OBJECTIVE -Inflammatory markers such as C-reactive protein (CRP) are associated with insulin resistance, adiposity, and type 2 diabetes. Whether inflammation causes insulin resistance or is an epiphenomenon of obesity remains unresolved. We aimed to determine whether first-degree relatives of type 2 diabetic subjects differ in insulin sensitivity from control subjects without a family history of diabetes, whether first-degree relatives of type 2 diabetic subjects and control subjects differ in CRP, adiponectin, and complement levels, and whether CRP is related to insulin sensitivity independently of adiposity.RESEARCH DESIGN AND METHODS -We studied 19 young normoglycemic nonobese first-degree relatives of type 2 diabetic subjects and 22 control subjects who were similar for age, sex, and BMI. Insulin sensitivity (glucose infusion rate [GIR]) was measured by the euglycemic-hyperinsulinemic clamp. Dual-energy X-ray absorptiometry determined total and abdominal adiposity. Magnetic resonance imaging measured abdominal adipose tissue volumes.RESULTS -First-degree relatives of type 2 diabetic subjects had a 20% lower GIR than the control group (51.8 Ϯ 3.9 vs. 64.9 Ϯ 4.6 mol ⅐ min Ϫ1 ⅐ kg fat-free mass Ϫ1 , P ϭ 0.04). However, first-degree relatives of subjects with type 2 diabetes and those without a family history of diabetes had normal and comparable levels of CRP, adiponectin, and complement proteins. When the cohort was examined as a whole, CRP was inversely related to GIR (r ϭ Ϫ0.33, P ϭ 0.04) and adiponectin (r ϭ Ϫ0.34, P ϭ 0.03) and positively related to adiposity (P Ͻ 0.04). However, CRP was not related to GIR independently of fat mass. In contrast to C3 (r ϭ 0.41, P ϭ 0.009) and factor B (r ϭ 0.43, P ϭ 0.005), CRP was unrelated to factor D.CONCLUSIONS -The insulin-resistant state is not associated with changes in inflammatory markers or complement proteins in subjects at high risk of type 2 diabetes. Our study confirms a strong relationship between CRP and fat mass. Increasing adiposity and insulin resistance may interact to raise CRP levels. Diabetes Care 27:2033-2040, 2004I nsulin resistance is fundamental to the pathogenesis of the metabolic syndrome and type 2 diabetes (1) and is a heritable trait (2). Type 2 diabetes is also strongly genetically determined (3). Consequently, first-degree relatives of subjects with type 2 diabetes demonstrate the metabolic accompaniments of insulin resistance before they develop overt diabetes (4). Because hyperglycemia further impairs both insulin action and insulin secretion (5), the study of primary metabolic defects leading to insulin resistance is best undertaken before insulin secretion begins to fail and blood glucose rises (6). In addition to genetic factors, excess body fat, particularly visceral fat, has been linked to the pathogenesis of insulin resistance and type 2 diabetes. We have reported that increased central adiposity is strongly related to reduced insulin sensitivity in subjects with and without firstdegree relatives with type 2 diabetes (7). Furthermo...