Abstract
Insulin resistance is a state of impaired responsiveness to insulin action. This condition not only results in deficient glucose uptake but increases the risk for cardiovascular diseases (CVD), stroke, and obesity. The present work investigates the molecular mechanisms of high carbohydrate and fat diet in inducing prediabetic hyperinsulinemia and effect of exercise on InsR signaling events, muscular AChE, and lactate dehydrogenase activity. Adult male Wistar rats were divided into the control (C) diet group, high-carbohydrate diet (HCD) group, high-fat diet (HFD) group, and HCD and HFD groups with exercise (HCD Ex and HFD Ex, respectively). Acetyl choline esterase activity, lactate dehydrogenase activity, total lactate levels, IRS1 phosphorylations, and Glut4 expression patterns were studied in the muscle tissue among these groups. High carbohydrate and fat feeding led to hyperinsulinemic status with reduced acetylcholine esterase (AChE) activity and impaired phosphorylation of IRS1 along with increased lactate concentrations in the muscle. Exercise significantly upregulated phosphoinositide 3 kinase (PI3K) docking site phosphorylation and downregulated the negative IRS1 phosphorylations thereby increasing the glucose transporter (GLUT) expressions and reducing the lactate accumulation. Also, the levels of second messengers like IP3 and cAMP were increased with exercise. Increased second messenger levels induce calcium release thereby activating the downstream pathway promoting the translocation of GLUT4 to the plasma membrane. Our results showed that the metabolic and signaling pathway dysregulations seen during diet-induced hyperinsulinemia, a metabolic condition seen during the early stages in the development of prediabetes, were improved with vigorous physical exercise. Thus, exercise can be considered as an excellent management approach over drug therapy for diabetes and its complications.
Highlights
Type 2 diabetes mellitus is a complex metabolic disease with an environmental and genetic component affecting over 5% of the population in Western societies
Our studies showed that body weight, total cholesterol, and total circulating insulin of high-fat-and high-carbohydrate-fed rats increased compared to those of the control
The body weight, total cholesterol, total circulating insulin, and blood glucose levels were reduced to near to the control (P < 0:001 high-fat diet (HFD) Ex when compared to HFD, P < 0:01 high-carbohydrate diet (HCD) Ex when compared to HCD)
Summary
Type 2 diabetes mellitus is a complex metabolic disease with an environmental and genetic component affecting over 5% of the population in Western societies. Several studies suggest 3 phases for type 2 diabetes mellitus development: hyperinsulinemia stage, prediabetes stage, and diabetes stage [3]. One-third of ingested glucose is used by the liver and the rest by peripheral tissues, primarily the skeletal muscle via an insulin-dependent mechanism. High glucose stimulates the pancreas to secrete more insulin thereby increasing the high glucose uptake in the skeletal muscle leading to the clearance of ingested glucose. Insulin-stimulated glucose disposal in the skeletal muscle is markedly impaired. In the transition from normal to impaired and diabetic glucose tolerance, hyperinsulinemia is the initiating agent which exists long before type 2 diabetes occurs, and an intervention or treatment during this early stage/hyperinsulinemic period may have a better opportunity to prevent or delay the occurrence or development of diabetes and its complications. The harmful effect of insulin on the vascular endothelium has been supported
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