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

Abstract

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 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 b...

Biosynthesis, structure, and folding of the insulin precursor protein

“…It is thus of particular interest that db/db diabetic mice also show little evidence of PERK being active even in the face of ongoing high‐level proinsulin synthesis . And despite this active proinsulin biosynthesis, these are not conditions in which intracellular insulin levels are maintained—in fact there is dramatic β‐cell insulin depletion, indicating significant functional defects along the pathway of proinsulin folding, trafficking, processing and storage …”

“…269 And despite this active proinsulin biosynthesis, these are not conditions in which intracellular insulin levels are maintained-in fact there is dramatic β-cell insulin depletion, indicating significant functional defects along the pathway of proinsulin folding, trafficking, processing and storage. 271 Indeed, in WT mice trying to dispose of high glucose (continuous intravenous infusion of 277 μmoles/h) over a 4-day period, blood glucose is observed to rise within the normal range by 5 to 10 mg/dL each day, while circulating insulin in the bloodstream begins to decline between days 2, 3 and 4. 272 As extracellular glucose levels rise higher still, β-cells can continuously sustain a very high level of proinsulin biosynthesis.…”

Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes

“…46 Of course, the relevance of these findings to beta cell failure in human obesity–related type 2 diabetes still remains to be proven. 47 …”

Frutosamina como principal parâmetro glicêmico do paciente diabético em hemodiálise

“…Essas lesões não atingem apenas os rins, como também são frequentemente vistas no sistema cardíaco, em especial coração e artéria aorta; na artéria renal, gerando aterosclerose da artéria renal; olhos, principalmente retina, cristalino e íris; e incidência de lesões no sistema nervoso entre 40% a 60% em pacientes diabéticos 4 . Além da diabetes mellitus, outras condições como hipertensão arterial, glomerulonefrite e doença renal policística 21 apresentaram relativa correlação à doença renal crônica (DRC), sendo denominados como fatores agravantes para o aparecimento desta.…”

“…A falência das células beta pancreáticas no diabetes mellitus tipo II ocorre quando as mesmas se tornam incapazes de fazer a compensação da resistência à insulina 3 . Esta falência é progressiva com perda de células beta 4 , particularmente quando a hiperglicemia está estabelecida 3 . Em seguida, há diminuição da secreção de insulina devido à progressiva redução da função das células beta (responsáveis pela produção da insulina), havendo hipossensibilidade destas células à glicose, fato este relacionado ao esgotamento funcional ocasionado pela hiperestimulação inicial ao avançar da idade do indivíduo acometido pela doença.…”