Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patient's ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. Serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patient's nonketotic sera, normal sera, or Trasylol. Glutathione-insulin-transhydrogenase (GIT) activity was 66% of normal. The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP). The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.

Oral glucose tolerance tests (1.75 gm./kg. ideal body weight) were performed on sixty-six obese children and adolescents, four to sixteen years of age. Ten subjects of normal height and weight of the same age range and without a family history of diabetes served as controls. Plasma glucose, immunoreactive insulin, and free fatty acid levels were determined. Twenty-seven (45 per cent) of the subjects had normal tolerance, fifteen (23 per cent) had distinctly abnormal tolerance. Hyperinsulinemia was observed in nearly all the obese subjects, but it was significantly greater in those with abnormal tolerance than in those with normal tolerance. Free fatty acids fell rapidly after the ingestion of glucose in the majority of subjects. In some there was a delay in return to fasting levels. Thirty-four of the obese subjects had close diabetic relatives (diabetic family history [DHF+]) and thirty-two did not (DFH −). The incidence of moderately abnormal tolerance in the two groups, was the same but markedly abnormal tolerance was found only in the DFH + group. DFH + children had significantly greater elevations in insulin levels than DFH − children at both levels of tolerance. The DFH + subjects with severe hyperglycemia had somewhat increased levels of insulin occurring only after the first hour of the test. The hyperinsulinemia observed in the obese children in this study cannot be completely explained by compensatory overproduction due to peripheral resistance to insulin, and an alternate hypothesis is suggested.

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