Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits

Abstract

Loss of pancreatic islet β-cell mass and β-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulincontaining β-cells can convert into glucagon-containing a-cells ex vivo. This loss of β-cell identity was characterized by the presence of β-cell transcription factors (Nkx6.1, Pdx1) in glucagon+ cells. Here, we investigated whether the loss of β-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin+ cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1+ but insulin- coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1+ glucagon+ insulin- cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1+ glucagon+ insulin- cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of b-cell identity occurs in T2DM and could contribute to the decrease of functional β-cell mass. Maintenance of β-cell identity is a potential novel strategy to preserve β-cell function in diabetes.