Site of Insulin Resistance in Type 1 Diabetes: Insulin-Mediated Glucose Disposalin Vivoin Relation to Insulin Binding and Action in Adipocytesin Vitro*

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Abstract
To evaluate the mechanism of insulin resistance in type 1 diabetes mellitus, we measured insulin sensitivity in vivo and insulin action in adipocytes in vitro. The study groups consisted of 18 insulin-treated type 1 diabetic patients and 14 matched normal subjects. In each subject, insulin-mediated glucose disposal in vivo was measured by the euglycemic clamp technique. An open surgical biopsy was performed in 9 diabetic and 7 healthy subjects to obtain abdominal sc adipose tissue for the measurement of [125I]insulin binding, D-[14C]-glucose transport, oxidation, and lipogenesis. During the euglycemic clamp studies, similar steady state plasma glucose (4.8 mmol/liter) and insulin (80 mU/liter = 700 pM) levels were maintained in both groups. The rate of glucose metabolism (M) was 43% lower in the diabetic patients (4.75 ± 0.34 mg/kg · min) than in the normal subjects (8.27 ± 0.43 mg/kg · min; P < 0.001). [125I]Insulin binding to adipocytes was reduced in the diabetic patients (26% reduction in tracer binding; P < 0.05) due to a reduction in receptor number. Insulin binding was not related to the M value at any insulin concentration. Basal and insulin-stimulated rates of glucose transport were not significantly different in diabetic and normal subjects. The basal glucose oxidation rate was reduced by 50% (P < 0.02), and maximal glucose oxidation was reduced by 49% (P < 0.03) in the diabetic patients (237 ± 30 $$$vs. 359 ± 49 pmol/30,000 cells-90 min, basal vs. maximal glucose oxidation, respectively) compared to those in normal subjects (513 ± 101 vs. 700 ± 133 pmol/30,000 cells · 90 min). The percentage responses of glucose oxidation and glucose transport to insulin were similar in both groups. Glucose oxidation rates at basal (r = 0.68; P < 0.01), half-maximally (ED50; r = 0.70; P < 0.01), and maximally (r = 0.64; P < 0.05) effective insulin concentrations were positively related to the M value. Basal and insulin-stimulated rates of lipogenesis were comparable between the diabetic and normal subjects. In conclusion, insulin-mediated glucose disposal in vivo is reduced in conventionally treated type 1 diabetic patients. In vitro, adipocytes from diabetes bound slightly less insulin at tracer insulin concentrations, but the magnitude of this reduction was not related to impairment of glucose metabolism in vivo. Of the pathways of glucose metabolism studied, the rate of glucose oxidation was most affected. A significant relationship was found between the M value and the rate of in vitro glucose oxidation. All pathways of glucose metabolism (transport, oxidation, and lipogenesis) responded normally to insulin, indicating that the reduction of glucose metabolism in vivo is more closely associated with changes in the maximal capacity for uptake and metabolism of glucose than with changes in insulin sensitivity.