Reversibility of Defects in Proinsulin Processing and Islet β-Cell Failure in Obesity-Related Type 2 Diabetes.

Abstract

Islet β-cell failure is mostly progressive in type 2 diabetes, resulting in the need for serial escalations in glucose-lowering therapies for many patients with this condition (1–4). This failure is a consequence of impaired β-cell function and loss of β-cell mass, with varying contributions of each likely to relate to the heterogeneity in causative factors from patient to patient (1–5). It is a commonly held view that impaired proinsulin synthesis contributes to the β-cell dysfunction aspect of β-cell failure (1,2). This can be a consequence of the endoplasmic reticulum (ER) stress response that inhibits protein synthesis (including proinsulin) and/or β-cell de-differentiation in which the expression of the essential elements required for a mature β-cell function, including the transcription of the insulin gene, are reduced or absent (1,2). In this issue of Diabetes , however, Alarcon et al. (6) convincingly show that islet β-cell proinsulin synthesis is increased rather than decreased in two obese mouse models of type 2 diabetes. They do find severe depletion in the number of mature insulin granules in the β-cells of these obese diabetic mice, but the evidence is that this results from accelerated, dysfunctional proinsulin processing and trafficking rather than the consequence of deficient proinsulin synthesis (6). Furthermore, these defects can be rapidly reversed by a short period of β-cell rest, at least in vitro (6). These findings are important, as reversibility of this form of islet β-cell dysfunction, if better understood, may lead to improved approaches for the prevention of progressive β-cell failure in affected patients with type 2 diabetes. Alarcon et al. (6) used the C57BL/6J db/db and the C57BLKS/J db/db obese diabetic mouse models (referred to hereon as 6J db/db and KS db/db ), the difference between …