EFFECT OF INSULIN ON GLUT-4 MESSENGER-RNA AND PROTEIN CONCENTRATIONS IN SKELETAL-MUSCLE OF PATIENTS WITH NIDDM AND THEIR 1ST-DEGREE RELATIVES

We examined whether insulin resistance, i.e. impaired insulin stimulated glucose uptake in NIDDM patients and their first-degree relatives is associated with alterations in the effect of insulin on the expression of the GLUT-4 gene in skeletal muscle in vivo. Levels of GLUT-4 mRNA and protein were measured in muscle biopsies taken before and after a euglycaemic insulin clamp from 14 NIDDM patients, 13 of their first-degree relatives and 17 control subjects. Insulin stimulated glucose uptake was decreased in the diabetic subjects (19.8 +/- 3.0 mumol.kg LBM-1.min-1, both p<0.001) compared with control subjects (44.1 +/- 2.5 mumol.kg LBM-1.min-1) and relatives (39.9 +/- 3.3 mumol.kg LBM-1.min-1). Basal GLUT-4 mRNA levels were significantly higher in diabetic subjects and relatives compared to control subjects (99 +/- 8 and 108 +/- 9 pg/mug RNA vs 68 +/- 5 pg/mug RNA; both p < 0.01). Insulin increased GLUT-4 mRNA levels in all control subjects (from 68 +/- 5 to 92 +/- 6 pg/mug RNA; p < 0.0001), but not in the diabetic patients (from 99 +/- 8 to 90 +/- 8 pg/mug RNA, NS), or their relatives (from 94 +/- 9 to 101 +/- 11 pg/mug RNA, NS). In the relatives, individual basal GLUT-4 mRNA concentrations varied between 55 and 137 pg/mug RNA. Insulin-resistant (n = 6, mean glucose uptake rate = 30.6 +/- 3.4 mumol.kg LBM-1.min-1) but not insulin-sensitive relatives (n = 7, mean glucose uptake rate = 47.4 +/- 3.2 mumol.kg LBM-1 .min-1) had higher basal GLUT-4 mRNA concentrations compared to control subjects (108 +/- 9 vs 68 +/- 5 pg/mug RNA, p < 0.01). GLUT-4 protein content in muscle did not differ between the groups in the basal state and remained unchanged in all groups after insulin infusion. Neither insulin-stimulated GLUT-4 mRNA nor protein concentrations correlated with insulin-stimulated glucose uptake in any of the groups studied. We conclude, that impaired glucose uptake in NIDDM is not related to insulin-stimulated GLUT-4 mRNA or protein concentrations. Acute stimulation of GLUT-4 mRNA by insulin is altered in skeletal muscle of NIDDM patients and their first-degree relatives. This might be a consequence of chronic hyperinsulinaemia elevating basal GLUT-4 mRNA concentrations rather than the cause of insulin resistance.