00!21-97!2x/92/7503-0795$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society Vol. 75, No. 3 Printrd in L’S A Defect in Insulin Action on Expression of the Muscle/ Adipose Tissue Glucose Transporter Gene in Skeletal Muscle of Type 1 Diabetic Patients* HANNELE YKI-J;iRVINEN, HELENA VUORINEN-MARKKOLA, LASZLO KORANYI, RAY BOUREY, KAREN TORDJMAN, MIKE MUECKLER, ALAN M. PERMUTT, AND VEIKKO A. KOIVISTO Second Department of Medicine, Helsinki University (H. Y., H. V.M., V.A.K.), Helsinki, Finland; Metabolism Division, Department of Internal Medicine (L.K., R.B., A.M.P.), and Department of Cell Biology, Washington University School of Medicine (K.T., M.M.), St. Louis, Missouri 63110 ABSTRACT Recently several members of the glucose transporter family have been identified by molecular cloning techniques. We determined the effect of a 4-h insulin infusion on the expression of the muscle/adipose tissue (GLUT-4) glucose transporter mRNA and protein in 14 insulin- treated type 1 diabetic patients and 15 matched nondiabetic subjects. GLUT-4 mRNA and protein concentrations were determined in muscle biopsies taken before and at the end of the insulin infusion during maintenance of normoglycemia. In response to insulin, muscle GLUT- 4 mRNA increased in the nondiabetic subjects from 24 + 3 to 36 + 4 pg/pg RNA (P < 0.001) but remained unchanged in the insulin- resistant diabetic patients (24 f 2 us. 26 + 2 pg/bg RNA, before us. after insulin). The glucose transporter protein concentrations were similar in the basal state and decreased by 21 f 7% (P < 0.02) in the normal subjects but remained unchanged in the diabetic patients. The increase of the GLUT-4 mRNA and the decrease in the GLUT-4 protein correlated with the rate of glucose uptake [correlation coeffi- cient (r) = -0.55, P < 0.01, and r = -0.44, P < 0.05, respectively]. We conclude that the insulin response of both the GLUT-4 glucose trans- porter mRNA and protein are absent in skeletal muscle of insulin- resistant type 1 diabetic patients. Thus, impaired insulin regulation of glucose transporter gene expression can be one of the underlying mechanisms of insulin resistance in type 1 diabetes. (J Clin Endocrinol Metab 75: 795-799, 1992) T HE MAJORITY of type 1 diabetic patients treated with conventional insulin injection regimens are insulin re- sistant (1). This resistance to insulin is characterized by a decrease in the ability of body tissues, especially skeletal muscle, to use glucose through both oxidative and glycogen synthetic pathways (2). At the cellular level, glucose transport has recently been shown to be the rate-limiting step for glucose metabolism in these patients (2). Thus, the abnor- malities in intracellular glucose metabolism could be second- ary to reduced glucose transport in insulin-sensitive tissues. In recent years, major advances have been made in our understanding of the molecules transporting glucose across the cell membrane in various tissues. At least four members of the glucose transporter gene family have been identified. In skeletal muscle, glucose transport occurs through a facili- tated diffusion system that involves two glucose transporter isoforms, the HepG2/rat brain (GLUT-l) and the muscle/ adipose tissue (GLUT-4) glucose transporter (3). Whereas the GLUT-l is widely distributed and is found, e.g. in neural tissue, connective tissue, and blood cells, GLUT-4 is ex- pressed exclusively in insulin-sensitive tissues, especially skeletal muscle, fat, and heart (3). In muscle of severely insulin-deficient streptozotocin dia- betic rats, the rate of glucose transport is reduced, and the GLUT-4 mRNA and protein are both depleted (4, 5). In contrast, the concentration of the GLUT-l protein is normal (4). Insulin treatment normalizes GLUT-4 messenger RNA (mRNA) and protein levels but does not change GLUT-l mRNA or protein (4,5). In patients with noninsulin depend- ent diabetes mellitus, muscle GLUT-4 mRNA and protein levels are normal when measured in the basal state after an overnight fast (6-8). However, because GLUT-4 is only expressed in insulin-sensitive tissues and could be responsi- ble for glucose transport during insulin stimulation, it seems of interest to compare GLUT-4 mRNA and protein levels in the insulin-stimulated state in diabetic and nondiabetic sub- jects. In the present study we determined whether and how the putative insulin-sensitive glucose transporter (GLUT-4) responds to hyperinsulinemia induced by a 4-h insulin in- fusion in insulin-resistant type 1 diabetic patients. Received August 5, 1991. Address all correspondence and requests for reprints to: Dr. Hannele Yki-Jarvinen, M.D., Second Department of Medicine, Helsinki Univer- sity, Haartmaninkatu 4, SF-00290 Helsinki, Finland. * This study was supported by grants from the Finnish Academy of Science (to H.Y., V.A.K.), S&rid Juselius Foundation (to V.A.K.), the Nordisk Insulinfond (to H.Y., V.A.K.), and the Finnish Diabetes Asso- ciation (to H.Y.), and NIH Grants DK-16746 (to A.M.P.) and DK-38495 (to M.M.). Subjects and Methods Subjects and study design Fourteen type 1 diabetic patients and 15 nondiabetic males partici- pated in the studies. Clinical characteristics of the study groups are given in Table 1. Except for diabetes, the patients were healthy, and they did not use any medication in addition to insulin. None of the patients had 795 at UNIVERSITY OF TOLEDO LIBRARIES on January 16, 2009 jcem.endojournals.org Downloaded from