Muscle enzyme activity and insulin sensitivity in Type 1 (insulin-dependent) diabetes mellitus

Summary The mechanisms of insulin insensitivity in diabetes are poorly understood. We have therefore assessed the relationship between glucose disposal during a euglycaemic clamp, muscle glycogen formation, and the activities of insulin regulated enzymes within skeletal muscle in five Type 1(insulin-dependent) diabetic patients, both on conventional injection therapy (HbA₁ 11.0±1.0 (SD) %) and after 6 weeks continuous subcutaneous insulin infusion (HbA₁ 7.6±1.4%,p < 0.01). On both regimens, overnight euglycaemia before the clamp was maintained with an intravenous insulin infusion. The increase in clamp glucose requirements (insulin 0.1 U kg^–1·h^–1) between injection therapy and continuous subcutaneous insulin infusion was significant (6.2±0.9 (SE) to 7.0 ± 0.9 mg·kg^–1·min^–1,p<0.05), but small compared to differences between subjects. Glucose requirement remained lower than in control subjects (10.4 ± 0.7 mg·kg^–1·min^–1,p < 0.05). The increase in muscle glycogen with the clamp was slightly higher on continuous subcutaneous insulin infusion (9.5 ± 2.5 mg/g protein) than on injection therapy (8.5 ± 2.4 mg/g,p < 0.05), but less than in control subjects (17.9 ± 2.1 mg/g,p < 0.05). The expressed activity of glycogen synthase and pyruvate dehydrogenase increased significantly between fasting and the end of the clamps in the patients (p < 0.001 and < 0.005), but was not significantly different between the two treatment regimens. Expressed glycogen synthase activity at the end of the clamp was lower on both treatments than in control subjects (p < 0.05). Both enzyme activities were, however, highly correlated with glucose requirement between patients, (r=0.89–0.94,p<0.05-0.02), and glycogen synthase was similarly correlated in the control subjects (r = 0.84,p < 0.05). Patients had significantly different enzyme activities, glucose requirement, and glycogen stored by analysis of variance (p < 0.05-0.01). Correlation of each enzyme activity between subjects on the two treatment regimens was also high (r=0.94–0.98,p < 0.02–0.01). At the end of the clamp the enzyme activities were themselves closely related (injectionsr = 0.99,p < 0.001; infusionr = 0.88,p < 0.05), and glycogen synthase activity predicted muscle glycogen deposition (r=0.94–0.97,p < 0.02–0.01). We suggest that: (1) preceding metabolic control has a relatively small influence on whole body insulin sensitivity measured immediately after careful overnight control; (2) insulin sensitivity derived from glucose clamp data is strongly related to skeletal muscle glycogen deposition and skeletal muscle enzyme activities.