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.

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The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)