Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes.

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in non-insulin-dependent diabetes mellitus (NIDDM). Which cellular effectors of glucose metabolism are involved is still unknown. We investigated whether transmembrane glucose transport in vivo is impaired in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in six nonobese NIDDM patients and five age- and weight-matched controls. Unlabeled D-mannitol (a nontransportable molecule) and radioactive 3-O-methyl-D-glucose (the reference molecular probe to assess glucose transport activity) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo transmembrane transport of 3-O-methyl-D-glucose in forearm muscle was determined by computerized analysis of the washout curves. At similar steady-state plasma concentrations of insulin (approximately 500 pmol/liter) and glucose (approximately 5.15 mmol/liter), transmembrane inward transport of 3-O-methyl-D-glucose in skeletal muscle was markedly reduced in the NIDDM patients (6.5 x 10(-2) +/- 0.56 x 10(-2).min-1) compared with controls (12.5 x 10(-2) +/- 1.5 x 10(-2).min-1, P < 0.005). Mean glucose uptake was also reduced in the diabetics both at the whole body level (9.25 +/- 1.84 vs. 28.3 +/- 2.44 mumol/min per kg, P < 0.02) and in the forearm tissues (5.84 +/- 1.51 vs. 37.5 +/- 7.95 mumol/min per kg, P < 0.02). When the latter rates were extrapolated to the whole body level, skeletal muscle accounted for approximately 80% of the defect in insulin action seen in NIDDM patients. We conclude that transmembrane glucose transport, when assessed in vivo in skeletal muscle, is insensitive to insulin in nonobese NIDDM patients, and plays a major role in determining whole body insulin resistance.

[1]  C. Cobelli,et al.  Effect of insulin on system A amino acid transport in human skeletal muscle. , 1993, The Journal of clinical investigation.

[2]  C Cobelli,et al.  Glucose Transport in Human Skeletal Muscle: The In Vivo Response to Insulin , 1993, Diabetes.

[3]  R. DeFronzo,et al.  The Metabolic Profile of NIDDM Is Fully Established in Glucose-Tolerant Offspring of Two Mexican-American NIDDM Parents , 1992, Diabetes.

[4]  L. Groop,et al.  Impaired Activation of Glycogen Synthase in People at Increased Risk for Developing NIDDM , 1992, Diabetes.

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

[6]  R. DeFronzo,et al.  The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. , 1992, Diabetes.

[7]  D. Galuska,et al.  Decreased insulin-stimulated 3-0-methylglucose transport in in vitro incubated muscle strips from type II diabetic subjects. , 1991, Acta physiologica Scandinavica.

[8]  M. Laakso,et al.  Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy. , 1991, The Journal of clinical investigation.

[9]  C. Carter-Su,et al.  Adipose Tissue Glucose Transporters in NIDDM: Decreased Levels of Muscle/Fat Isoform , 1991, Diabetes.

[10]  M. Birnbaum,et al.  Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. , 1991, The Journal of clinical investigation.

[11]  J. Friedman,et al.  Decreased expression of glucose transporter in muscle from insulin-resistant patients. , 1991, The American journal of physiology.

[12]  R. Henry,et al.  Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus. , 1991, The Journal of clinical investigation.

[13]  L. Mandarino,et al.  Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. , 1990, The Journal of clinical investigation.

[14]  A. Carruthers,et al.  Facilitated diffusion of glucose. , 1990, Physiological reviews.

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

[16]  P. Bennett,et al.  Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. , 1990, Diabetes/metabolism reviews.

[17]  C. Bogardus,et al.  Insulin resistance is associated with reduced fasting and insulin-stimulated glycogen synthase phosphatase activity in human skeletal muscle. , 1990, The Journal of clinical investigation.

[18]  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.

[19]  T. Jenssen,et al.  Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. , 1990, Diabetes.

[20]  C Cobelli,et al.  A compartmental model to quantitate in vivo glucose transport in the human forearm. , 1989, The American journal of physiology.

[21]  L. Groop,et al.  Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. , 1989, The New England journal of medicine.

[22]  L. Groop,et al.  Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. , 1989, The Journal of clinical investigation.

[23]  G I Bell,et al.  Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. , 1989, The Journal of biological chemistry.

[24]  M. Birnbaum.  Identification of a novel gene encoding an insulin-responsive glucose transporter protein , 1989, Cell.

[25]  H. Lodish,et al.  A glucose transport protein expressed predominately in insulin-responsive tissues. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. James,et al.  Molecular cloning and characterization of an insulin-regulatable glucose transporter , 1989, Nature.

[27]  P. Bennett,et al.  The natural history of impaired glucose tolerance in the Pima Indians. , 1988, The New England journal of medicine.

[28]  R. Napoli,et al.  Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance. , 1988, The Journal of clinical endocrinology and metabolism.

