GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease?

To gain further insight into the mechanisms underlying muscle insulin resistance, the influence of obesity and type 2 diabetes on GLUT4 immunoreactivity in slow and fast skeletal muscle fibers was studied. Through a newly developed, very sensitive method using immunohistochemistry combined with morphometry, GLUT4 density was found to be significantly higher in slow compared with fast fibers in biopsy specimens from lean and obese subjects. In contrast, in type 2 diabetic subjects, GLUT4 density was significantly lower in slow compared with fast fibers. GLUT4 density in slow fibers from diabetic patients was reduced by 9% compared with the weight-matched obese subjects and by 18% compared with the lean control group. The slow-fiber fraction was reduced to 86% in the obese subjects and to 75% in the diabetic subjects compared with the control group. Estimated GLUT4 contribution from slow fibers was reduced to 77% in the obese subjects and to 61% in type 2 diabetic patients compared with the control subjects. We propose that a reduction in the fraction of slow-twitch fibers, combined with a reduction in GLUT4 expression in slow fibers, may reduce the insulin-sensitive GLUT4 pool in type 2 diabetes and thus contribute to skeletal muscle insulin resistance.

[1]  P. Poulsen,et al.  Direct evidence of fiber type-dependent GLUT-4 expression in human skeletal muscle. , 2000, American journal of physiology. Endocrinology and metabolism.

[2]  L. Rossetti,et al.  Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. , 1999, Diabetes.

[3]  J. Zierath,et al.  Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats. , 1999, Diabetes.

[4]  A. Baron,et al.  Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. , 1998, The Journal of clinical investigation.

[5]  H. Beck-Nielsen.  Mechanisms of Insulin Resistance in Non-Oxidative Glucose Metabolism: The Role of Glycogen Synthase , 1998, Journal of basic and clinical physiology and pharmacology.

[6]  S. Lillioja,et al.  Interrelationships between muscle morphology, insulin action, and adiposity. , 1996, The American journal of physiology.

[7]  L. Baur,et al.  Relationships between muscle membrane lipids, fiber type, and enzyme activities in sedentary and exercised rats. , 1995, The American journal of physiology.

[8]  C. Bouchard,et al.  Genetic determinism of fiber type proportion in human skeletal muscle , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  G. Dohm,et al.  Skeletal muscle fiber composition is related to adiposity and in vitro glucose transport rate in humans. , 1995, The American journal of physiology.

[10]  F. Dela,et al.  Physical Training Increases Muscle GLUT4 Protein and mRNA in Patients With NIDDM , 1994, Diabetes.

[11]  J. Zierath,et al.  Elevated free fatty acid levels inhibit glucose phosphorylation in slow-twitch rat skeletal muscle. , 1994, Acta physiologica Scandinavica.

[12]  H. Vestergaard,et al.  GLUT-4 content in plasma membrane of muscle from patients with non-insulin-dependent diabetes mellitus. , 1993, The American journal of physiology.

[13]  W. Soeller,et al.  Germline manipulation of glucose homeostasis via alteration of glucose transporter levels in skeletal muscle. , 1993, The Journal of biological chemistry.

[14]  M. Mueckler,et al.  Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle. , 1993, The Journal of biological chemistry.

[15]  C. Cobelli,et al.  Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. , 1993, The Journal of clinical investigation.

[16]  A. Marette,et al.  Insulin Induces the Translocation of GLUT4 From a Unique Intracellular Organelle to Transverse Tubules in Rat Skeletal Muscle , 1992, Diabetes.

[17]  A. Marette,et al.  Abundance, localization, and insulin-induced translocation of glucose transporters in red and white muscle. , 1992, The American journal of physiology.

[18]  A. Baron,et al.  Gene Expression of GLUT4 in Skeletal Muscle From Insulin-Resistant Patients With Obesity, IGT, GDM, and NIDDM , 1992, Diabetes.

[19]  J. Friedman,et al.  Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4. , 1992, The Journal of clinical investigation.

[20]  J. Friedman,et al.  Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors. , 1991, The American journal of physiology.

[21]  J. Stephens,et al.  Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level. , 1990, The Biochemical journal.

[22]  J. Flier,et al.  Evidence Against Altered Expression of GLUT1 or GLUT4 in Skeletal Muscle of Patients With Obesity or NIDDM , 1990, Diabetes.

[23]  G I Bell,et al.  Molecular Biology of Mammalian Glucose Transporters , 1990, Diabetes Care.

[24]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[25]  E. Horton,et al.  Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. , 1990, The Journal of biological chemistry.

[26]  H J Gundersen,et al.  The efficiency of systematic sampling in stereology and its prediction * , 1987, Journal of microscopy.

[27]  C Bogardus,et al.  Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. , 1987, The Journal of clinical investigation.

[28]  J. Olefsky,et al.  Effects of Weight Loss on Mechanisms of Hyperglycemia in Obese Non-Insulin-Dependent Diabetes Mellitus , 1986, Diabetes.

[29]  Marinos C. Dalakas,et al.  Muscle biopsy — a practical approach , 1986, The Ulster Medical Journal.

[30]  R. Hamman,et al.  The Effect of Insulin Treatment on Insulin Secretion and Insulin Action in Type II Diabetes Mellitus , 1985, Diabetes.

[31]  E. Richter,et al.  Increased muscle glucose uptake during contractions: no need for insulin. , 1984, The American journal of physiology.

[32]  J. A. Scarlett,et al.  The Acute and Chronic Effects of Sulfonylurea Therapy in Type II Diabetic Subjects , 1984, Diabetes.