Relationship of skeletal muscle glucose 6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys

• Published in: Diabetologia Vol. 37; no. 2; pp. 127 - 133
• Main Authors: ORTMEYER, H. K, BODKIN, N. L, HANSEN, B. C
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-02-1994
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - veterinary; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - metabolism; Glucose Clamp Technique; Glucose-6-Phosphate; Glucosephosphates - metabolism; Glycogen Synthase - metabolism; Glycolysis; Infusions, Intravenous; Insulin - administration & dosage; Insulin - blood; Insulin - pharmacology; Insulin Resistance - physiology; Macaca mulatta; Medical sciences; Monkey Diseases; Muscles - drug effects; Muscles - metabolism; Reference Values; Endocrinopathy; Pancreatic hormone; Enzyme; Pathogenesis; Transferases; Glycosyltransferases; Monkey; Glucose; Glycogen (starch) synthase; Striated muscle; Non insulin dependent diabetes; Insulin; Protein hormone; Target tissue resistance; Vertebrata; Mammalia; Enzymatic activity; Animal; Primates; Hexosyltransferases
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s001250050082

Reduced insulin action on skeletal muscle glycogen synthase activity and reduced whole-body insulin-mediated glucose disposal rates in insulin-resistant subjects may be associated with an alteration in muscle glucose transport (or phosphorylation) or with a defect distal to glucose 6-phosphate. To examine this issue we determined the glucose 6-phosphate concentration and glycogen synthase activity in muscle samples obtained under basal and euglycaemic hyperinsulinaemic clamp conditions in 27 rhesus monkeys (Macaca mulatta). They ranged from metabolically normal (n = 11) to insulin-resistant (n = 8) to overtly diabetic (non-insulin-dependent) (n = 8). The glucose 6-phosphate measured under insulin-stimulated conditions was inversely correlated to insulin-stimulated glycogen synthase independent activity (r = -0.54, p < 0.005), the change in glycogen synthase independent activity (insulin-stimulated minus basal) (r = -0.58, p < 0.002) and to whole-body insulin-mediated glucose disposal rate (r = -0.60, p < 0.002). The insulin-resistant and diabetic monkeys had significantly higher insulin-stimulated glucose 6-phosphate concentrations (0.57 +/- 0.11 and 0.62 +/- 0.11 nmol/mg dry weight, respectively) compared to the normal monkeys (0.29 +/- 0.05 nmol/mg dry weight) (p's < 0.05). We conclude that under euglycaemic/hyperinsulinaemic conditions, a defect distal to glucose 6-phosphate is a major contributor to reduced whole-body insulin-mediated glucose disposal rates and to reduced insulin action on glycogen synthase in insulin-resistant and diabetic monkeys.