[29]  G I Bell,et al.  Evidence for a family of human glucose transporter-like proteins. Sequence and gene localization of a protein expressed in fetal skeletal muscle and other tissues. , 1988, The Journal of biological chemistry.

[30]  G. Dohm,et al.  An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. , 1988, The Journal of clinical investigation.

[31]  B. Hansen,et al.  Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. , 1988, The Biochemical journal.

[32]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[33]  R. Barnard,et al.  Mechanism of insulin action on glucose transport in rat skeletal muscle. , 1988, The American journal of physiology.

[34]  J. Olefsky,et al.  Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. , 1988, The Journal of clinical investigation.

[35]  H. Joost,et al.  Qualitative and quantitative comparison of glucose transport activity and glucose transporter concentration in plasma membranes from basal and insulin-stimulated rat adipose cells. , 1988, The Biochemical journal.

[36]  S. Cherry,et al.  Physics in Nuclear Medicine , 2004 .

[37]  E. Cerasi,et al.  In Vitro Autoregulation of Glucose Utilization in Rat Soleus Muscle , 1987, Diabetes.

[38]  H. Yki-Järvinen,et al.  Hyperglycemia Decreases Glucose Uptake in Type I Diabetes , 1987, Diabetes.

[39]  E. Barrett,et al.  Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. , 1987, The Journal of clinical investigation.

[40]  H. Yki-Järvinen,et al.  Kinetics of glucose disposal in whole body and across the forearm in man. , 1987, The Journal of clinical investigation.

[41]  R. DeFronzo,et al.  Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. , 1987, The Journal of clinical investigation.

[42]  N. Toyoda,et al.  Reassessment of insulin effects on the Vmax and Km values of hexose transport in isolated rat epididymal adipocytes. , 1987, The Journal of biological chemistry.

[43]  R. Horuk,et al.  Dissociation of insulin-stimulated glucose transport from the translocation of glucose carriers in rat adipose cells. , 1987, The Journal of biological chemistry.

[44]  J. Olefsky,et al.  Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. A new mechanism of insulin resistance. , 1987, The Journal of biological chemistry.

[45]  E. Cerasi,et al.  Substrate regulation of the glucose transport system in rat skeletal muscle. Characterization and kinetic analysis in isolated soleus muscle and skeletal muscle cells in culture. , 1986, The Journal of biological chemistry.

[46]  S. Lillioja,et al.  Insulin sensitivity in adipocytes from subjects with varying degrees of glucose tolerance. , 1986, The American journal of physiology.

[47]  J B Bassingthwaighte,et al.  Multiple tracer dilution estimates of D- and 2-deoxy-D-glucose uptake by the heart. , 1986, The American journal of physiology.

[48]  R. DeFronzo,et al.  Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. , 1985, The Journal of clinical investigation.

[49]  J P Clarys,et al.  Gross tissue weights in the human body by cadaver dissection. , 1984, Human biology.

[50]  R. Maughan,et al.  The relative proportions of fat, muscle and bone in the normal human forearm as determined by computed tomography. , 1984, Clinical science.

[51]  S. Lillioja,et al.  Correlation between muscle glycogen synthase activity and in vivo insulin action in man. , 1984, The Journal of clinical investigation.

[52]  E. H. Twizell.  The mathematical modeling of metabolic and endocrine systems: E.R. Carson, C. Cobelli and L. Finkelstein John Wiley and Sons, Chichester, Sussex, UK, 394 pp., £45.15, 1983 , 1984 .

[53]  R. DeFronzo,et al.  Splanchnic and Peripheral Disposal of Oral Glucose in Man , 1983, Diabetes.

[54]  J. A. Scarlett,et al.  Insulin treatment reverses the postreceptor defect in adipocyte 3-O-methylglucose transport in type II diabetes mellitus. , 1983, The Journal of clinical endocrinology and metabolism.

[55]  R. DeFronzo,et al.  Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man , 1983, Diabetes.

[56]  J. A. Scarlett,et al.  Role of Glucose Transport in the Postreceptor Defect of Non-insulin-dependent Diabetes Mellitus , 1982, Diabetes.

[57]  R. DeFronzo,et al.  The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization , 1981, Diabetes.

[58]  T. Kôno,et al.  Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[59]  K. Zierler,et al.  THEORY OF THE USE OF ARTERIOVENOUS CONCENTRATION DIFFERENCES FOR MEASURING METABOLISM IN STEADY AND NON-STEADY STATES. , 1961, The Journal of clinical investigation.

[60]  D. R. Coles,et al.  The source of blood samples withdrawn from deep forearm veins via catheters passed upstream from the median cubital vein , 1958, The Journal of physiology.

[61]  O G EDHOLM,et al.  The blood flow in skin and muscle of the human forearm , 1955, The Journal of physiology.