Insulin resistance in Type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle

J. Eriksson, L. Koranyi, R. Bourey, C. Schalin-Jäntti, E. Widén, M. Mueckler, A. M. Permutt, L. C. Groop

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Abstract

To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a +45 mU· {Mathematical expression}·min-1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-3H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxyterminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5±2.1 and 34.0±4.8 vs 57.9±3.1 μmol·kg lean body mass-1·min-1; p<0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0±2.4 and 15.6±3.9 vs 36.9±2.2 μmol·kg lean body mass-1·min-1; p<0.01). The levels of GLUT-4 mRNA expressed both per μg of total RNA and per μg DNA, were higher in the diabetic patients compared with the control subjects (116±25 vs 53±10 pg/μg RNA and 177±35 vs 112±29 pg/μg DNA; p<0.05, p<0.01, respectively). The GLUT-4 mRNA levels in the relatives were not significantly different from that observed in the control subjects (90±16 pg/μg RNA and 117±23 pg/μg DNA; p = NS). The GLUT-4 protein levels did not significantly differ between control subjects, diabetic patients and relatives (494±85, 567±133 and 323±80 cpm/100 μg protein). No correlation was observed between the level of GLUT-4 mRNA andits protein. However, the level of GLUT-4 mRNA and the rate of total-body glucose disposal correlated positively in the control group and in the relatives (both p<0.05) but not in the diabetic subjects. A positive correlation between the level of GLUT-4 protein and total-body glucose disposal was also observed in the control subjects (r = 0.759; p<0.05) and in the relatives (r = 0.794; p<0.01) but not in the diabetic subjects. We conclude that insulin resistance in Type 2 diabetes is not related to a defect in the expression of the GLUT-4 gene in skeletal muscle. Nevertheless, the levels of GLUT-4 mRNA and GLUT-4 protein are related to the rate of total-body glucose disposal in subjects with normal fasting glucose concentrations.

Original languageEnglish
Pages (from-to)143-147
Number of pages5
JournalDiabetologia
Volume35
Issue number2
DOIs
StatePublished - Feb 1992

Keywords

  • Type 2 (non-insulin-dependent) diabetes mellitus
  • genes
  • glucose transport
  • insulin resistance

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