β-Cell Identity in Type 2 Diabetes: Lost or Found?

Abstract

Type 2 diabetes (T2DM) is characterized by deficits of β-cell mass and function. The deficit in β-cell mass in patients with T2DM is up to ∼65% compared with those without diabetes (1). This deficit in β-cell mass has been attributed to increased β-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 β-cell mass in T2DM may reflect insufficient expansion of β-cell mass during fetal and neonatal life (5) or a failure to adaptively regenerate β-cells in response to β-cell loss. Recent studies have shown that loss of β-cell identity by de-differentiation may contribute to the measured β-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 β-cell identity in T2DM in humans and nonhuman primates. The authors confirm an increased ratio of α-cells to β-cells reported previously (8) and predicted by the selective loss of β-cells in T2DM. They also confirm an increased frequency of cells coexpressing insulin and glucagon in T2DM (0.52 ± 0.18% vs. 4.05 ± 1.37%; nondiabetic donors vs. T2DM; P < 0.01), as previously reported (0.4 ± 0.1% vs. 3.2 …