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Insulin Receptor Function and Glycogen Synthase Activity in Skeletal Muscle Biopsies from Patients with Insulin-Dependent Diabetes Mellitus: Effects of Physical Training^*

Department of Endocrinology and Internal Medicine, Aarhus Amtssygehus Aarhus
Department of Internal Medicine, Silkeborg Centralsygehus Silkeborg, Denmark

Address all correspondence and requests for reprints to: Jens Friis Bak, M.D., Medical Department III, Aarhus Amtssygehus, DK-8000 Aarhus C, Denmark.

This study was designed to examine the mechanisms causing peripheral insulin resistance in patients with insulin-dependent diabetes mellitus (IDDM) by studying insulin receptor function and glycogen synthase activity in biopsies of skeletal muscle. The results in seven such patients were compared with values obtained in a group of sedentary, age- and sex-matched normal subjects. In addition, since physical training appears to improve insulin sensitivity, the IDDM patients were reexamined after physical training for 6 weeks.

The mean maximal glycogen synthase activity was lower in the diabetic than in the normal group [34.5 ± 10.6 (±SD) us. 45.7 ± 8.6 nmol/mg protein-min; P < 0.05], whereas there was no difference in the half-maximal activation constant (A_0.5) for glucose-6-phosphate. Likewise, the mean yield of wheat germ agglutinin-purified insulin receptors recovered per mg muscle was 21% lower in the muscle biopsies from the diabetic patients (47 ± 8 vs. 66 ± 20 fmol/100 mg; P < 0.05. However, basal and insulin-stimulated receptor kinase activities, expressed as phosphorylation of the synthetic peptide poly-Glu-Tyr(4:l), were identical in the two groups.

After physical training in the diabetic patients the mean maximal oxygen uptake increased from 45.7 ± 7.4 to 48.9 ± 9.0 mL O₂/kg.min (P < 0.05), hemoglobin A_lc decreased from 7.9 ± 1.4% to 7.7 ± 1.5% (P < 0.05), and insulin requirements decreased from 43 ± 9 to 38 ± 8 U/day (P < 0.05). The number of recovered insulin receptors did not increase, and the receptor kinase activity was similar to the pre-training value. Maximal glycogen synthase activity increased by 15% (P < 0.02), whereas A_0.5 for glucose-6-phosphate did not change.

We conclude that insulin binding to muscle-derived insulin receptors is impaired in IDDM patients, whereas receptor kinase function appears to be normal. The capacity for glycogen storage in the diabetic skeletal muscle was reduced. Physical training tended to normalize glycogen synthase activity, but did not improve insulin receptor function significantly.

^* The work was supported by grants from the Danish Medical Research Council, Danish Diabetes Association, Direktør Jacob Madsen og Hustru Olga Madsens Fond, Aarhus Universitets Forskningsfond, NOVOs Fond, and Nordisk Insulin Fond.

Received November 14, 1988.

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