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Insulin Treatment Reverses the Postreceptor Defect in Adipocyte 3-O-Methylglucose Transport in Type II Diabetes Mellitus^*

J. A. Scarlett, O. G. Kolterman, T. P. Ciaraldi, M. Kao and J. M. Olefsky

Departments of Medicine, University of Colorado Health Sciences Center, and Veterans Administration Hospital, Denver, Colorado 80262

Address all correspondence and requests for reprints to: J. M. Olefsky, M.D., University of Colorado Health Sciences Center, Department of Medicine, B151, 4200 East Ninth Avenue, Denver, Colorado 80262.

The insulin resistance of type II diabetes mellitus is due to both receptor and postreceptor defects of in vivo insulin action, with the postreceptor defect being the predominant abnormality. Diminished glucose transport has been found in adipocytes from patients with type II diabetes, suggesting that decreased cellular glucose transport activity may be responsible in part for the in vivo postreceptor defect observed in these patients. Recent studies have shown that the in vivo postreceptor defect initially present in patients with Type II diabetes is significantly reversed by insulin therapy. For these reasons, we speculated that the defect in adipocyte glucose transport might also be corrected with exogenous insulin therapy. Therefore, we measured adipocyte 3-O-methylglucose transport in cells from five type II diabetic subjects before and after a 2-week period of intensive insulin treatment.

Glycemic control was significantly improved by this regimen. The mean (±SE) fasting serum glucose level fell from 292 ± 24 to 135 ± 29 mg/100 ml (P < 0.005), and the mean integrated glucose area under a 7-h meal tolerance test curve decreased from 171,212 ± 20,403 to 72,408 ± 9,292 mg/min·dl. The mean 3-O-methylglucose transport activity increased after treatment at all insulin concentrations studied, including basal (before, 0.18 ± 0.05; after, 0.45 ± 0.09 pmol/2 x 106 cells 10 sec; P < 0.005) and maximally effective (25 ng/ml) insulin concentrations (before, 0.50 ± 0.14; after, 1.32 ± 0.30 pmol/2 x 10⁵ cells·10 sec; P < 0.025), although the mean maximal glucose transport activity was still 25% decreased compared to normal values, indicating that a residual in vitro postreceptor defect remained. These results corresponded well with the degree of reversal (75%) of the in vivo postreceptor defect, as assessed by the euglycemic glucose clamp technique.

These studies demonstrated that the decrease in adipocyte glucose transport activity in type II diabetes is practically reversible by intensive insulin therapy. This closely corresponds to the reversal by insulin therapy of the postreceptor defect expressed in vivo and provides further evidence that a cellular cause of the postreceptor defect in type II diabetes is a decrease in glucose transport system activity in the major insulin target tissues. (J Clin Endocrinol Metab 56:1195,1983)

^* This work was supported in part by funds from the Medical Research Service of the V.A., Grants AM-19905 and AM-26180 from the NIH, Grant RR-00051 from the Clinical Research Center Branch of the NIH, and a grant from the Kroc Foundation.

Recipient of an Associate Investigator Award from the V.A.

Recipient of a Clinical Investigator Award (AM-00580) from the NIAMDD, NIH.

Received September 17, 1982.

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