Insulin Sensitivity in Newly Diagnosed Type 1 Diabetics after Ketoacidosis and after Three Months of Insulin Therapy*

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Abstract
Tissue sensitivity to insulin (euglycemic insulin clamp technique), hepatic glucose production (3-[3H]glucose infusion) and insulin binding to erythrocyte receptors were studied in 14 newly diagnosed type 1 diabetic patients after the disappearance of ketosis and after 3 months of insulin therapy. The control group consisted of 14 normal subjects. During the two insulin clamp studies, plasma glucose in the diabetic patients was maintained at 5.0 ± 0.04 (SEM) mmol/liter and 4.9 ± 0.05 mmol/liter, with corresponding steady state free insulin levels of 90 ± 4 mU/liter, and 67 ± 6 mU/liter (P < 0.02) during the first and second study, respectively. The decline in free insulin levels was due to the development of insulin antibodies during insulin therapy (10 ± 0.1% vs. 18 ± 2%, P < 0.001, serum insulin-binding capacity during the first and second study, respectively). In the normal subjects, steady state plasma glucose and insulin levels were 4.9 ±0.1 mmol/liter and 89 ± 4 mU/ liter, respectively. The rate of glucose metabolism (M) in the diabetic patients during the first study (5.13 ± 0.65 mg/kg-min) was 35% lower than that in the normal subjects (7.94 ± 0.50 mg/kgmin, P < 0.005). After 3 months of insulin therapy, M increased by 35% to 6.92 ± 0.58 mg/kg-min, which was comparable to that in the normal subjects. To compensate for the difference in plasma free insulin levels, we calculated an index for insulin sensitivity by dividing M by the ambient insulin concentration (I). During the 3 months of insulin therapy, M/I rose 2-fold to 11.63 ± 1.10 mg/kgmin per mU insulin/liter x 100, which was similar to that in normal subjects (9.16 ± 0.67 mg/kg-min per mU insulin/liter X 100). Five diabetic patients had a partial clinical remission, as determined by normal fasting C-peptide levels. In these patients, insulin sensitivity was 35–50% greater than in those who failed to have a remission (P < 0.05). Basal hepatic glucose production in the diabetic patients during the first study (2.78 ± 0.14 mg/kg-min) was 56% higher than in the normal subjects (1.78 ± 0.04 mg/kg-min, P < 0.001), and remained unchanged during insulin therapy. During the hyperinsulinemia induced by the clamp, hepatic glucose production was totally suppressed in both the diabetic and control subjects. Specific insulin binding to erythrocytes in the diabetic patients did not differ significantly from that in the normal subjects at either study. In conclusion, newly diagnosed postketotic diabetic patients have insulin resistance. It is localized to peripheral tissues and is possibly due to intracellular defects in glucose metabolism. Insulin resistance is ameliorated by exogenous insulin therapy, but even more by the recovery of endogenous insulin secretion. Consequently, clinical remission in type 1 diabetic patients may result from both recovery of endogenous insulin secretion and of enhancement of insulin sensitivity.