Role of endoplasmic reticulum stress in the alterations on pancreatic β cell mass and function induced by a fructose-rich diet

Abstract

Introduction: human prediabetes (PD) is an underdiagnosed disease that precedes the diagnosis of type 2 diabetes (T2D), so its early detection and appropriate intervention could delay or prevent its progression to T2D. PD is characterized by alterations in fasting blood glucose and/or glucose tolerance (AGT), together with an insulin-resistant (IR) state that induces β cell functional overload that triggers the activation of endoplasmic reticulum (ER) stress. In rats, the administration of a fructose-rich diet (FRD) generates endocrine-metabolic changes like those of human PD, with increased oxidative stress, AGT, and decreased β cell mass and function.

Objectives: our aim was to study ER stress and inflammatory response in male Sprague-Dawley rats fed an FRD for 21 days.

Materials and methods: rats were divided into two groups, a control group (C), fed a standard commercial diet and water; and a FRD group, which drank a 10% w/v fructose solution. After the treatment period, blood was drawn from each animal to measure serum glucose, triglyceride (TG), total cholesterol (chol), and HDL-chol levels. The IR index was calculated as TG/HDL-chol. The pancreas was also removed to isolate islets with collagenase to study glucose-stimulated insulin secretion (GSIS) and gene expression (qPCR and western blot) of ER stress markers, autophagy, inflammatory response, and apoptotic pathways.

Results: FRD rats presented dyslipidemia and IR, characterized by decreased HDL-chol (46.7±4.0 vs 58.7±3.0 mg/dl; p<0.05) and significant increase (p<0.05) of TG (276.7±22.0 vs 102.2±23.0 mg/dl), total cholesterol (83.5±4 vs 72.5±0.6 mg/dl) and IR index (6.2±0.9 vs 1.7±0.3). FRD rats had an increased GSIS in the presence of 16.7 mM glucose (FRD: 8.4±0.8; C: 5.3±0.6 ng/islet/h; p<0.05), and a significant increase (% increase respect to C) in gene expression (at mRNA level) of genes encoding ER stress associated factors (CHOP: 24.0±0.7; ATF4: 49±1 and XBP1s: 92±1), autophagy (HSc70: 121±2), apoptosis (Casp-3: 25.0±0.8, Casp-12: 199±3 and Bad: 72±1) and inflammation (TNF-α: 281±9, IL-1β: 185±4 and PAI-1: 20±1). These alterations were correlated with changes at protein level of most apoptosis markers (Casp-3: 225±3; Bcl2: 31.0±1.2; Bad: 131.2±0.8 and Casp-8: 93±9% increase with respect to C).

Conclusions: our results demonstrate that FRD-induced dyslipidemia, IR, and functional overload of β cells are accompanied by an increase in ER stress, apoptosis process, and the inflammatory response, thus contributing to promoting β cell mass and function alteration.