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Fat Distribution, Lipid Accumulation in the Liver, and Exercise Capacity Do Not Explain the Insulin Resistance in Healthy Males with a Family History for Type 2 Diabetes

Lundberg Laboratory for Diabetes Research (E.H.J., P.-A.J., U.S., M.A.), Departments of Body Composition and Metabolism, Radiology (L.L.), and Internal Medicine, Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden; Department of Internal Medicine and Molecular Science (Y.M., T.F.), Osaka University, 565-0871 Osaka, Japan; and Department of Medicine (M.-R.T.), University of Helsinki, Helsinki, Finland FIN-00029

Address all correspondence and requests for reprints to: Else H. Johanson, The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: else{at}medic.gu.se.

To explore the mechanisms for the insulin resistance associated with a family history of type 2 diabetes, we studied 16 healthy men with at least two first-degree relatives with type 2 diabetes and 16 control subjects without known heredity. They were pair-wise matched for age, body mass index, and fasting triglycerides and underwent an oral glucose tolerance test, iv glucose infusion to measure the early insulin secretion, euglycemic hyperinsulinemic clamp, computed tomography scan, 7-d food record, and a cardiopulmonary exercise test to measure peak oxygen uptake. Insulin sensitivity index was 30% lower (P = 0.02) in relatives, compared with controls, but fasting and 2-h blood glucose and first-phase insulin secretion were similar. There were no differences in mean fasting free fatty acid levels, amount of sc or visceral adipose tissue, or fat accumulation in the liver. Dietary intake and peak oxygen uptake were also similar. However, multiple regression analysis of both groups showed that fat in the liver and physical capacity were, like known heredity for type 2 diabetes, independent predictors of insulin sensitivity. Thus, lipid accumulation in the liver and physical capacity are related to insulin sensitivity, but neither of these factors nor the amount and distribution of the body fat can explain the insulin resistance associated with a family history for type 2 diabetes.

This work was supported by grants from the Arne and Inga Britt Lundberg Foundation, Swedish Research Council, Swedish Diabetes Association, European Union (QLGI-CT-1999-00674), Novo Nordisk Foundation, Novo Nordisk Pharma AB, Sweden, Swedish Medical Society, Göteborg Medical Society, Sonya Hedenbratt Memorial Fund, and Helsinki University Central Hospital Research Foundation.

Abbreviations: BMI, Body mass index; CT, computerized tomography; E%, energy-adjusted intake; FFA, free fatty acid; HU, Hounsfield unit; IAUC, incremental area under the curve; IGT, impaired glucose tolerance; ISI, insulin sensitivity index; IVGTT, iv glucose tolerance test; LBM, lean body mass; M-value, glucose infusion rate divided by kilogram LBM; OGTT, oral glucose tolerance test; VO₂, oxygen uptake.

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