Liver cirrhosis (LC) and insulin resistance (IR) are closely correlated, clinically presenting hyperglycemia, hyperinsulinism, hyperlipidemia and high cytokines levels, however, the underlying mechanism is not completely clear. Recent reports show that insulin receptor substrate-1 (IRS-1) is associated with IR in LC. IRS-1 plays a pivotal role on insulin signal transduction; it changes insulin signaling by up-or down-regulating of protein presentation, post-translational modification and subcellular localization of proteins, particularly in phosphorylation/dephosphorylation of post-translational modification. Furthermore, LC with different etiology may have different mechanism of IRS-1 effect on IR.
Humans ; Insulin ; metabolism ; Insulin Receptor Substrate Proteins ; metabolism ; physiology ; Insulin Resistance ; Liver Cirrhosis ; metabolism

Skeletal muscle is the largest organ of human body, which completes 80%-90% of glucose intake stimulated by insulin, and is closely related to the occurrence and development of insulin resistance (IR). Skeletal muscle is one of the main places of lipid metabolism, and lipid metabolites participate in skeletal muscle metabolism as signal molecules. Fatty acids regulate skeletal muscle insulin sensitivity through insulin signaling pathway, inflammatory response and mitochondrial function. Saturated fatty acids (SFAs) induce insulin resistance by impairing insulin signal transduction, inducing mitochondrial dysfunction and inflammatory response, while unsaturated fatty acids reverse the adverse effects of SFAs and ameliorate IR by enhancing insulin signal transduction and anti-inflammatory effect. In addition, disorders of lipid metabolism in skeletal muscle cause accumulation of harmful metabolic intermediates, such as diacylglycerol, ceramide and long-chain acyl-coenzyme A, and induce IR by directly or indirectly damaging insulin signaling pathway. This article reviews the research progress of lipid metabolic intermediates regulating insulin sensitivity in skeletal muscle, which will help to better understand the pathogenesis of diabetes.
Humans ; Insulin Resistance/physiology* ; Muscle, Skeletal/metabolism* ; Insulin/metabolism* ; Lipid Metabolism ; Fatty Acids/metabolism*

Insulin resistance is a common pathophysiological mechanism of obesity and type 2 diabetes mellitus. Skeletal muscle is one of the major target organs of insulin-mediated glucose uptake, metabolism and utilization, and it is the earliest and most important site of insulin resistance. Studies have shown that the impairments of glucose uptake, insulin signaling pathway and mitochondrial biosynthesis are closely related to skeletal muscle insulin resistance. When insulin resistance develops in skeletal muscle, multiple microRNAs (miRNAs) are up-regulated (miR-106b, miR-23a, miR-761, miR-135a, Let-7 and miR-29a) or down-regulated (miR-133a, miR-149 and miR-1). They participate in the regulation of skeletal muscle glucose uptake, insulin signaling pathway and mitochondrial biogenesis, and thus play important roles in the occurrence and development of skeletal muscle insulin resistance. Therefore, these miRNAs may serve as potential targets for the treatment of skeletal muscle insulin resistance or diabetes.
Diabetes Mellitus, Type 2 ; Humans ; Insulin ; Insulin Resistance ; MicroRNAs ; genetics ; Muscle, Skeletal ; physiology

The AMP-activated protein kinase (AMPK) widely exists in skeletal muscle, liver, pancreas, adipose tissue and central nervous system. As a "cellular energy regulator", activation of AMPK can improve insulin resistance in various mechanisms. To overall understand the importance of AMPK in exercise, the article summarized the research progress on AMPK exercise activation in skeletal muscle, liver and adipose tissue as well as exercise improving cardiovascular insulin resistance by AMPK, and looked forward to the study future of AMPK exercise activation.
AMP-Activated Protein Kinases ; physiology ; Adipose Tissue ; physiology ; Exercise ; physiology ; Humans ; Insulin Resistance ; Liver ; physiology ; Muscle, Skeletal ; physiology

Insulin resistance is a major risk factor for developing type 2 diabetes caused by the inability of insulin-target tissues to respond properly to insulin, and contributes to the morbidity of obesity. Insulin action involves a series of signaling cascades initiated by insulin binding to its receptor, eliciting receptor autophosphorylation and activation of the receptor tyrosine kinase, resulting in tyrosine phosphorylation of insulin receptor substrates (IRSs). Phosphorylation of IRSs leads to activation of phosphatidylinositol 3-kinase (PI3K) and, subsequently, to activation of Akt and its downstream mediator AS160, all of which are important steps for stimulating glucose transport induced by insulin. Although the mechanisms underlying insulin resistance are not completely understood in skeletal muscle, it is thought to result, at least in part, from impaired insulin-dependent PI3K activation and downstream signaling. This review focuses on the molecular basis of skeletal muscle insulin resistance in obesity and type 2 diabetes. In addition, the effects of insulin-sensitizing agent treatment and lifestyle intervention of human insulin-resistant subjects on insulin signaling cascade are discussed. Furthermore, the role of Rho-kinase, a newly identified regulator of insulin action in insulin control of metabolism, is addressed.
Blood Glucose/*metabolism ; Diabetes Mellitus, Type 2/*metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/*physiology ; Obesity, Abdominal/*metabolism ; Signal Transduction/physiology

Female ; Fetal Growth Retardation ; genetics ; physiopathology ; Humans ; Insulin Resistance ; physiology ; Insulin-Secreting Cells ; physiology ; Metabolic Syndrome ; embryology ; etiology ; Pregnancy

OBJECTIVETo investigate the mechanism of hepatocytic insulin signal transduction defects in severely scalded rats, so as to clarify the molecular basis of postburn insulin resistance.

