Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus.
Insulin resistance in non-insulin-dependent diabetes is associated with a defective insulin activation of the enzyme glycogen synthase in skeletal muscles. To investigate whether this may be a primary defect, we studied 20 young (25 +/- 1 yr) Caucasian first-degree relatives (children) of patients with non-insulin-dependent diabetes, and 20 matched controls without a family history of diabetes. Relatives and controls had a normal oral glucose tolerance, and were studied by means of the euglycemic hyperinsulinemic clamp technique, which included performance of indirect calorimetry and muscle biopsies. Insulin-stimulated glucose disposal was decreased in the relatives (9.2 +/- 0.6 vs 11.5 +/- 0.5 mg/kg fat-free mass per (FFM) min, P less than 0.02), and was due to a decreased rate of insulin-stimulated nonoxidative glucose metabolism (5.0 +/- 0.5 vs 7.5 +/- 0.4 mg/kg fat-free mass per min, P less than 0.001). The insulin-stimulated, fractional glycogen synthase activity (0.1/10 mmol liter glucose-6-phosphate) was decreased in the relatives (46.9 +/- 2.3 vs 56.4 +/- 3.2%, P less than 0.01), and there was a significant correlation between insulin-stimulated, fractional glycogen synthase activity and nonoxidative glucose metabolism in relatives (r = 0.76, P less than 0.001) and controls (r = 0.63, P less than 0.01). Furthermore, the insulin-stimulated increase in muscle glycogen content over basal values was lower in the relatives (13 +/- 25 vs 46 +/- 9 mmol/kg dry wt, P = 0.05). We conclude that the defect in insulin activation of muscle glycogen synthase may be a primary, possibly genetically determined, defect that contributes to the development of non-insulin-dependent diabetes.
Vaag
A
A
Department of Endocrinology and Internal Medicine M, Odense University Hospital, Denmark.
Henriksen
J E
JE
Beck-Nielsen
H
H
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D006006:Glycogen Synthase / Q000032:analysis*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D009132:Muscles / Q000201:enzymology*; D044465:White People
D001786:Blood Glucose; D007328:Insulin; D006006:Glycogen Synthase