Nutrient-induced insulin resistance in human skeletal muscle

Nutrient excess is associated with reduced insulin sensitivity (insulin resistance) and plays a central role in the pathogenesis of type 2 diabetes. Recently, free fatty acids as well as amino acids were shown to induce insulin resistance by decreasing glucose transport/phosphorylation with subsequent impairment of glycogen synthesis in human skeletal muscle. These results do not support the traditional concept of direct substrate competition with glucose for mitochondrial oxidation but indicate that the cellular mechanisms of such lipotoxicity and "proteotoxicity" might primarily affect the insulin signaling cascade. The signaling pathways involved in nutrient dependent modulation of insulin action include protein kinase C isoforms and IkappaB kinase. Therefore, pharmacological modulation of these enzymes might represent a promising target for future treatment of insulin resistance. Finally, hyperglycemia which occurs late in the insulin resistance syndrome further augments insulin resistance by mechanisms summarized as glucose toxicity. Chronic hyperglycemia might lead to inhibition of lipid oxidation and thereby to accumulation of intracellular lipid metabolites. Therefore, glucotoxicity might be in part indirectly caused by lipotoxicity (glucolipotoxicity). In conclusion, different nutrients affect common metabolic pathways and thereby induce insulin resistance in humans.     

The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact

Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM.     

The insulin-sensitizing role of the fat derived hormone adiponectin

Adiponectin is an insulin-sensitizing hormone whose blood concentration is reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin in rodents increases glucose uptake and increases fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole body insulin resistance. The exact receptor and signaling systems are unknown, however, recent studies suggest adiponectin activates AMPK, a putative master metabolic regulator. Thus, excitement surrounds the potential for adiponectin, or a homologue of adiponectin, as pharamacotherapy agents for patients suffering from the metabolic syndrome and more particularly for individuals with insulin resistance and type 2 diabetes.     

From a glucocentric to a lipocentric approach towards metabolic syndrome

Insulin resistance, the essential component of metabolic syndrome, has traditionally been defined from a glucocentric viewpoint, with glucotoxicity playing a lead role. However, as overabundant circulating fatty acids are now known to be overt contributors, there is a paradigm shift in the understanding of metabolic syndrome acknowledging the importance of lipotoxicity as a major perpetuator of insulin resistance. Ectopic accumulation of fat in liver, adipose, muscle and pancreatic islets, provokes insulin resistance through various mechanisms. Chronic inflammation/adipocytokine generation, endoplasmic reticulum stress and mitochondrial dysfunction/oxidative stress also contribute significantly towards insulin resistance. Targets that can act as counter regulators/master switches at the converging point of all these metabolic pathways are currently under intense development.     

Hepatobiliary diseases and insulin resistance

In recent years, there has been an increasing prevalence of obesity and related diseases. This epidemiological change has increased the interest of researchers in the molecular and biochemical pathways involved in the pathogenesis of hepatic and biliary diseases. Insulin resistance is considered the major mechanism involved in the hepatic and biliary manifestations of obesity. Epidemiological, clinical, and basic research demonstrates that insulin resistance is associated with gallstone disease, nonalcoholic fatty liver disease, and poor outcomes in viral hepatitis C treatments. Fascinating experimental evidence demonstrates that fat-induced hepatic insulin resistance may result from the activation of kinases leading to impaired insulin signaling. The insulin-resistant state is characterized by a failure to suppress hepatic glucose production and glycogenolysis, with enhanced fat accumulation in hepatocytes because of increased lipolysis, increased free fatty acid uptake by hepatocytes, and increased hepatic synthesis of triglycerides. This molecular signaling induces a low-grade chronic inflammatory state, characterized by increased levels of proinflammatory molecules and acute-phase proteins. This review summarizes the most important molecular and biochemical issues in the hepatic and biliary diseases associated with insulin resistance.     

High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS

Insulin resistance is the hallmark of type 2 diabetes. As an essential trace element, selenium (Se) is recommended worldwide for supplementation to prevent Se-deficient pathological conditions, including diabetes and insulin resistance. However, recent evidence has shown that supra-nutritional Se intake is positively associated with the prevalence of diabetes. In the present research, we examined the effect of high Se on insulin sensitivity, and studied possible mechanisms in rats and in rat hepatocytes. Insulin sensitivity and glucose/lipid metabolism were determined by glucose/insulin tolerance test, western blot, immunofluorescence, specific probes and other biochemical assays. We show that high Se activates selenoproteins, including glutathione peroxidase and selenoprotein P, and depletes chromium, leading to a common metabolic intersection—lipolysis in adipose tissue and influx of fatty acids in liver. Fatty acid β-oxidation generates acetyl-CoA, which is metabolized in trichloroacetic acid cycle, supplying excessive electrons for mitochondrial oxidative phosphorylation and leading to increased “bad” reactive oxygen species (ROS) production in mitochondria and final disturbance of insulin signaling. Furthermore, high Se-activated selenoproteins also weaken insulin-stimulated “good” ROS signal generated by NAD(P)H oxidase, leading to attenuation of insulin signaling. Taken together, these data suggest that excessive intake of Se induces hepatic insulin resistance through opposite regulation of ROS.     

