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Endoplasmic reticulum stress and destruction of pancreatic ? cells in type 1 diabetes.

ABSTRACT: Type 1 diabetes (T1D) results from dysfunction of pancreatic islets ? cells. Recent studies supported that endoplasmic reticulum (ER) stress takes an important role in pancreatic ? cell excessive loss, resulting in T1D. Here, we aimed to review the relationship between ER stress and T1D. Additionally, we also reviewed the potential mechanisms underlying ER stress mediated T1D. Studies have shown that severe ER stress is directly involved in the pancreatic ? cells destruction and pathogenesis of T1D. ER stress plays a key part in pancreatic ? cells and T1D, which will help in developing new effective therapeutics for T1D.

SUBMITTER: Cao ZH

PROVIDER: S-EPMC7028193 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes.

Cao Zhao-Hui ZH Wu Zhuan Z Hu Cong C Zhang Min M Wang Wu-Zhou WZ Hu Xiao-Bo XB

Chinese medical journal 20200101 1

Type 1 diabetes (T1D) results from dysfunction of pancreatic islets β cells. Recent studies supported that endoplasmic reticulum (ER) stress takes an important role in pancreatic β cell excessive loss, resulting in T1D. Here, we aimed to review the relationship between ER stress and T1D. Additionally, we also reviewed the potential mechanisms underlying ER stress mediated T1D. Studies have shown that severe ER stress is directly involved in the pancreatic β cells destruction and pathogenesis of ...[more]

PMID: 31923106

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Project description:Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n = 17; age 65 ± 21 years; gender: 5 M/12 F; BMI 23.4 ± 3.3 kg/m2) and T2D (n = 9; age 76 ± 6 years; 4 M/5 F; gender: BMI 25.4 ± 3.7 kg/m2) organ donors. Nine ND organ donors were treated for hypertension and 1 for both hypertension and hypercholesterolemia. T2D organ donors were treated with metformin (1), oral hypoglycemic agents (2), diet + oral hypoglycemic agents (3), insulin (3) or insulin plus metformin (3) as for antidiabetic therapy and, of these, 3 were treated also for hypertension and 6 for both hypertension and hypercholesterolemia. Two days after isolation, they were cultured for 1-5 days with 10 ng/ml rapamycin (autophagy inducer), 5 mM 3-methyladenine or 1.0 nM concanamycin-A (autophagy blockers), either in the presence or not of metabolic (0.5 mM palmitate) or chemical (0.1 ng/ml brefeldin A) ER stressors. In ND islets palmitate exposure induced a 4 to 5-fold increase of beta cell apoptosis, which was significantly prevented by rapamycin and exacerbated by 3-MA. Similar results were observed with brefeldin treatment. Glucose-stimulated insulin secretion from ND islets was reduced by palmitate (-40 to 50%) and brefeldin (-60 to 70%), and rapamycin counteracted palmitate, but not brefeldin, cytotoxic actions. Both palmitate and brefeldin induced PERK, CHOP and BiP gene expression, which was partially, but significantly prevented by rapamycin. With T2D islets, rapamycin alone reduced the amount of p62, an autophagy receptor that accumulates in cells when macroautophagy is inhibited. Compared to untreated T2D cells, rapamycin-exposed diabetic islets showed improved insulin secretion, reduced proportion of beta cells showing signs of apoptosis and better preserved insulin granules, mitochondria and ER ultrastructure; this was associated with significant reduction of PERK, CHOP and BiP gene expression. This study emphasizes the importance of autophagy modulation in human beta cell function and survival, particularly in situations of ER stress. Tuning autophagy could be a tool for beta cell protection.

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Endoplasmic reticulum stress and destruction of pancreatic ? cells in type 1 diabetes.

Publications

Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes.

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