Eight weeks after liraglutide or human umbilical cord mesenchymal stem cell administration, FPG, HbA<sub>1c</sub> , glucagon, body weight, and pancreatic ASK1, JNK, and BAX mRNA and proteins were significantly decreased, and the levels of serum C-p, INS and GLP-1, ratio of insulin positive area, and Bcl-2 expression were significantly increased in three treatment groups compared with T2DM group (P<.05).
Proinsulin associates with poor β-cell function, glucose-dependent insulinotropic peptide, and insulin resistance in persistent type 2 diabetes after Roux-en-Y gastric bypass in humans.
We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325.
The association of common intronic single-nucleotide variants in the human TRAPα gene with susceptibility to type 2 diabetes and pancreatic β cell dysfunction suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of type 2 diabetes.
These results reveal for the first time that misfolded proinsulin can interact with ProIR in the ER, impairing intracellular processing of ProIR and leading to defective insulin signaling that may contribute to β-cell failure in both MIDY and T2D.-Liu, S., Li, X., Yang, J., Zhu, R., Fan, Z., Xu, X., Feng, W., Cui, J., Sun, J., Liu, M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in β cells.
These findings suggest the presence of intraislet, but not interislet, variation in the expression of the proinsulin processing enzymes in non-diabetic subjects and a heterogeneous effect of type 2 diabetes on enzyme expression in islets.
Finally, the rs7163757proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets.
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.
This is most obvious in mutant INS gene-induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.
The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY).
In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D.
We assessed proinsulin expression by using flow cytometry in dendritic cells from control participants and patients with type 2 diabetes with or without peripheral neuropathy or accompanied by diabetic foot.
ER stress due to proinsulin misfolding has an important role in the pathophysiology of rare forms of permanent neonatal diabetes (PNDM) and probably also of common type 1 (T1D) and type 2 diabetes (T2D).
A prospective evaluation of a large set of potential predictors of beta cell stress, measured as change in the proinsulin/insulin (PI/I) ratio, was conducted in a cohort of 235 outpatients with T2DM on stable treatment with oral hypoglycaemic agents or diet followed up for ~4 years (median value 3.9 years; interquartile range 3.8-4.1 years).
These data suggest that pancreatic Zn<sup>2+</sup> and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.
These findings suggest that intracellular high-lipid may trigger defective autophagy, defective downstream signaling of insulin and accumulated intracellular preproinsulin, leading to dysregulation of cell homeostasis mechanism, which may be one of reasons involved in insulin-resistance in type 2 diabetes.
Human islets isolated from non-diabetic controls and individuals with type 2 diabetes, as well as human islets and INS-1E cells exposed to increased glucose (22.2 mmol/l), were examined for mTORC1/2 activity by western blotting analysis of phosphorylation of mTORC1 downstream targets ribosomal protein S6 kinase 1 (S6K1), S6 and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and mTORC2 downstream targets Akt and N-myc downstream regulated 1 (NDRG1). mTORC1/2 complexes' integrity was assessed by immunoprecipitation and subsequent western blot analysis.
In this study, we examine the mechanism by which the voltage-dependent K<sup>+</sup> (Kv) channel Kv2.1 (<i>KCNB1</i>) facilitates depolarization-induced exocytosis in INS 832/13 cells and β-cells from human donors with and without type 2 diabetes (T2D).