Anomalous leucine metabolism in total lipoatrophic diabetes: a possible mechanism of muscle mass hypertrophy

Total acquired lipoatrophic diabetes (LD) is characterized by muscle mass hypertrophy, non-ketotic hyperglycaemia and insulin resistance with respect to glucose and lipid metabolism. To assess whether the defect in insulin action extends to leucine/protein metabolism, a female subject (age=33 years; body weight=44 kg; HbAlc=9.5%) with LD was studied twice: in study I we used a three-step euglycaemic hyperinsulinaemic clamp (40, 80 and 200 mU · m-2 · min-1) combined with [3-3H]glucose and [1-14C]leucine infusions along with indirect calorimetry. In study II we used a 40 mU · m-2 · min-1 euglycaemic hyperaminoacidaemic (plasma leucine 160 μmol/l) hyperinsulinaemic clamp. Five controls were also studieD. In the basal state the patient with LD had plasma leucine (130 μmol/l), isoleucine (63), valine (169) and phenylalanine levels (48) comparable to those of the controls. Basal hepatic glucose production (3.2 vs 2.0±0.2 mg · kg-1 · min-1), endogenous leucine flux (ELF=45.4 vs 40±1 μmol · m-2 · min-1) and non-oxidative leucine disposal (NOLD=37.2 vs 34±1 μmol · m-2 · min-1) were increased in the patient with LD, while basal leucine oxidation (LO=8.2 vs 6.0±2 μmol · m-2 · min-1) was similar in LD and controls. Following the three-step insulin infusion, insulin-stimulated glucose metabolism was defective in the subject with LD (glucose oxidation=60%, 50%, and 52% of controls; non-oxidative glucose disposal =39%, 34% and 30% of controls at 40, 80 and 200 mU · m-2 · min-1 respectively). The decrease of leucine, isoleucine, valine and phenylalanine, as well as the suppression of ELF, LO and NOLD was defective in the subject with LD at each insulin step. In vitro studies demonstrated a defect in receptor insulin binding on erythrocytes, the absence of anti-insulin receptor antibodies and the presence of insulin antibodies in the serum of the patient with LD. Following combined hyperaminoacidaemia/hyperinsulinaemia a similar stimulation of protein synthetic rate (20 vs 30%) was demonstrated in the patient with LD and controls respectively. In conclusion the patient with LD shows a reduced insulin sensitivity and a reduced maximal response to insulin in both glucose and protein metabolism. The present data support the hypothesis that in LD the defect in insulin action is both at the receptor and post-receptorial sites. The patient with LD showed a normal stimulation of protein synthesis under combined hyperinsulinaemic/hyperaminoacidaemic conditions. Our results may explain the muscle mass hypertrophy in LD. © 1992 Springer-Verlag