Changes in Hepatic Glucose Production and Insulin Sensitivity in Monkeys Progressing Toward and Reaching Noninsulin-Dependent Diabetes Mellitus (Niddm).

Abstract

Defects in beta cell insulin secretion, the presence of insulin resistance, hyperglycemia, and an increased hepatic glucose production have been reported in Type 2 (noninsulin-dependent) diabetes. However, the question as to which of these defects is primary remains unanswered and is of critical importance. The metabolic events associated with the spontaneous development of obesity-associated Type 2 diabetes mellitus were studied. The purpose was to determine whether an increased basal hepatic glucose production precedes hyperinsulinemia in monkeys progressing toward Type 2 diabetes. Secondly, we studied whether changes in peripheral glucose utilization would precede, accompany, or be subsequent to changes in hepatic glucose production. Male rhesus monkeys (Macaca mulatta) (n = 29) ranging in age from 5.0 to 24.4 years and weighing 6.7 to 22.2 kg were studied. Fasting plasma levels of glucose (FPG) and insulin (FIRI) were determined concurrently with measurements of hepatic glucose production (HGP) using 3-('3)H -glucose (0.1 (mu)Ci prime and 0.1 (mu)Ci/min continuous infusion) and insulin sensitivity (M) using a euglycemic clamp technique (400 mU/M('2) BSA/min). Results showed the earliest change which could be detected in the progression toward diabetes was a significant reduction in sensitivity to insulin, accompanied by a slight increase in fasting plasma insulin levels. A progressive and significant rise in plasma insulin accompanied further decreases in insulin sensitivity and preceded a gradual deterioration of glucose tolerance. Basal hepatic glucose production changed in parallel with fasting plasma glucose, becoming significantly elevated only as FPG rose to levels diagnostic of diabetes. In summary, we suggest that hepatic glucose production and fasting glucose levels showed no significant changes early in the development of Type 2 diabetes. In contrast, insulin sensitivity decreased very early in the progression, prior to a significant increase in fasting plasma insulin levels. We suggest that the early decreases in insulin sensitivity, the increases in fasting plasma insulin, and the decreased glucose tolerance, may be used, in combination, as prognostic indicators of the future development of diabetes. Further studies in humans may increase the underst and ing of the natural history and progression of Type 2 diabetes and the framework within which individuals could be identified at a very early time-point.