Insulin Signal Transduction in Skeletal Muscle From Glucose-Intolerant Relatives With Type 2 Diabetes
- Heidi Storgaard1,
- Xiao Mei Song2,
- Christine B. Jensen1,
- Sten Madsbad1,
- Marie Björnholm2,
- Allan Vaag13 and
- Juleen R. Zierath2
- 1Department of Endocrinology, Hvidovre Hospital and Clinical Trial Unit, University of Copenhagen, Copenhagen, Denmark
- 2Department of Clinical Physiology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
- 3Steno Diabetes Center, Gentofte, Denmark
Abstract
To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinsase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS). The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin resistance in skeletal muscle from relatives of patients with type 2 diabetes.
Footnotes
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Address correspondence and reprint requests to Heidi Storgaard, Department of Endocrinology, Hvidovre Hospital, DK-2650 Hvidovre, University of Copenhagen, Copenhagen, Denmark. E-mail: hstorgaard{at}dadlnet.dk. Or Juleen R. Zierath, Department of Clinical Physiology, and Department of Physiology, Karolinska Institute, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}fyfa.ki.se.
Received for publication 2 November 2000 and accepted in revised form 5 September 2001.
H.S. and X.M.S. contributed equally to this study.
AUC, area under the curve; DTT, dithiothreitol; ECL, enhanced chemiluminescence; FFA, free fatty acid; FFM, fat-free body mass; IGT, impaired glucose tolerance; IGT relatives, glucose-intolerant first-degree relatives of type 2 diabetic patients; IRS, insulin receptor substrate; IRTK, insulin receptor tyrosine kinase; IVGTT, intravenous glucose tolerance test; HGP, hepatic glucose production; OGTT, oral glucose tolerance test; PI 3-kinase, phosphoinositide 3-kinase; PVDF, polyvinylidene difluoride; SA, specific activity; Rd, glucose disposal rate.
