Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives

Abstract

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 μmol · kg LBM-1 · min-1, both p<0.001) compared with control subjects (44.1±2.5 μmol · kg LBM-1 · min-1) and relatives (39.9±3.3 μmol · 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/μg RNA vs 68±5 pg/μg RNA; both p<0.01). Insulin increased GLUT-4 mRNA levels in all control subjects (from 68±5 to 92±6 pg/ug RNA; p<0.0001), but not in the diabetic patients (from 99±8 to 90±8 pg/μg RNA, NS), or their relatives (from 94±9 to 101±11 pg/μg RNA, NS). In the relatives, individual basal GLUT-4 mRNA concentrations varied between 55 and 137 pg/μg RNA. Insulin-resistant (n=6, mean glucose uptake rate=30.6±3.4 μmol · kg LBM-1 · min-1) but not insulin-sensitive relatives (n=7, mean glucose uptake rate=47.4±3.2 μmol · kg LBM-1 · min-1) had higher basal GLUT-4 mRNA concentrations compared to control subjects (108±9 vs 68±5 pg/ug 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. © 1994 Springer-Verlag.