It is generally accepted that insulin resistance precedes the development of type 2 diabetes, but the precise mechanism that links insulin resistance to overt diabetes is not well understood. Genetic defects of the insulin receptor, although the prevalence is low, are regarded as one of the specific causes of diabetes (1). However, few studies have reported long-term observations of subjects with the insulin receptor mutation (2). Here, we describe a family with the abnormal insulin receptor who was followed-up for ∼20 years.

The proband is a 34-year-old Japanese woman. At 16 years of age, she noticed acanthosis nigricans in her axillae and groin. Her BMI was 19.0 kg/m2. Fasting glucose was normal, but fasting insulin concentration was as high as 240 pmol/l. Anti-insulin and anti–insulin receptor antibodies were negative. The 100-g oral glucose challenge revealed normal glucose tolerance, with peak insulin level of 4,476 pmol/l. Intravenous administration of 0.1 units/kg regular insulin only decreased her glucose level to 64% of the basal value. The number of insulin receptors on her erythrocytes was normal, and subsequent molecular analysis revealed the heterozygous deletion of Leu999 in the β-subunit of the insulin receptor, resulting in the decrease in autophosphorylation stimulated by insulin (3). Acanthosis nigricans began to fade beginning at 18 years of age, and she bore two children uneventfully. At 34 years of age, she was still nonobese, with BMI 19.7 kg/m2. Fasting glucose was normal, although hypoglycemia of 2.39 mmol/l, together with cold sweat and palpitation, was noted after lunch. Because prolonged fasting of 24 h did not cause hypoglycemia, the diagnosis of reactive hypoglycemia was made. Fasting insulin concentration was 128 pmol/l. Her oral glucose tolerance was again normal, and insulinogenic index, a marker of early-phase insulin secretion (4), was as high as 9.8 (normal population values 0.7–1.3). The intravenous insulin injection successfully decreased her glucose level to 42% of the basal value, with normal responses of counter-regulatory hormones.

The heterozygous deletion of Leu999 in the β-subunit of the insulin receptor was also demonstrated in her mother and elder and younger brothers (3). Her mother was obese, with BMI 30.0 kg/m2, and was diagnosed as having diabetes at 44 years of age. Her fasting insulin was as high as 222 pmol/l. The insulinogenic index of 1.1 was within normal population values but was regarded as decreased considering the underlying mutation. Her elder brother was normal glucose tolerant at 18 years of age (BMI 23.0 kg/m2) but became impaired glucose tolerant at 26 years of age (BMI 25.0 kg/m2). Fasting insulin simultaneously increased from 216 to 366 pmol/l, while the insulinogenic index decreased from 8.5 to 1.6. At 36 years of age, he had developed overt diabetes, with BMI 30.0 kg/m2, and was treated with oral hypoglycemic agents. Her younger brother’s fasting insulin was as high as 396 and 144 pmol/l at 12 and 20 years of age, respectively, but he was not available for follow-up.

The glucose tolerance of the lean proband remained normal during the 20-year observation period, and insulin resistance seemed to be rather ameliorated. In contrast, all the other family members with the same insulin receptor mutation who developed diabetes were obese. Thus, obesity appears to be required to develop overt diabetes for the family members of the abnormal insulin receptor. Because the diabetic members had reduced capacity to secrete insulin after oral glucose load, as estimated by the low insulinogenic index, obesity may play a pivotal role in the decompensation of β-cell function. Insufficient β-cell compensation for insulin resistance is generally considered to play an important role in the development of diabetes (5). In particular, there are several lines of evidence that β-cell dysfunction results from an increase in inherited insulin resistance (6,7) and increased abdominal adiposity (8). Obesity may increase the risk of diabetes not only by simply increasing insulin resistance but also by causing β-cell dysfunction under certain circumstances.

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Address correspondence to Dr. Shoichiro Nagasaka, Division of Endocrinology and Metabolism, Jichi Medical School, Yakushiji 3311-1, Minami-kawachi, Tochigi 329-0498, Japan. E-mail: