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Influence of Ethnicity and Familial Diabetes on Glucose Tolerance and Insulin Action: A Physiological Analysis

Metabolism Unit (E.F., A.G., M.P.), National Research Council Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa 56100, Italy; and Diabetes Division (E.F., A.G., M.M., Y.M., L.G., R.A.D.), University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: E. Ferrannini, M.D., National Research Council Institute of Clinical Physiology, Via Savi, 8, 56100 Pisa, Italy. E-mail: ferranni{at}ifc.cnr.it.

Both ethnicity and familial diabetes (FHD) confer risk for type 2 diabetes [diabetes mellitus (DM)], but their relative influence has not been established. To analyze the separate impact of ethnicity, Mexican-American vs. Caucasian, and FHD on the physiological determinants of glucose tolerance, we measured insulin sensitivity of glucose uptake (IS_GU) (by the clamp technique), endogenous glucose production (by 3-[³H]glucose infusion), and insulin secretory response (to oral glucose) in 172 Mexican-Americans and 60 Caucasians with normal glucose tolerance (NGT) or DM. IS_GU was markedly reduced in diabetics vs. NGT (3.9 ± 0.2 vs. 8.4 ± 0.5 ml·min^-1·kg_ffm^-1, P < 0.0001), and lower in Mexican-Americans than in Caucasians (5.3 ± 0.3 vs. 7.3 ± 0.7 ml·min^-1·kg_ffm^-1, P < 0.003; ffm, fat-free mass). In a multivariate analysis including both ethnicity and FHD (and adjusting for body mass index, age, and diabetes), ethnicity was still a significant (P = 0.02) independent correlate of IS_GU. Insulin resistance of glucose production was increased in diabetics (14 ± 1 mmol·min^-1·[µU/ml], P < 0.0001 vs. 9 ± 1 of NGT), whereas the 30' insulin/glucose ratio was decreased (16 ± 1 µU/mg, P < 0.0001 vs. 60 ± 5). In multivariate models, neither ethnicity nor FHD were significant independent correlates of glucose production and early insulin response.

We conclude that the primary physiological target of the propensity to diabetes of Mexican-Americans is insulin resistance of glucose uptake.

This work was supported by NIH Grant DK-24092, NIH General Clinical Research Centers Grant MOI-RR-01346, a Veterans Affairs Merit Award, funds from the Veterans Affairs Research Foundation, and funds from the Italian Ministry of University and Scientific Research (MURST).

Abbreviations: BMI, Body mass index; DM, type 2 diabetes (diabetes mellitus); EGP, endogenous glucose production; FFA, free fatty acids; FFM, fat-free mass; FHD, familial diabetes; FPI, fasting plasma insulin; IR_GP, insulin resistance of EGP (EGP x FPI); IR_LL, insulin resistance of lipolysis (fasting FFA-kg_fm x FPI); IS_GU, insulin sensitivity of glucose uptake; M value, insulin-mediated glucose uptake; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; WHR, waist-to-hip circumference ratio.

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