Glucose Effectiveness in Nondiabetic Relatives: Dysglycemia and β-Cell Function at 10 Years

Aims: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release. Methods: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)(IVGTT), and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIR(OGTT) were determined. Results: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIR(OGTT) were reduced (P <= .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG(10y) correlated significantly with FG(0y) and body mass index(0y) and negatively with root GE and 2-hour OGTT glucose(10y) with FG(0y) and negatively with AIR(IVGTT0y) and AIR(OGTT0y). Log AIR(OGTT10y) correlated with root GE, log AIR(IVGTT0y) and log AIR(OGTT0y). Multiple regression analyses demonstrated the following: REL FG(10y) was predicted by combined FG(0y), root GE and body mass index(0y) (r(adj)(2) = 56%; P <= .001) and 2-hour OGTT glucose(10y) weakly related by FG(0y), and root GE (r(adj)(2) = 25%; P = .06). Log AIR(OGTT10y) was predicted by AIR(IVGTT0y) and root GE (r(adj)(2) = 46%; P <= .004). Conclusion: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.