Dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of malonyl-CoA

Abstract

Aims/hypothesis: An elevated lipid content within skeletal muscle cells is associated with the development of insulin resistance and type 2 diabetes mellitus. We hypothesised that in subjects with type 2 diabetes muscle malonyl-CoA (an inhibitor of fatty acid oxidation) would be elevated at baseline in comparison with control subjects and in particular during physiological hyperinsulinaemia with hyperglycaemia. Thus, fatty acids taken up by muscle would be shunted away from oxidation and towards storage (non-oxidative disposal).

Materials and methods: Six control subjects and six subjects with type 2 diabetes were studied after an overnight fast and during a hyperinsulinaemic (0.5 mU kg(-1) min(-1)), hyperglycaemic clamp (with concurrent intralipid and heparin infusions) designed to increase muscle malonyl-CoA and inhibit fat oxidation. We used stable isotope methods, femoral arterial and venous catheterisation, and performed muscle biopsies to measure palmitate kinetics across the leg and muscle malonyl-CoA.

Results: Basal muscle malonyl-CoA concentrations were similar in control and type 2 diabetic subjects and increased (p<0.05) in both groups during the clamp (control, 0.14+/-0.05 to 0.24+/-0.05 pmol/mg; type 2 diabetes, 0.09+/-0.01 to 0.20+/-0.02 pmol/mg). Basal palmitate oxidation across the leg was not different between groups at baseline and decreased in both groups during the clamp (p<0.05). Palmitate uptake and non-oxidative disposal were significantly greater in the type 2 diabetic subjects at baseline and during the clamp (p<0.05).

Conclusions/interpretation: Contrary to our hypothesis, the dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of muscle malonyl-CoA. However, elevated fatty acid uptake in type 2 diabetes may be a key contributing factor to the increase in fatty acids being shunted towards storage within muscle.

Figures

Fig. 1

Study design. A basal period was followed by a hyperglycaemic–hyperinsulinaemic clamp. ICG Indocyanine green, ICal indirect calorimetry

Fig. 2

Palmitate uptake across the leg in controls and patients with type 2 diabetes (T2DM) under basal (open bars) and clamp (closed bars) conditions. FFM Fat-free mass. Kinetic rates are mean±SEM. *p≤0.05 for difference from basal values; tp≤0.05 for difference from healthy controls

Fig. 3

Skeletal muscle malonyl-CoA concentration in controls and patients with type 2 diabetes (T2DM). Malonyl-CoA concentration increased significantly from basal (open bars) to clamp conditions (closed bars) in both groups. Values are mean±SEM. *p≤0.05 for difference from basal values