α-Cell deficit in obese type 2 diabetes, a minor role of α-Cell dedifferentiation and degranulation

Context: Type 2 diabetes is characterized by a α-Cell deficit and a progressive defect in α-Cell function. It has been proposed that the deficit in α-Cells may be due to α-Cell degranulation and transdifferentiation to other endocrine cell types. Objective: The objective of the study was to establish the potential impact of α-Cell dedifferentiation and transdifferentiation on α-Cell deficit in type 2 diabetes and to consider the alternative that cells with an incomplete identity may be newly forming rather than dedifferentiated. Design, Setting, and Participants: Pancreata obtained at autopsy were evaluated from 14 nondiabetic and 13 type 2 diabetic individuals, from four fetal cases, and from 10 neonatal cases. Results: Whereas there was a slight increase in islet endocrine cells expressing no hormone in type 2 diabetes (0.11 0.03 cells/islet vs 0.03 0.01 cells/islet, P < .01), the impact on the α-Cell deficit would be minimal. Furthermore, we established that the deficit in α-Cells per islet cannot be accounted for by an increase in other endocrine cell types. The distribution of hormone negative endocrine cells in type 2 diabetes (most abundant in cells scattered in the exocrine pancreas) mirrors that in developing (embryo and neonatal) pancreas, implying that these may represent newly forming cells. Conclusions: Therefore, although we concur that in type 2 diabetes there are endocrine cells with altered cell identity, this process does not account for the deficit in α-Cells in type 2 diabetes but may reflect, in part, attempted α-Cell regeneration.