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

Abstract

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 I (insulin-dependent) diabetic patients, both on conventional injection therapy (HbA1 11.0-4-1.0 (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 Ukg-1. h-1) between injection therapy and continuous subcutaneous insulin infusion was significant (6.2+0.9 (SE) to 7.0_0.9mg.kg-l.min -1, p<0.05), but small compared to differences between subjects. Glucose requirement remained lower than in control subjects (10.4+0.7mg.kg-l.min 1, p < 0.05). The increase in muscle glycogen with the clamp was slightly higher on continuous subcutaneous insulin infusion (9.5±2.5mg/g protein) than on injection therapy (8.5± 2.4rag/g, p <0.05), but less than in control subjects (17.9± 2.1 rag/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 (injections r = 0.99, p < 0.001 ; infusion r = 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.

Expression of glycogen synthase and phosphofructokinase in muscle from Type 1 (insulin-dependent) diabetic patients before and after intensive insulin treatment

“…Furthermore, changes in serum insulin within the physiological range with a 2.8-fold increase over a 24-h period did not contribute to the acute regulation of total GS activity and GS mRNA and immunoreactive protein abundance in muscle but normalized the muscle GS activation in diabetic patients. Hence, the present data suggest that the impaired glycogen synthesis of skeletal muscle from Type 1 diabetic patients in poor metabolic control [1][2][3] is caused by post-translational modifications of the GS enzyme which may be secondary to metabolic derangements [3,7]. This interpretation of results is compatible with the study of Vuorinen-Markkola et al [28] demonstrating that 24 h of hyperglycaemia induces a severe impairment of whole-body non-oxidative glucose metabolism in Type I diabetic patients.…”

“…The two forms of the enzyme are interconverted by phosphorylation-dephosphorytation reactions with G6P allosterically activating the phosphorylated form of GS, whereas insulin acts covalently on GS by reducing and increasing the activities of specific kinases and phosphatases, respectively [12]. The decreased glucose clearance of peripheral tissues in Type i diabetic patients has been shown to be accompanied by decreased glycogen synthase activity in skeletal muscle [1,10]. Phosphofructokinase (PFK) is a rate-limiting enzyme in glycolysis [13] catalysing the transformation of fructose 6-phosphate to fructose-l,6-diphosphate, a process which is allosterically regulated by several metabolites [13] and previous studies in diabetic rodents have shown an impairment of muscle PFK activity [14].…”

Sprint Training Increases Muscle Oxidative Metabolism During High-Intensity Exercise in Patients With Type 1 Diabetes

“…However, PDHa did not differ between groups. The only previous study to examine muscle PDHa in pa- tients with type 1 diabetes also reported no difference at rest compared with control subjects (14). Thus, although speculative, it is possible that our type 1 diabetic group had lower muscle lactate transport during intense exercise than the control group.…”

Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity.

“…Muscle glycogen synthase is also less activated by insulin in type I diabetic human subjects, in whom total glycogen synthase activity is not reduced (26). To our knowledge, however, human glycogen synthase phospha- tase has only been measured in PMN (27,28 (14,17) in animal experiments.…”