How insulin receptor substrate proteins regulate the metabolic capacity of the liver--implications for health and disease

The liver plays a key role in glucose homeostasis, lipid and energy metabolism. Its function is primarily controlled by the anabolic hormone insulin and its counterparts glucagon, catecholamines and glucocorticoids. Dysregulation of this homeostatic system is a major cause for development of the metabolic syndrome and type 2 diabetes mellitus. The features of the underlying dynamic molecular network that coordinates systemic nutrient homeostasis are less clear. But recently, considerable progress has been made in elucidating molecular pathways and potential factors involved in the regulation of energy and lipid metabolism and affected in diabetic states. In this review we will focus on important stations in the complex network of molecules that control the balance between glucose production, glucose utilization and regulation of lipid metabolism. Special attention will be paid to the insulin receptor substrate (IRS) proteins with the two major isoforms IRS-1 and IRS-2 as a critical node in hepatic insulin signalling. IRS proteins act as docking molecules to connect tyrosine kinase receptor activation to essential downstream kinase cascades, including activation of the PI-3 kinase or MAPK cascade. IRS-1 and IRS-2 are complementary key players in the regulation of hepatic insulin signalling and expression of genes involved in gluconeogenesis, glycogen synthesis and lipid metabolism. The function of IRS proteins is regulated by their expression levels and posttranslational modifications. This regulation within the dynamic molecular network that coordinates systemic nutrient homeostasis will be outlined in detail under the following conditions: after feeding, during fasting and during exercise. Dysfunction of IRS proteins initially leads to post-prandial hyperglycemia, increased hepatic glucose production, and dysregulated lipid synthesis and is discussed as major pathophysiological mechanism for the development of insulin resistance and type 2 diabetes mellitus. Understanding the molecular regulation and the pathophysiological modifications of IRS proteins is crucial in order to identify new sites for potential intervention to treat or prevent hepatic insulin resistance and type 2 diabetes mellitus.     

Regulation of mitochondrial biogenesis in metabolic syndrome

Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessive lipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrial metabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation of intramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss of mitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation of mitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancing mitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transport chain and thus reducing metabolic inflammation.     

Multiple drug targets in the management of type 2 diabetes

Diabetes mellitus (DM) is being diagnosed at an alarming rate around the world. More than 90% of the estimated 200 million affected persons with diabetes worldwide have type 2 DM, an often clinically silent disorder. In the United States, nearly half of the estimated 16 million persons with diabetes remain undiagnosed. Type 2 diabetes is preceded by a long period of impaired glucose tolerance (IGT), a potentially reversible metabolic state associated with increased risk for macrovascular complications. At the time of diagnosis more than one-third of patients have already developed long-term complications of diabetes. Genetic and acquired factors contribute to the pathogenesis of type 2 diabetes. The pathophysiological hallmarks consist of progressive insulin resistance, pancreatic beta-cell dysfunction, and excessive hepatic glucose production. The ideal treatment for type 2 diabetes should correct insulin resistance, beta-cell dysfunction, and normalize hepatic glucose output, as well as prevent, delay, or reverse diabetic complications. Emerging targets for therapy of type 2 diabetes include inhibition of gluconeogenesis, lipolysis, and fatty acid oxidation, as well as stimulation of beta3-adrenergic receptors. Drug intervention for obesity is a legitimate adjunct to diabetes management. Additional drug targets include interventions to prevent or delay the progression of specific complications. Finally, primary prevention of type 2 diabetes is an important emerging strategy. The specific pharmacological agents acting at the various targets are discussed in this review. A targeted approach to the multiple underlying pathophysiologic processes offers the best chance of controlling diabetes and complications.     

