Type 2 diabetes (T2DM) is characterized by deficits of b-cell mass and function. The deficit in b-cell mass in patients with T2DM is up to; 65% compared with those without diabetes (1). This deficit in b-cell mass has been attributed to increased b-cell apoptosis (1) due to endoplasmic reticulum stress mediated by protein misfolding due to the accumulation of toxic oligomers of islet amyloid polypeptide (2) and/or gluco-or lipotoxicity (3) and disruption of the mitochondrial network (4). Alternatively, decreased b-cell mass in T2DM may reflect insufficient expansion of b-cell mass during fetal and neonatal life (5) or a failure to adaptively regenerate b-cells in response to b-cell loss. Recent studies have shown that loss of b-cell identity by de-differentiation may contribute to the measured b-cell deficit in mouse models of T2DM characterized by impaired leptin signaling, a finding not yet confirmed in humans with T2DM (6). In this issue of Diabetes, Spijker et al.(7) present data highlighting the loss of b-cell identity in T2DM in humans and nonhuman primates. The authors confirm an increased ratio of a-cells to b-cells reported previously (8) and predicted by the selective loss of b-cells in T2DM. They also confirm an increased frequency of cells coexpressing insulin and glucagon in T2DM (0.52 6 0.18% vs. 4.05 6 1.37%; nondiabetic donors vs. T2DM; P, 0.01), as previously reported (0.4 6 0.1% vs. 3.2 6 1.4%; nondiabetic donors vs. T2DM; P, 0.05)(9). The authors note that about half of these bihormonal cells lack the b-cell transcription factor Nkx6. 1 in both T2DM and control subjects. They report that more than half of cells positive for Nkx6. 1 and glucagon do not express insulin. In the majority of T2DM subjects, the transcription factors MafA, Pdx1, and FOXO1 display aberrant islet subcellular localization, reminiscent of their expression pattern in diabetic mice (6) and humans with T2DM (10, 11). The data in diabetic nonhuman primates further emphasize that altered endocrine cell identity is a conserved feature associated with T2DM. Interestingly, the authors observe a greater frequency of Nkx6. 1+glucagon+insulin 2 cells in areas of the pancreas positive for islet amyloid.

Loss of b-cell identity is a potential contributory factor toward b-cell dysfunction in diabetes, although the percentage of cells described in the current study (7)(; 4%) seems too small to induce diabetes. The studies in mouse models have suggested that b-cell de-differentiation is a likely explanation for the presence of endocrine cells with “confused” identity (6), a view also proposed by Spijker et al. As an alternative, these aberrant cells may be an early developmental endocrine cell type and a reflection of attempted compensatory b-cell neogenesis. While neogenesis is rare in mouse models (12, 13), some evidence suggests that it may occur in human and primate pancreata (14, 15). Spijker et al. cite studies showing that bihormonal cells are present in both obese prediabetic and diabetic states, but b-cell mass is reduced only in diabetes, arguing against bihormonal cells contributing significantly to b-cell loss.