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.
Highlights
The prevalence and incidence of type 2 diabetes (T2D) are dramatically increasing worldwide in both developed and developing countries
Materials In the immunofluorescence studies we used anti-cytokines antibodies against IL-1ß, IL-6, tumor necrosis factor a (TNFa), IFNc, and anti-cytokine receptor antibodies against IL-1R1, IL-1R2, IL-6R, TNF-R1, IFN-Ra, IFN-Rß (Santa Cruz Biotechnology, Santa Cruz, CA); guinea pig anti-insulin antibody was from MP Biomedicals (MP Biomedicals, Irvine, CA)
Concerning circulating cytokines, most of them were found at similar levels in fa/fa and fa/+ rats; only IFNc appeared drastically reduced by 50–75% and LIX (CCXCL5) was moderately higher in fa/fa rats
Summary
The prevalence and incidence of type 2 diabetes (T2D) are dramatically increasing worldwide in both developed and developing countries. This multifactorial disease results from the interaction of environmental factors and genetic predisposition leading to two major abnormalities: insulin resistance and defective b-cell function. Hyperglycemia develops with a progressive b-cell dysfunction, but the mechanisms involved remain to be determined. In this context, inappropriate food intake and related obesity are major risk factors for the onset of T2D. High carbohydrate and high fat diets, the major cause of obesity, represent two diabetogenic factors that can lead, by their own, to b-cell dysfunction
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