Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4.

Abstract

A major defect contributing to impaired insulin action in human obesity is reduced glucose transport activity in skeletal muscle.This study was designed to determine whether the improvement in whole body glucose disposal associated with weight reduction is related to a change in skeletal muscle glucose transport activity and levels of the glucose transporter protein GLUT4. Seven morbidly obese (body mass index = 45.8±2.5, mean ± SE) patients, including four with non-insulin-dependent diabetes mellitus (NIDDM), underwent gastric bypass surgery for treatment of their obesity. In vivo glucose disposal during a euglycemic clamp at an insulin infusion rate of 40 mU/mi per min was reduced to 27% of nonobese controls (P < 0.01) and improved to 78% of normal after weight loss of 43.1±3.1 kg (P < 0.01). Maximal insulin-stimulated glucose transport activity in incubated muscle fibers was reduced by _ 50% in obese patients at the time of gastric bypass surgery but increased twofold (P < 0.01) to 88% of normal in five separate patients after similar weight reduction. Muscle biopsies obtained from vastus lateralis before and after weight loss revealed no significant change in levels of GLUT4 glucose transporter protein. These data demonstrate conclusively that insulin resistance in skeletal muscle of mobidly obese patients with and without NIDDM cannot be causally related to the cellular content of GLUT4 protein. The results further suggest that morbid obesity contributes to whole body insulin resistance through a reversible defect in skeletal muscle glucose transport activity. The mechanism for this improvement may involve enhanced transporter translocation and/or activation. (J. Clin.

Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.

“…Decreased GLUT4 levels are also seen in several animal models of chronic hyperglycemia such as in the streptozotocin treated diabetic rat and the Zucker ZDF/Drt-fa rat (26)(27)(28). Decreased GLUT4 levels such as are seen in these animal models are not observed in human NIDDM where total GLUT4 levels are normal but GLUT4 function or translocation is impaired (29,30). On the other hand, GLUT4 levels do correlate with insulin sensitivity in nondiabetic humans (31).…”

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

“…In MetS, increased visceral adipose tissue disturbs adipokine secretion and leads to a low-grade chronic inflammatory state mediated by the infiltration of macrophages into adipose tissue [14]. This inflammatory state is found to be associated with IR [15][16][17] and with atherosclerosis [14]. Visceral adipose tissue functions as a paracrine and an endocrine organ, secreting a number of adipokines, some of which are proinflammatory and atherogenic, such as leptin, tumor necrosis factor-α (TNF-α), resistin, interleukin-6 (IL-6), and fatty acid-binding protein 4, and others, which have anti-inflammatory, protective effects such as adiponectin [12,13].…”

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

“…When animals were chronically treated with insulin, mRNA level in adipose tissue is increased whereas chronic treatment of insulin to 3T3-L1 adipocytes with insulin resulted in a decrease or no change in GLUT4 mRNA (16), suggesting that insulin plays an indirect role in regulating GLUT4 gene expression. Insulin resistance associated with obesity or T2DM does not seem to affect GLUT4 gene expression in skeletal muscle of spontaneously obese db/db rats (17). Reduction in the glucose transporter activity in skeletal muscle in insulin resistance is the result of a decrease in insulin-stimulated GLUT4 translocation (18).…”