Body Composition is Main Determinant for the Difference in Type 2 Diabetes Pathophysiology between Japanese and Caucasians Short running title: Type 2 Diabetes in Japanese and Caucasians

OBJECTIVE This cross-sectional clinical study compared the pathophysiology of type 2 diabetes in Japanese and Caucasians and investigated the role of demographic, genetic, and lifestyle-related risk factors for insulin resistance and beta-cell response. RESEARCH DESIGN AND METHODS A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity. RESULTS Insulin sensitivity was higher in Japanese compared to Caucasians as indicated by the HOMA-IR and Matsuda indices, whereas beta-cell response was higher in Caucasians as measured by HOMA-B, the insulinogenic indices, and insulin secretion ratios. Disposition indices were similar for Japanese and Caucasians at all glucose tolerance states, indicating similar beta-cell response relative to the degree of insulin resistance. Main determinants for differences in metabolic indices were measures of body composition, such as BMI and distribution of adipose tissue. Differences in beta-cell response between Japanese and Caucasians were not statistically significant following adjustment by differences in BMI. CONCLUSIONS Our study showed similar disposition indices in Japanese and Caucasians, and that the major part of the differences in insulin sensitivity and beta-cell response between Japanese and Caucasians can be explained by differences in body composition. Page 2 of 29 Diabetes Care