Abstract： Objective To investigate the roles of insulin resistance and insulin secretory function in the pathogenesis of type 2 diabetes mellitus (T2DM). Methods We recruited six groups of subjects. Individuas (n= 282) with previously diagnosed T2DM were selected from families included in our T2DM family study. They were divided according to the median duration of DM (4 years) into a group of 153 patients with duration 4 years or less and a group of 129 patients with duration more than 4 years. From the same families,we recruited 72 subjects with diabetes newly diagnosed by OGTT. Also from these same families,we recruited non-diabetic first-degree relatives (n=188) that we divided into the groups of 78 with HbAlc less than or equal 5. 5% and 110 with HbAlc over 5. 5%. In addition,we recruited 98 unrelated non-diabetic controls. In each group,we used the HOMA model to calculate HOMA-IR as an index of insulin resistance and HOMAβ as an index of beta-cell function. We also calculated the insulin sensitivity index (ISI). Results In all of the groups of subjects selected from the T2DM families,mean HOMA-IR was significantly (P＜0.01) higher than that in non-diabetic controls,with the exception of the group of non-diabetic relatives with HbAlc less than 5. 5%. In both groups of relative without diabetes,mean HOMA β was significantly (P＜0. 01 ) higher than that in normal controls,while in all 3 group of relatives with diabetes,mean HOMA β was significantly (P＜0. 01 ) lower than that of normal controls. In conclusion,in the families of patients with type 2 diabetes in the Beijing area,first degree relatives with normal glucose tolerance and low HbAlc have higher insulin secretion (HOMAβ) than nondiabetic controls,despite having a mean HOMA-IR comparable to the nondiabetic controls. Conclusion This evidence of over-active insulin secretory function in some non-diabetic relatives in T2DM families may point to a role of insulin secretion in the induction of insulin resistance and to the’development of glucose intolerance and T2DM. Diabetes occurs when insulin resistance worsens and insulin secretion declines.