Repeated Hypoglycemia Caused by the Overproduction of Anti-insulin Antibodies and Isolated ACTH Deficiency in a Type 2 Diabetic Patient Receiving Insulin Therapy

A 46-year-old man with untreated type 2 diabetes visited our hospital. His plasma glucose and HbA 1c levels were 429 mg/dL and 11.5%, respectively. He had no renal dysfunction. Insulin therapy (18 units aspart and 22 units biphasic insulin aspart 30/70) was initiated, and the HbA 1c level improved (5.7–6.4%). One year later, he started experiencing frequent hypoglycemic attacks , which persisted despite significantly reducing his insulin dosage (total 9 units). Fasting plasma glucose, serum immunoreactive insulin (IRI), C-peptide, and HbA 1c levels were 75 mg/dL, 420 mU/mL (reference, 1.7–10.4), 1.2 ng/mL (reference, 0.6–1.8), and 5.4%, respectively. His anti-insulin immunoglobulin G antibody (IA) titer (125I-insulin binding rate) was 95.5% (reference, 0–7.0); free and total IRI levels were 11.0 and .240 mU/mL, respectively. After insulin cessation, nocturnal hypoglycemia persisted (28–50 mg/dL). In addition, his serum sodium level gradually decreased in the past 2 months (from 142 to 128 mmol/L [reference, 138–146]). Adrenal function was evaluated: plasma ACTH and cortisol levels at 0700 and 2300 h were 21.0 pg/mL (reference , 7.4–54.7) and 2.3 mg/dL (reference, 4.0–18.3), and 11.0 pg/mL and ,1.0 mg/dL, respectively. His 24-h urinary free cor-tisol level was 6.5 mg (reference, 11.2– 80.3). Corticotropin-releasing hormone (100 mg i.v.) test revealed blunted responses of plasma ACTH and cortisol levels (20.0–23.0 pg/mL and 1.4–1.9 mg/dL, respectively). His basal levels of growth hormone, gonadotropins, thyrotropin, and prolactin, and their responsiveness to growth hormone-, gonadotropin-, and thyrotropin-releasing hormones were almost normal. Magnetic resonance imaging revealed a normal pituitary gland. These observations indicated a recent-onset isolated ACTH deficiency (IAD). Replacement with 15-mg hydrocorti-sone normalized the 24-h urinary free cortisol level (24.8 mg) and improved hy-ponatremia. Since diurnal hyperglycemia remained, 90-mg nateglinide was initiated and increased to 270 mg. Frequency of hypoglycemia gradually decreased. The IA titers and IRI levels were 62.7% and 57.3 mU/mL, 47.9% and 12.2 mU/mL, and 15.3% and 7.9 mU/mL after 5, 7, and 11 months, respectively. HbA 1c level was 5.7–6.3% without hypoglycemia. The HLA haplotype was DRB1*090102/150201– DQB1*030302/060101. The DRB1*0406 allele was undetectable, which is common in Japanese patients with insulin autoim-mune syndrome (1). An excessive production of IAs against exogenous insulin causes unexpected hypoglycemia (2). In this patient, a high titer of IAs and IAD occurred almost simultaneously after 1 year of insulin treatment, resulting in recurrent hypogly-cemia. An accurate diagnosis was important to initiate appropriate treatment; glucocorticoid supplementation and nateglinide substitution for insulin reduced the IA titers. …