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Familial Hyperinsulinemia Associated with Secretion of an Abnormal Insulin, and Coexistence of Insulin Resistance in the Propositus^*

Departments of Internal Medicine (Division of Endocrinology and Metabolism) and Physiology, The University of Michigan Ann Arbor, MI 48109

Address requests for reprints to: A. I. Vinik, M.D., University of Michigan Medical Center, Room D2226 Medical Professional Building, Box 046,1405 East Ann Street, Ann Arbor, Michigan 48109.

A 45-yr-old muscular nonobese white man who had a 9-yr history of syncopal episodes was studied on several occasions between April 1979 and August 1984. Fasting glucose concentrations ranged between 74–115 mg/dl, and those of insulin ranged between 14–64 µ/ml. Reactive hypoglycemia 3–4 h after ingestion of glucose occurred in the first 2 yr. Glucose tolerance was impaired in 1979, from February 1982 through September 1983, and again in August 1984. The maximum plasma insulin response to glucose ranged between 475–1630 µU/ml. When studied in November 1982, insulin (0.1 U/kg) caused a fall in blood glucose concentration of only 25% (normal, >50%), and maximal glucose utilization during the euglycemic hyperinsulinemic clamp was 7.5 mg/kgmin (normal, >12 mg/kg·min). Plasma counterregulatory hormone concentrations were normal, and antibodies to insulin and the insulin receptor were absent. Binding of exogenous insulin to the patient's cellular receptors (monocytes, red blood cells, and skin fibroblasts) was normal. Insulin was purified from plasma by immunoaffinity and molecular sieve chromatography and was found to elute later than human insulin on reversed phase high performance liquid chromatography. It was more hydrophobic than normal human insluin and had only 10% of the activity of normal insulin in terms of ability to bind to and stimulate glucose metabolism in isolated rat adipocytes.

The abnormal insulin was identified in two of three sons and a sister, but not in the mother, brother, or niece. Sensitivity to insulin was normal in the two sons who had abnormal insulin.

These results suggest that in this family the abnormal insulin was due to a biosynthetic defect, inherited as an autosomal dominant trait. The hyperinsulinemia was not associated with diabetes in family members who had no insulin resistance.

^* An abstract based on this study was presented at the Central Society for Clinical Research, Chicago,IL, November 1983. This work was supported by a grant from the American Diabetes Association and the Michigan Affiliate of the ADA and NIH Grants 5M01-RR-00042-22 (Clinical Research Center) and 5-P60-AM-20572-07 (Diabetes Research and Training Center)

Received May 10, 1985.

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