游离脂肪酸与骨骼肌胰岛素抵抗的研究进展

胰岛素抵抗与肥胖、2型糖尿病、高血压、脂代谢紊乱、异常血凝及纤溶等代谢综合征的发生和发展密切相关。虽然胰岛素抵抗发生机制尚不完全清楚,但大量研究表明游离脂肪酸在机体胰岛素抵抗,特别是骨骼肌胰岛素抵抗方面发挥重要作用。本文就游离脂肪酸引起骨骼肌胰岛素抵抗的作用及其机制进行综述,以期为胰岛素抵抗的改善及治疗带来新的手段。     

Targeting the liver in the metabolic syndrome: evidence from animal models

The metabolic syndrome is an emerging global epidemic characterized by clustering of metabolic abnormalities leading to increased cardiovascular risk: glucose intolerance or type 2 diabetes, dyslipidemia, hypertension, and "central" obesity. Scientists are decoding and piecing together the molecular texture underlying the metabolic syndrome: insulin resistance and dyslipidemia stand out as central pathophysiological events. In this picture, the liver rises as the leading organ in the maintenance of metabolic fitness; it serves as the first relay station for processing dietary information, and encloses the whole biochemical machinery for both glucose and lipid storage and disposal. In addition, the liver is a target of the different endocrine molecules secreted by pancreatic beta-cells and adipose tissue. Evidence collected in animal models supports the central role of the liver in the metabolic syndrome. While specific bereft of insulin sensitivity in skeletal muscle and adipose tissue fails to induce diabetes at certain extent, this is constantly the outcome in case of hepatic insulin resistance. Also, dyslipidemia is currently interpreted as the result of increased flux of free fatty acids to the liver with ensuing misbalance of lipoprotein synthesis and removal. In this review we bring together recent advances in the field of lipid sensing nuclear receptors, adipokines and other molecules responsible for metabolic fitness, and provide a putative coherent frame to conceive the pathophysiology of the metabolic syndrome.     

Antimycin A-induced mitochondrial dysfunction is consistent with impaired insulin signaling in cultured skeletal muscle cells

Insulin resistance and mitochondrial dysfunction are characteristic features of type 2 diabetes mellitus. However, a causal relationship between insulin resistance and mitochondrial dysfunction has not been fully established in the skeletal muscle. Accordingly, we have evaluated the effect of antimycin A (AA), a mitochondrial electron transport chain complex III inhibitor, on mitochondrial bioenergetics and insulin signaling by exposing C2C12 skeletal muscle cells to its concentrations of 3.125, 6.25, 12.5, 25, and 50 μM for 12 h. Thereafter, metabolic activity, ROS production, glucose uptake, Seahorse XF Real-time ATP and Mito Stress assays were performed. Followed by real-time polymerase chain reaction (RT-PCR) and Western blot analysis. This study confirmed that AA induces mitochondrial dysfunction and promote ROS production in C2C12 myotubes, culminating in a significant decrease in mitochondrial respiration and downregulation of genes involved in mitochondrial bioenergetics (TFAM, UCP2, PGC1α). Increased pAMPK and extracellular acidification rates (ECAR) confirmed a potential compensatory enhancement in glycolysis. Additionally, AA impaired insulin signaling (protein kinase B/AKT) and decreased insulin stimulated glucose uptake. This study confirmed that an adaptive relationship exists between mitochondrial functionality and insulin responsiveness in skeletal muscle. Thus, therapeutics or interventions that improve mitochondrial function could ameliorate insulin resistance as well.     

Effects of pioglitazone on glucose and lipid metabolism in Wistar fatty rats

Insulin resistance is one of pathogenic factors for non-insulin-dependent diabetes mellitus (NIDDM). Pioglitazone (5-[4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzyl]-2,4-thiazolidinedione, AD-4833, also known as U-72, 107E) is a promising candidate to lower hyperglycemia by reducing insulin resistance. The genetically obese-hyperglycemic rats. Wistar fatty, were used to test the action of pioglitazone, because they develop severe insulin resistance in the peripheral tissues (muscle and adipose tissue) and liver. Pioglitazone administered orally (0.3-3 mg/kg/d for 7 days) dose dependently reduced hyperglycemia, hyperlipidemia, and hyperinsulinemia in male fatty rats. Pioglitazone improved glucose tolerance and augmented the glycemic response to exogenous insulin and clearance of plasma triglyceride. These effects on glucose and lipid metabolism seem to be due to increased insulin sensitivity and responsiveness in the peripheral tissues, because pioglitazone increased insulin-stimulated glycogen synthesis and glycolysis in the isolated soleus muscles, and insulin-stimulated glucose oxidation and lipogenesis in adipocytes. The latter effects were not accompanied by any changes in insulin binding. The actions of insulin mimickers (vanadate and vitamin K5), which act on the post-insulin binding sites, on these metabolic events were also potentiated by pioglitazone. These findings suggest that pioglitazone can improve glucose and lipid metabolism by reducing insulin resistance on the post-binding system. Therefore, pioglitazone may be efficacious for treating human NIDDM.     

