucose response to the oral glucose tolerance test (OGTT) were studied. Insulin secretion by the pancreas was estimated by means of fasting C-peptide levels in peripheral blood. Insulin resistance was estimated by the rate of glucose disappearance from plasma after i.v. insulin injection. Insulin metabolism was estimated indirectly by the C-peptide: insulin molar ratio. A negative correlation was found between the glucose disappearance rate from plasma after i.v. insulin injection and fasting insulin levels (r = -0.677, p less than 0.001), but not fasting C-peptide concentrations (r = -0.164, p = NS). Glucose disappearance rate from plasma correlated positively with the C-peptide: insulin molar ratio (r = 0.626, p less than 0.001). These results suggest that in mild glucose intolerance insulin resistance and insulin secretion by the pancreas are not related phenomena, and that the defect responsible for insulin resistance might also be implicated in the impaired insulin metabolism.     

Digitalis-like factor response to hyperinsulinemia in human pregnancy,a model of insulin resistance

Insulin resistance is strongly associated with hypertension and is postulated to participate in the elevation of blood pressure, although the mechanisms involved are not understood. Recently, we reported that acute increases in plasma insulin levels in normal subjects resulted in increased serum levels of a sodium pump inhibitor, termed the digitalis-like factor (DLF), which has been implicated in both experimental and essential human hypertension. This study looked at the DLF response to hyperinsulinemia, achieved by an oral glucose tolerance test (OGTT), in the setting of a naturally occurring and self-resolving state of human insulin resistance, during third-trimester pregnancy. This model allowed us the further opportunity to compare the DLF response to insulin in the same subjects postpartum, after resolution of their insulin resistance. Administration of an OGTT during pregnancy and postpartum in the same subjects elicited a comparable serum glucose response but a significantly greater insulin response during third-trimester pregnancy, consistent with diminished insulin sensitivity (integrated insulin response during pregnancy: 1611+/-236 vs postpartum: 685+/-101 pmol/l, P=0.004). The time courses of the glucose and insulin responses were identical whether women were pregnant or not. Plasma free fatty acids fell significantly and to a comparable degree during pregnancy and postpartum, but the response was slower during pregnancy. DLF levels increased in response to oral glucose in both pregnant and nonpregnant states. The response was more rapid during pregnancy than after. These findings showed that the increment of insulin induced by oral glucose during pregnancy caused a more rapid rise in circulating DLF levels than it did during the nonpregnant state. At the same time, the response of circulating fatty acids to glucose is retarded during pregnancy. This suggests that the insulin resistance of pregnancy impairs insulin's influence on intermediary metabolism but not its influence on DLF. As a vasoactive substance, DLF might contribute to the hypertension characteristic of insulin-resistant states.     

Myocardial fatty acid metabolism and cardiac performance in heart failure

It is well established that cardiac metabolism is abnormal in heart failure (HF). Experimental studies suggest that in severe HF, cardiac metabolism reverts to a more fetal-like substrate use characterized by enhanced glucose and downregulated free fatty acid (FFA) metabolism. Correspondingly, in humans, when FFA levels are similar, myocardial glucose metabolism is increased, and FFA metabolism is decreased. However, depression of left ventricular function and insulin resistance induces a shift back to greater FFA uptake and oxidation by increasing circulating FFA availability. Myocardial insulin resistance may further impair myocardial glucose uptake and lead to an energy depletion state. Experimental and preliminary clinical studies suggest that metabolic modulators enhancing myocardial glucose oxidation may improve cardiac function in patients with chronic HF. However, it has been found that acute FFA deprivation is harmful to the cardiac performance. Optimizing myocardial energy metabolism may serve as an additional approach for managing HF, but further studies are warranted.     

Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals.

The ability of insulin to stimulate glucose disposal varies sixfold to eightfold among apparently healthy individuals. The only way that insulin-resistant persons can prevent the development of type 2 diabetes is by secreting the increased amount of insulin that is necessary to compensate for the resistance to insulin action. The greater the magnitude of muscle and adipose tissue insulin resistance, the more insulin must be secreted to maintain normal or near-normal glucose tolerance. Although compensatory hyperinsulinemia may prevent the development of fasting hyperglycemia in insulin-resistant individuals, the price paid is the untoward physiologic effects of increased circulating insulin concentrations on tissues that retain normal insulin sensitivity. This article focused on the interplay between insulin resistance at the level of the muscle and adipose tissue and normal hepatic insulin sensitivity; this leads to the atherogenic lipoprotein profile that is characteristic of insulin-resistant individuals. It would be inappropriate to minimize the importance of differential insulin sensitivity in the genesis of the changes in lipoprotein metabolism that increase CVD risk in insulin-resistant persons. It would be equally remiss not to emphasize that differential tissue insulin resistance also is necessary to explain why insulin-resistant/hyperinsulinemic individuals are more likely to develop the clinical syndromes (with the exception of type 2 diabetes mellitus) that are listed in Box 1.