Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Abstract

Aims/hypothesis In type 2 diabetes, reduced insulinstimulated glucose disposal, primarily glycogen synthesis, is associated with defective insulin activation of glycogen synthase (GS) in skeletal muscle. Hyperglycaemia may compensate for these defects, but to what extent it involves improved insulin signalling to glycogen synthesis remains to be clarified. Methods Whole-body glucose metabolism was studied in 12 patients with type 2 diabetes, and 10 lean and 10 obese non-diabetic controls by means of indirect calorimetry and tracers during a euglycaemic-hyperinsulinaemic clamp. The diabetic patients underwent a second isoglycaemichyperinsulinaemic clamp maintaining fasting hyperglycaemia. Muscle biopsies from m. vastus lateralis were obtained before and after the clamp for examination of GS and relevant insulin signalling components. Results During euglycaemia, insulin-stimulated glucose disposal, glucose oxidation and non-oxidative glucose metabolism were reduced in the diabetic group compared with both control groups (p<0.05). This was associated with impaired insulin-stimulated GS and AKT2 activity, deficient dephosphorylation at GS sites 2+2a, and reduced Thr308 and Ser473 phosphorylation of AKT. When studied under hyperglycaemia, all variables of insulin-stimulated glucose metabolism were normalised compared with the weightmatched controls. However, insulin activation and dephosphorylation (site 2+2a) of GS as well as activation of AKT2 and phosphorylation at Thr308 and Ser473 remained impaired (p<0.05). Conclusions/interpretations These data confirm that hyperglycaemia compensates for decreased whole-body glucose disposal in type 2 diabetes. In contrast to previous less wellcontrolled studies, we provide evidence that the compensatory effect of hyperglycaemia in patients with type 2 diabetes does not involve normalisation of insulin action on GS or upstream signalling in skeletal muscle.

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

“…Although impaired insulin activation of muscle GS represents one of the more consistent defects found in insulinresistant cohorts with obesity, polycystic ovary syndrome (PCOS) and type 2 diabetes [4,6,7,25], not all studies have been able to detect a difference between type 2 diabetic and weight-matched obese individuals [6,17,44]. In the present study, the insulin-stimulated GDR in the type 2 diabetic patients was 51-77% higher than values reported in our previous studies [6,44].…”

“…In line with previous studies of insulinresistant conditions including individuals with obesity, PCOS and type 2 diabetes [4-6, 25, 29], we did, however, observe a lack of insulin-induced dephosphorylation of GS at sites 2+2a in both type 2 diabetes and obesity. These phosphosites have previously been found to be responsive to insulin stimulation in a number of healthy lean participant populations [4,25,43].…”

“…Baseline euglycaemic-hyperinsulinaemic clamp After an overnight fast, participants underwent a euglycaemichyperinsulinaemic clamp with tracer glucose (2 h basal period and 4 h insulin infusion, 40 mU m −2 min −1 ) combined with indirect calorimetry (see ESM Methods) to assess total glucose disposal rates (GDR), rates of glucose and lipid oxidation, and non-oxidative glucose disposal (NOGD) as described previously [4,6,25]. Muscle biopsies were obtained from vastus lateralis muscle before and after insulin (see ESM Methods).…”

Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

“…Insulin resistance in human skeletal muscle is characterised by decreased insulinstimulated glucose disposal and metabolism, triacylglycerol accumulation, as well as reduced content and functional capacity of mitochondria [3][4][5][6][7]. At the molecular level, there is evidence of impaired insulin signalling through IRS-1, phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase in skeletal muscle of insulin-resistant individuals [8][9][10][11][12][13].…”

“…Since both deficient and excessive autophagy is harmful, a well-orchestrated regulation of this process is of great importance for muscle homeostasis. Based on the presence of impaired insulin signalling to Akt [4,11], mitochondrial dysfunction and altered protein metabolism, we hypothesised that autophagy is dysregulated in human skeletal muscle in obesity and type 2 diabetes.…”