肾素-血管紧张素系统阻断剂治疗代谢综合征的进展

代谢综合征以胰岛素抵抗为主要特征,是心血管疾病的危险因素。非酒精性脂肪性肝病（non—alcoholic fatty liver disease,NAFLD）是代谢综合征在肝脏的表现。肾素-血管紧张素系统（renin—angiotensin system,RAS）的激活参与了代谢综合征的发生、发展,阻断RAS的激活是代谢综合征的治疗途径之-。RAS阻断剂包括血管紧张素转换酶抑制剂（angiotensin converting enzyme inhibitor, ACEI）和血管紧张素Ⅱ受体拮抗剂（angiotensin receptor blockade, ARB）,可降低血压、改善胰岛β细胞功能和胰岛素抵抗,但RAS阻断剂对NAFLD的疗效尚存在争议。该文就RAS阻断剂治疗代谢综合征的进展进行了综述。     

Central role of the adipocyte in insulin resistance

Mechanisms of insulin resistance in subjects at risk for type 2 diabetes remain to be elucidated. Insulin acts slowly in vivo, but rapidly in vitro, suggesting that the pathway insulin traverses from B-cell to insulin sensitive tissue may be altered in diabetes. An important component of that pathway is transport of insulin across the capillary endothelium. Several groups have demonstrated that insulin resistance may result from reduced capillary permeability to insulin--it remains to be determined whether reduced permeability contributes to insulin resistance in any stage leading to type 2 diabetes. Interestingly, the transport of insulin across the endothelial barrier not only limits the rate of insulin to stimulate glucose uptake by skeletal muscle, but appears also to determine the rate at which insulin suppresses liver glucose output. Because the liver circulation is fenestrated, it is not possible that insulin transport into the liver is the rate determining step for suppression of liver glucose output. An alternative hypothesis was considered--that insulin is transported into an extrahepatic tissue. A "second signal" is generated by the extrahepatic tissue, the signal is released into the blood, and the signal in turn controls hepatic glucose output. Several lines of evidence suggest that the second signal is free fatty acids (FFA): 1) There is a strong correlation between FFA and liver glucose output under a variety of experimental conditions. 2) If FFA are maintained at basal concentrations during insulin administration, glucose output fails to decline. 3) If FFA are reduced independent of insulin administration, glucose output is reduced. These three points support the concept that insulin, by regulating adipocyte lipolysis, controls liver glucose production. Thus, the adipocyte is a critical mediator between insulin and liver glucose output. Evidence that FFA also suppress skeletal muscle glucose uptake and insulin secretion from the B-cell supports the overall central role of the adipocyte in the regulation of glycemia. Insulin resistance at the fat cell may be an important component of the overall regulation of glycemia because of the relationships between FFA and glucose production, glucose uptake, and insulin release. It is possible that insulin resistance at the adipocyte itself can be a major cause of the dysregulation of carbohydrate metabolism in the prediabetic state.     

New solutions for type 2 diabetes mellitus: the role of pioglitazone

Type 2 diabetes mellitus remains a significant burden to the Canadian healthcare system. Over 2 million Canadians have diabetes, with 85 to 90% having type 2 diabetes. Insulin resistance is a major pathophysiological mechanism in the development of type 2 diabetes. Insulin resistance can be defined as an impaired biological response to the metabolic and/or mitogenic effects of either exogenous or endogenous insulin. As a consequence of insulin resistance, type 2 diabetes is characterised by decreased glucose transport and utilisation at the level of muscle and adipose tissue and increased glucose production by the liver. The traditional oral agents used to treat type 2 diabetes clearly do not address the underlying insulin resistance responsible for the development of diabetes. Thiazolidinediones (TZDs) represent a relatively new class of oral hypoglycaemic medications that have been shown to reverse some of the metabolic processes believed responsible for the development of insulin resistance and, ultimately, type 2 diabetes. Research has demonstrated that TZDs activate peroxisome proliferator activator receptors, in particular, the gamma-receptor isoform. Pioglitazone is a TZD that reduces plasma glucose levels by increasing peripheral glucose utilisation and decreasing hepatic glucose production. Clinical studies with pioglitazone have demonstrated the following: absolute reductions in glycosylated haemoglobin of 0.8 to 2.6%; reductions in fasting plasma glucose of 1.7 to 4.4 mmol/L; an increase in high density lipoprotein cholesterol of 8.7 to 12.6%; and a decrease in triglycerides of 18.2 to 26.0%, with no significant effects on low density lipoprotein or total cholesterol.     

Insulin sensitiser drugs

Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease.     

Insulin sensitiser drugs

Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease.