Beta cell death in hyperglycaemic Psammomys obesus is not cytokine-mediated

Abstract

Aims/hypothesis It has recently been proposed that IL-1β may be responsible for beta cell death in type 2 diabetes mellitus. Major support for this assumption was derived from experiments in the gerbil Psammomys obesus (sand rat), a model for nutritionally induced non-insulin-dependent type 2 diabetes. Using gerbil-specific primers for the analysis of gene expression, we investigated the validity of this hypothesis. Methods Gene expression was analysed by real-time RT-PCR of isolated and laser-microdissected islets and by in situ RT-PCR, both in beta cells and in immune cells, as well as in lymph nodes and spleen. Results We were unable to detect Il-1β and the IL-1β-inducible enzyme inducible nitric oxide synthase (iNos) by in situ RT-PCR, either in the pancreatic beta cells, or in the small number of non-activated immune cells of healthy and diabetic Psammomys obesus after 1 and 3 weeks on a highenergy diet. Very low levels of Il-1β and iNos mRNA were detectable in collagenase-isolated and laser-microdissected islets of normoglycaemic gerbils by real-time RT-PCR without any increase of these mRNAs in islets from diabetic animals. These results were confirmed by electron microscopy with immunogold staining for IL-1β and insulin. Conclusions/interpretation The diabetic syndrome induced in Psammomys obesus by high-energy diet is a classical type 2 diabetes model, which does not show any evidence of an involvement of the proinflammatory cytokine IL-1β or of activated immune cells in its pathogenesis. This is clearly at variance with the situation in type 1 diabetes.

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

“…In obesity, a major risk factor for peripheral insulin resistance and diabetes mellitus type 2, elevated levels of proinflammatory cytokines are found, with TNFα and IL-6 secreted by the adipocytes [2]. IL-1β might be produced and secreted in human beta cells during hyperglycaemic periods [25], although an elevation of IL-1β levels has not been demonstrated in the islets of type 2 diabetic patients or in the islets of hyperglycaemic Psammomys obesus, an animal model of type 2 diabetes [41,42]. However, for the pathogenesis of type 1 diabetes, the involvement of IL-1β secreted by infiltrating mononuclear cells seems undisputed [41 and references therein].…”

Cellular Stress Responses: Cell Survival and Cell Death

“…In Type 2 diabetes, glucolipotoxicity, rather than proinflammatory cytokines, is considered to be an important contributing factor to β -cell dysfunction [230–234]. It is evident from studies on β -cells exposed to a combination of high glucose and a saturated fatty acid that NO • generation through iNOS induction does not contribute to β -cell dysfunction [235].…”

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

“…In situ RT-PCR Sections from the pancreas-draining lymph nodes fixed on three-chamber slides (SuperFrost Plus; Fisher Scientific, Schwerte, Germany) were subjected to in situ RT-PCR gene expression analysis using a two-step protocol with reverse transcription and PCR amplification on a specific thermal cycler (PTC-200 Twin Tower DNA Engine; MJ Research, Waltham, MA, USA) as described before [14]. The primer sequences are listed in Electronic supplementary material (ESM) Table 1.…”