Abstract
BackgroundThe progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansionResultsHere we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.ConclusionsOur data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.
Highlights
The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance
Signalling and more importantly Type 1 Diabetes Mellitus Signalling (Table 3). Overall these results demonstrate that b-cell mass expansion in the context of obesity brings about a subtle, but coordinated increase in the basal level of a wide array of genes involved in the inflammatory and autoimmune response of ob/ob islets that does not occur in PPARg2-ablated POKO islets
Expression of Slc30A8 was not altered in the two comparisons in our microarray data, we found that expression of Slc30A8 detected by RTPCR was decreased in islets from POKO compared to ob/ob mice and in islets from PPARg2KO compared to wild type (WT) mice
Summary
The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. We have recently shown that ob/ob mice with genetic ablation of PPARg2, a mouse model known as the POKO mouse failed to expand its beta cell mass This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Valuable insights into the key role of b-cell failure in the pathogenesis of T2D has come from genome-wide association studies, an important resource to identify new unexpected susceptibility gene candidates for the development of T2D [4] Of interest these studies identified validated variants associated with insulin-secretory defects in the general population and showed little if any relationship to insulin resistance [5,6,7,8,9]
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