Hepatic glucose production and metabolic clearance rate of glucose were measured using (3-3H) glucose at steady state, basally and during two sequential 2 h insulin (25 and 40 mU . kg -1 . h -1)/glucose (2 and 3 mg. kg -1 . min -1) infusion periods. Eight diabetic subjects were studied before and after 1 week of twice daily insulin therapy; six control subjects matched for age, weight and degree of obesity were also studied. In the diabetic patients, pre-treatment hepatic glucose production was 20.0 +/- 2.2, 9.9 +/- 2.9, and 1.4 +/- 0.8 mu mol . kg -1 . min -1 respectively (+/- SEM) for each of the three periods, and fell significantly with treatment to 12.8 +/- 1.7, 4.0 +/- 1.5 and 1.9 +/- 1.0 mu mol . kg -1 . min -1. Hepatic glucose production in normal subjects was 13.2 +/- 0.6, 2.2 +/- 0.8 and less than 1 mu mol . kg -1 . min -1. The pre-treatment metabolic clearance rate in all diabetic studies with insulin levels greater than or equal to 30 mU/l was 1.10 +/- 0.14 ml . kg -1 . min -1 and remained virtually unchanged following insulin therapy; this was significantly lower than in the control subjects (6.83 +/- 1.02, p less than 0.001). Basal non-esterified fatty acid levels were higher (p less than 0.02) in the pre-treated diabetic patients compared to post-treated diabetic patients and control subjects. Non-esterified fatty acids in each group fell to similar levels during the insulin infusions, but the rate of fall was slower in the pre-treated diabetic patients. Insulin receptor binding to erythrocytes was normal in the diabetic subjects and unchanged by treatment. Therefore, following insulin treatment of uncontrolled Type 2 (non-insulin-dependent) diabetes, the initially increased basal hepatic glucose production, and decreased hepatic sensitivity, return towards normal. However, the glucose clearance remains low, despite good diabetic control, and appears to be a major factor in the continuing glucose intolerance. As insulin receptor binding is normal, the defect of glucose clearance in Type 2 diabetes appears compatible with a post-receptor defect of glucose metabolism.

Oral glucose (75 g) tolerance tests were performed on 189 urbanized Micronesians with an age range of 15 to 70 years. The subjects were divided into 6 groups on the basis of the 2 h plasma glucose and the pattern of insulin response examined. Fasting plasma insulin levels were not significantly different over the entire range of glucose tolerance. The 2 h plasma insulin levels were highest in the group with 2 h plasma glucose value of 140-199 mg/ 100 ml. There was a progressive fall in 2 h plasma insulin with increasing glucose intolerance, so that in the group with a 2 h plasma glucose /> 400 mg/ 100 ml, the 2 h plasma insulin level was significantly less than that in all the other groups. Obesity was the most important factor influencing both fasting and 2 h insulin levels and no effect of corresponding plasma glucose level was demonstrated. In maturityonset diabetes, a wide range of insulin responses may be seen and the earlier controversy regarding patterns of insulin response has arisen from equating groups of diabetic subjects with varying degrees of glucose intolerance.

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