Metabolic Pathways of Glucose in Skeletal Muscle of Lean NIDDM Patients

OBJECTIVE To characterize the ability of insulin to activate the skeletal muscle metabolic pathways of glucose storage, oxidation, and glycolysis in normal weight patients with NIDDM and nondiabetic volunteer subjects closely matched for age, sex, relative weight, and body composition. RESEARCH DESIGN AND METHODS Ten patients with NIDDM (body mass index 23.9 ± 0.74 kg/m2) and 8 nondiabetic volunteer subjects (body mass index 23.4 ± 0.41 kg/m2) were studied. Leg muscle glucose uptake, non-oxidized glycolysis, glucose oxidation, and glucose storage were determined during euglycemic-hyperinsulinemic clamp experiments using the leg balance technique combined with leg indirect calorimetry. Percutaneous muscle biopsies were obtained to assay insulin stimulation of muscle glycogen synthase activity as a biochemical marker of insulin action. RESULTS During hyperinsulinemic clamp experiments, leg glucose uptake was equivalent in NIDDM patients and nondiabetic subjects (6.38 ± 1.14 vs. 6.41 ± 0.73 μmol.min−1 · 100 ml tissue−1), as were rates of leg glucose oxidation (1.63 ± 0.25 vs. 2.14 ± 0.17 μmol.min−1 · 100 ml tissue−1) and leg glucose storage (4.35 ± 1.10 vs. 3.48 ± 0.65 μmol·min−1 · 100 ml tissue−1). The combined net balance of lactate and Ala (non-oxidized glycolysis) was lower in NIDDM patients (−0.39 ± 0.06 vs. −0.79 ± 0.11 μmol·min−1 · 100 ml tissue−1, P = 0.01). Muscle glycogen synthase was activated to a similar extent during the hyperinsulinemic clamp in NIDDM patients and nondiabetic volunteer subjects, through basal glycogen synthase activity was lower in NIDDM patients. Nondiabetic subjects and NIDDM patients who were withdrawn from sulfonylurea therapy had impaired insulin secretion during a 75-g oral glucose tolerance test, with similar basal levels as nondiabetic subjects (54 ± 12 vs. 42 ± 6 pM), but reduced peak insulin levels (126 ± 30 vs. 468 ± 102 pM, P < 0.01). CONCLUSIONS Detailed in vivo and in vitro assessment of insulin regulation of skeletal muscle glucose metabolism in lean NIDDM patients indicates that insulin action is intact in the muscle tissue of these patients.

[1]  G. Reaven,et al.  A Comparison of the Relative Effects of Obesity and Non-insulin-dependent Diabetes Mellitus on In Vivo Insulin-stimulated Glucose Utilization , 1984, Diabetes.

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

[3]  R. Steele,et al.  ON THE HORMONAL REGULATION OF CARBOHYDRATE METABOLISM; STUDIES WITH C14 GLUCOSE. , 1963, Recent progress in hormone research.

[4]  F. Capani,et al.  Predominant Role of Gluconeogenesis in Increased Hepatic Glucose Production in NIDDM , 1989, Diabetes.

[5]  L. Mandarino,et al.  Intracellular Defects in Glucose Metabolism in Obese Patients With NIDDM , 1992, Diabetes.

[6]  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.

[7]  M. Taskinen,et al.  Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. , 1989, American Journal of Physiology.

[8]  V. Herbert,et al.  Coated charcoal immunoassay of insulin. , 1965, The Journal of clinical endocrinology and metabolism.

[9]  J. A. Scarlett,et al.  Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. , 1981, The Journal of clinical investigation.

[10]  P. Brunetti,et al.  Role of hepatic autoregulation in defense against hypoglycemia in humans. , 1985, The Journal of clinical investigation.

[11]  K. Frayn,et al.  Calculation of substrate oxidation rates in vivo from gaseous exchange. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[12]  R. Rizza,et al.  Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. , 1987, Metabolism: clinical and experimental.

[13]  G. Reaven,et al.  Quantification of Insulin Secretion and In Vivo Insulin Action in Nonobese and Moderately Obese Individuals with Normal Glucose Tolerance , 1983, Diabetes.

[14]  M. Taskinen,et al.  Bedtime Insulin for Suppression of Overnight Free–Fatty Acid, Blood Glucose, and Glucose Production in NIDDM , 1989, Diabetes.

[15]  H. Lebovitz,et al.  Patterns of Glucose and Lipid Abnormalities in Black NIDDM Subjects , 1991, Diabetes Care.

[16]  L. Mandarino,et al.  Mechanism and Significance of Insulin Resistance in Non-insulin-dependent Diabetes Mellitus , 1981, Diabetes.

[17]  D. Kipnis,et al.  A microfluorometric enzymatic assay for the determination of alanine and pyruvate in plasma and tissues. , 1972, The Journal of laboratory and clinical medicine.

[18]  R. Henry,et al.  Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. , 1990, The Journal of clinical investigation.

[19]  J. Olefsky,et al.  Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. , 1980, The Journal of clinical investigation.