Excessive Food Intake, Obesity and Inflammation Process in Zucker fa/fa Rat Pancreatic Islets

Abstract

Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced β-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to ß-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro-inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and β-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1β, IL-6 and TNFα expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning β-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35) and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1β and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of β-cell function by IL-1β. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an inflammatory process. That the latter could contribute to β-cell hyperactivity/proliferation and possibly lead to progressive β-cell failure in these animals, deserves further investigations.

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

“…Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).…”

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

“…In type 2 diabetes, mitochondrial dysfunction in the tissues, particularly in the pancreas, due to proinflammatory responses and disturbance in redox homeostasis signaling have also been reported which may lead to increased oxidative stress [7,32,33]. Our previous studies on type 1 and type 2 diabetic rat models have also suggested that increase in oxidative stress is associated with increased mitochondrial dysfunction [13,14,15,17].…”

“…The ZDF rats exhibit progressive metabolic complications associated with increased insulin resistance, oxidative and nitrosative stress [3,4,5,6]. Studies have shown that obesity, inflammatory cytokines, excessive food intake are risk factors for development of hyperglycemia, insulin resistance and pancreatic β-cell dysfunction in ZDF rats when compared to Zucker lean controls (ZL,FA/+) [7]. The precise molecular mechanism that links progressive metabolic syndrome and insulin resistance in different tissues of ZDF rats is not completely understood.…”

Physical exercise and pancreatic islets

“…15 Afterward, we sought to analyze body weight and adiposity on different groups, since there is a direct relationship between the increase of adiposity and malfunction of pancreatic β-cells. 16,17 As observed, trained groups presented reduced adiposity compared with sedentary groups with what could reflect positively on glycemic homeostasis and/or malfunction of pancreatic islets. The lack of significant differences between groups T and AT and S and AS seems to be directly related to chronic effects.…”