Circulating Anti-Insulin Antibodies Protect Against Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Treated with Long-Acting Insulin Analogues

Background: Long-acting insulin analogues have been widely used in patients with type 2 diabetes with reduced insulin secretion. In these patients, hypoglycemia may occur during the night when they do not consume food. We have already reported that anti-insulin antibodies developed at a fairly high frequency in patients with type 2 diabetes treated with insulin analogues. Therefore, clinical factors associated with nocturnal hypoglycemia, including anti-insulin antibodies, were searched in patients with type 2 diabetes treated with insulin analogues. Methods: The subjects consisted of 55 patients with type 2 diabetes with relatively stable glucose control treated with long-acting insulin analogues and 15 non-diabetic subjects. Using a continuous glucose monitoring, glucose fluctuation was observed for 10 days. Hypoglycemia was defined as a glucose monitoring level of less than 54 mg/dL for more than 15 min. Results: Nocturnal (duration 6 h, from midnight to 6 a.m.) hypoglycemia was observed in 13 patients (23.6%). All of the cases were unrecognized. Daytime (duration 18 h, from 6 a.m. to midnight) hypoglycemia was also observed in 14 patients (25.5%). Stratified analysis and logistic regression analysis disclosed that anti-insulin antibodies were significantly associated with nocturnal hypoglycemia in contrast to daytime hypoglycemia, which was not associated with anti-insulin antibodies but associated with lower HbA1c. That is, the frequency of nocturnal hypoglycemia was significantly higher in the negative group and lower in the positive group of the anti-insulin antibodies. Conclusions: These results suggest that circulating anti-insulin antibodies protect against nocturnal hypoglycemia.