METHODSWistar rats inflicted by 30% III degree scalding on the back were employed as the model. The rat hepatocytic insulin receptor was partially purified by wheat-germ agglutinin (WGA)-sepharose 4B affinity chromatography. The change of receptor tyrosine protein kinase (TPK) activity, the receptor beta-subunit autophosphorylation and the hepatocytic insulin receptor binding behavior of scalded rats during early stage of scalding were observed by means of insulin receptor binding test, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) autoradiography of phosphorylation of insulin receptor and phosphorylation of exogenous substrate.

RESULTSThere exhibited no evident changes of hepatocytic insulin receptor maximal binding capacity and affinity at 3 postburn days (PBDs) in scalded rats. The autophosphorylation capacity of the receptor beta-subunit decreased significantly. And the receptor TPK activity decreased obviously and its reaction to insulin stimulation decreased markedly.

CONCLUSIONThe defects of the insulin receptor signal transduction in hepatocyte leading to the post-receptor defects of insulin biological effects might be molecular mechanism of postburn insulin resistance.

Animals ; Burns ; metabolism ; pathology ; physiopathology ; Disease Models, Animal ; Hepatocytes ; metabolism ; Insulin ; physiology ; Insulin Resistance ; physiology ; Phosphorylation ; Rats ; Rats, Wistar ; Receptor, Insulin ; metabolism ; Signal Transduction ; physiology

More and more evidence suggests that microRNA is widely involved in the regulation of cardiovascular function. Our preliminary experiment showed that miR-494-3p was increased in heart of diabetic rats, and miR-494-3p was reported to be related to metabolism such as obesity and exercise. Therefore, this study was aimed to explore the role of miR-494-3p in diabetic myocardial insulin sensitivity and the related mechanism. The diabetic rat model was induced by high fat diet (45 kcal% fat, 12 weeks) combined with streptozotocin (STZ, 30 mg/kg), and cardiac tissue RNA was extracted for qPCR. The results showed that the level of miR-494-3p was significantly up-regulated in the myocardium of diabetic rats compared with the control (P < 0.05). The level of miR-494-3p in H9c2 cells cultured in high glucose and high fat medium (HGHF) was significantly increased (P < 0.01) with the increase of sodium palmitate concentration, whereas down-regulation of miR-494-3p in HGHF treated cells led to an increase in insulin-stimulated glucose uptake (P < 0.01) and the ratio of p-Akt/Akt (P < 0.05). Over-expression of miR-494-3p in H9c2 cell line significantly inhibited insulin-stimulated glucose uptake and phosphorylation of Akt (P < 0.01). Bioinformatics combined with Western blotting experiments confirmed insulin receptor substrate 1 (IRS1) as a target molecule of miR-494-3p. These results suggest that miR-494-3p reduces insulin sensitivity in diabetic cardiomyocytes by down-regulating IRS1.
Animals ; Diabetes Mellitus, Experimental ; physiopathology ; Down-Regulation ; Insulin ; Insulin Receptor Substrate Proteins ; physiology ; Insulin Resistance ; MicroRNAs ; genetics ; Myocytes, Cardiac ; physiology ; Rats

It is well known that many Korean patients with type 2 diabetes mellitus (T2DM) were non-obese and had decreased insulin secretion in past. However, during the past three decades, lifestyles in Korea have been westernized. As a result, the prevalence of obesity, the main cause of diabetes has increased. Thus, there is still a question as to whether the main pathophysiology of current Korean T2DM is insulin resistance or an insulin secretion defect. Because various anti-diabetes medications having different mechanisms of action are currently used as therapeutics, it is important to understand which of these factors is the main physiology in the development of diabetes in Koreans. In this review, we review changes in obesity prevalence, insulin resistance and insulin secretion defects in Korean T2DM during three decades.
Asian Continental Ancestry Group ; Diabetes Mellitus, Type 2* ; Humans ; Insulin Resistance* ; Insulin* ; Korea ; Life Style ; Obesity ; Physiology ; Prevalence

Obesity is a major cause of insulin resistance and type 2 diabetes. The altered glucose homeostasis is caused by faulty insulin signal transduction, which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, leading to the induction of inducible nitric oxide synthase and release of high levels of nitric oxide and reactive nitrogen species, which together cause posttranslational modifications in the signaling proteins. There are substantial differences in the molecular mechanisms of insulin resistance in muscle versus liver. Hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The role of the central nervous system in glucose homeostasis also has been well established. Multi-pronged therapies aimed at rectifying obesity induced anomalies in both central nervous system and peripheral tissues may prove to be beneficial. The golden standard method to evaluate the insulin sensitivity is hyperinsulinemic euglycemic clamp.
Diabetes Mellitus, Type 2 ; etiology ; Glucose ; metabolism ; Humans ; Insulin ; metabolism ; Insulin Resistance ; physiology ; Obesity ; complications ; metabolism ; physiopathology