Diabetologia (2008) 51:309–319
I. M. Jazet & G. Schaart & A. Gastaldelli & E. Ferrannini & M. K. Hesselink & P. Schrauwen & J. A. Romijn & J. A. Maassen & H. Pijl & D. M. Ouwens & A. E. Meinders
Aims/Hypothesis: Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients.
Methods: A euglycaemic–hyperinsulinaemic clamp with stable isotopes ([6,6-2 H2]glucose and [2 H5]glycerol) combinedwith skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively.
Results: Loss of 50% EWR (20.3±2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8±2.0 to 39.1±2.8 μmol kg fat-free mass−1 min−1, p=0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content.
Conclusions/Interpretation: Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect.