Diabetes Due to Secretion of an Abnormal Insulin

A 51-year-old, nonobese man with diabetes mellitus had marked hyperinsulinemia (70 to 120 μU per milliliter; 502 to 860 pmol per liter) and fasting hyperglycemia (140 to 170 mg per 100 ml; 7.8 to 9.4 mmol per liter). Plasma proinsulin, glucagon, growth hormone, and cortisol levels were normal; insulin antibodies and insulin-receptor antibodies were not detected. The patient showed relatively normal insulin sensitivity, and insulin receptors on circulating monocytes were within the normal range. Insulin from the patient's serum bound to IM-9 lymphocytes and rat adipocytes approximately 40 per cent as well as insulin standards. Its biologic activity on rat adipocytes averaged 15 per cent of that expected from its immunologic concentration. The impaired biologic activity of this patient's circulating insulin was probably due to a structural abnormality. Subsequent studies of the patient's insulin (fortuitously obtained from his pancreas during a laparotomy for a pancreatic cyst) have confirmed this conclusion. (N Engl J Med 302:129–135, 1980) THE possibility that some patients with diabetes synthesize a structurally abnormal insulin molecule with reduced biologic activity has been considered for many years. 1 2 3 4 In 1966, Elliott et al. 5 showed that the circulating insulin in patients with juvenile-onset diabetes was relatively resistant to degradation by a proteolytic enzyme, insulinase, that was isolated from rat skeletal muscle. These authors suggested that an alteration in the structure of insulin in diabetics was responsible for this resistance to insulinase. 5 Kimmel and Pollock 6 analyzed the amino acid composition of insulins isolated from the pancreases of 11 non-diabetics and eight diabetics. Analysis of one sample from . . .