INS mutations have a broad spectrum of clinical presentations, ranging from severe neonatal onset to mild adult onset, which suggests that the products of different mutant INS alleles behave differently and utilize distinct mechanisms to induce diabetes.
In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes.
Male Wistar rats were treated with or without streptozotocin (STZ, an insulinopenic model of diabetes) and either α-lipoic (90 mg/kg ip.), α-tocopherol (200 mg/kg po.) or with STZ and supplemented with insulin (STZ + INS: 2.5U/day) for 4 weeks.
Proinsulin processing is quite sensitive to nutrient flux, and β-cell-specific deletion of the nutrient-sensing protein modifier OGlcNAc transferase (βOGTKO) causes β-cell failure and diabetes, including early development of hyperproinsulinemia.
Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab<sup>+</sup> in combination with GADA<sup>+</sup> and IA-2A<sup>+</sup> , compared with 84.37% in those with IAA<sup>+</sup> , GADA<sup>+</sup> , and IA-2A<sup>+</sup> (P = 0.04).
Given the fact that proinsulin misfolding plays an important role in diabetes, this study suggests that enhancing ER export may be a potential therapeutic target to prevent/delay β-cell failure caused by proinsulin misfolding and ER stress.
The exercise in sole (EX) and simultaneous forms with INS (DM + INS + EX group) ameliorated the DM-suppressed spermatogenesis and spermiogenesis indices, up-regulated the serum testosterone and insulin levels, enhanced testicular SOD content, inhibited the apoptosis and improved almost all sperm parameters.
We have previously shown that the introduction of furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes resulted in the reversal of diabetes and partial pancreatic transdifferentiation of liver cells.
Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.
Herein, we critically review the literature on the effects of proinsulin misfolding and ER stress on β-cell dysfunction and loss in diabetes with emphasis on β-cell dynamics, and discuss the gaps in understanding the role of proinsulin misfolding in the pathophysiology of diabetes.