Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes

Context: It has been suggested that beta cell loss in type 2 diabetes (T2D) may be due to beta cell degranulation and/or altered cell identity. While shown to have a minor role in obese T2D, this has not been evaluated in lean T2D. Objective: To establish the contribution of altered beta cell identity in lean T2D and, using a rodent model of lean T2D, whether changes in beta cell identity precede hyperglycemia. Design, Setting, and Participants: We investigated the frequency of chromogranin A positive hormone negative (CPHN) and polyhormonal endocrine cells in pancreas from 10 lean nondiabetic and 10 lean T2D subjects and in pancreas from wild-type and human IAPP transgenic rats at the prediabetic and diabetic stages. Results: CPHN cells and polyhormonal-expressing cells were comparably increased in lean T2D and human IAPP transgenic rats, in the latter both before and at onset of diabetes. However, the extent of these cells could only account for approximately 2% of beta cell loss. Conclusion: Degranulation and altered identity play at most a minor role in the beta cell deficit in lean T2D. Because the increase in CPHN and polyhormonal cells precede diabetes onset, these changes are likely a response to stress rather than hyperglycemia, and may reflect attempted regeneration.