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

Diabetologia. 2012 May;55(5):1435-45. doi: 10.1007/s00125-012-2482-8. Epub 2012 Feb 10.


Aims/hypothesis: In type 2 diabetes, reduced insulin-stimulated 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 isoglycaemic-hyperinsulinaemic 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 weight-matched 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 well-controlled 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Glucose / metabolism*
  • Glucose Clamp Technique
  • Glycogen Synthase / metabolism*
  • Humans
  • Hyperglycemia / metabolism*
  • Insulin / administration & dosage*
  • Male
  • Middle Aged
  • Muscle, Skeletal / enzymology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Serine / metabolism
  • Threonine / metabolism


  • Insulin
  • Threonine
  • Serine
  • Glycogen Synthase
  • Proto-Oncogene Proteins c-akt
  • Glucose