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

Christopher J. Nolan, Viviane Delghingaro-Augusto
2016 Diabetes  
Islet b-cell failure is mostly progressive in type 2 diabetes, resulting in the need for serial escalations in glucoselowering therapies for many patients with this condition (1-4). This failure is a consequence of impaired b-cell function and loss of b-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 b-cell dysfunction aspect of
more » ... b-cell failure (1,2). This can be a consequence of the endoplasmic reticulum (ER) stress response that inhibits protein synthesis (including proinsulin) and/or b-cell dedifferentiation in which the expression of the essential elements required for a mature b-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 b-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 b-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 b-cell rest, at least in vitro (6). These findings are important, as reversibility of this form of islet b-cell dysfunction, if better understood, may lead to improved approaches for the prevention of progressive b-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 them being that KS db/db , compared with 6J db/db mice, are less able to compensate for insulin resistance by b-cell mass expansion. At 16 weeks of age, both db/db strains were shown to have diabetes with fasting hyperglycemia and hyperinsulinemia. Following an intraperitoneal glucose load, however, only the 6J db/db mice were able to mount a glucose-stimulated insulin secretory response, indicating that 6J db/db mice have less severe islet failure than KS db/db mice (6). The fasting hyperinsulinemia of both these obese mouse strains, however, is consistent with them having some capacity to synthesize and release insulin, even though this is poorly regulated. Ultrastructural analysis of the islet b-cells of both db/db mouse strains showed marked reduction in the number of mature insulin granules, an increased number of immature granules, and the expansion of both the Golgi apparatus and the ER (6). Also seen were some very complex multivesicular bodies (MVBs), which are elaborated on further in the Supplementary Data online (see ref. 6) using elegant tomographic electron microscopy methods. The authors speculate that the appearance of these MVBs may be a consequence of increased requirements for membrane bilayers for b-cell granule formation (6) . The proinsulin synthesis rates, as measured by the incorporation of L-[3,4,5-3 H]leucine into proinsulin, were markedly increased within the islets of both db/db mice strains compared with their respective wild-type counterparts (6). This finding, together with the reduction in mature and an increase in immature insulin granules within the b-cells of these islets, is indicative of a failure of normal proinsulin processing, including insulin granule formation and trafficking. Importantly, a failure of proinsulin synthesis could not be demonstrated. At basal glucose levels, proinsulin biosynthesis was increased 4-and 11-fold in the islets of 6J db/db and KS db/db mice, respectively, relative to the islets of their respective nonobese controls (6). Additionally, proinsulin biosynthesis was shown to be glucose responsive (measured at 17 mmol/L compared
doi:10.2337/dbi15-0020 pmid:26798122 fatcat:eg5b5ut7lzfyhaz42w76b5ieqe