Insulin-Sensitive and Insulin-Resistant Variants in NIDDM

Abstract

To define the sequence of events that is involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we studied 16 NIDDM individuals (15 of 16 Black patients) with a mean age of 44 yr who had been near normoglycemic for 2–91 mo while off of antidiabetic medicine. With the euglycemic insulin clamp at 100 (μU/ml insulin, we defined two populations, one with normal peripheral insulin sensitivity (glucose disposal 7.51 ± 0.97 mg · kg−1 · min−1) and the other with insulin resistance (glucose disposal 3.35 ± 0.58 mg · kg−1 · min−1; P <.001). The populations did not differ in age, degree of obesity, fasting plasma glucose, glycosylated hemoglobin, clinical presentation, or clinical course. Basal plasma insulin levels were normal in the sensitive group and significantly elevated in the resistant group. Islet cell cytoplasmic antibodies were absent in all patients. Insulin action on the liver was normal in both groups. Basal hepatic glucose production measured with D-[3−3H]glucose was lower in the insulin-resistant group (1.53 ± 0.11 mg · kg−1 · min−1) than in the insulin-sensitive group (1.88 ± 0.06 mg · kg1 · min−1) or normal control subjects (1.93 ± 0.05 mg · kg−1 · min1). The decreased basal hepatic glucose production appeared to be secondary to the twofold higher fasting plasma insulin level seen in the insulin-resistant group. The insulin concentration necessary to suppress basal hepatic glucose production by 50% was 29.6 μU/ml in the insulin-sensitive group and 30.5 μU/ml in the insulin-resistant group. The absolute insulin-secretory responses to oral glucose and intravenous glucagon were significantly lower (50%) in the insulin-sensitive group than in the insulin-resistant group, whose absolute responses were similar to normal control subjects. Compared with individuals with impaired glucose tolerance, the insulin response to oral glucose in the insulin-resistant group was somewhat reduced. We hypothesize that NIDDM in this particular population consists of two subpopulations, one with primary insulin deficiency and normal insulin action and the other with primary peripheral insulin resistance and a mild impairment in glucose-mediated insulin secretion. In both, insulin action in the liver was initially normal.