Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome

Abstract

SUMMARYThe events that contribute to the expansion of -cell mass and enhanced -cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that -cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of  cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the  cells, (2) identify molecular effectors that contribute to increasing -cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate -cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of -cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult  cells contribute to the failure of the POKO  cell. Our results indicate that the rapid development of insulin resistance and -cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and -cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in  cells with either therapeutic or diagnostic potential.

Ghrelin and lipid metabolism: key partners in energy balance

“…Consistent with these observations, we demonstrated that ghrelin reduces the hypothalamic levels of CHOP-10 and the phosphorylated form of its upstream regulator phosphorylated eukaryotic translation initiation factor 2a (peIF2a; Lage et al 2010). Taking into account that 1) hypothalamic ER stress has recently been suggested as a pathophysiological mechanism mediating leptin resistance and obesity (Hosoi et al 2008, Zhang et al 2008, Ozcan et al 2009, Martínez de Morentin et al 2010b, de Morentin & López 2010, Ropelle et al 2010 and 2) central ghrelin administration increases hypothalamic reactive oxygen species (ROS; Andrews et al 2008), which are well-recognized ER-stress inducers , Tagawa et al 2008, Medina-Gomez et al 2009, Santos et al 2009, Martínez de Morentin et al 2010b, we have recently proposed that ghrelin-induced elevation in hypothalamic pFOXO1 might be part of an allostatic response protecting against ER stress ), a hypothesis that will involve further investigation.…”

Metabolomics applied to the pancreatic islet

“…In contrast, mice with islet specific knockout of PPARγ did not become hyperglycemic [81], indicating that the POKO mouse phenotype is not due to loss of PPARγ in islets. Lipidomic analysis of islets isolated from POKO and PPARγ2 KO mice at 4 weeks of age showed no dysregulation of lipid content [82], whereas at 16 weeks diacylglycerides and short chain tri-acylglycerides were decreased in the knockout strains compared to wild-type. This was associated with decreased levels of ethanol-amine plasmalogen (36:2), and increased levels of phosphatidylethanolamine (36:2) and ceramides (20:0 and 22:0) in islets of POKO mice compared to PPARγ2 knockouts -and wild type mice [80].…”

Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

“…We previously generated a mouse model of PPARγ2 deficiency (PPγ2KO) (11), which is insulin resistant and presents adipose tissue dysfunction, particularly when challenged with positive energy balance (12). Moreover, PPARγ2 seems to be important for pancreatic β-cell mass adaptation in murine models of the metabolic syndrome (13,14). We previously showed that PPARγ agonists reverse IR associated with late pregnancy in rats (3), and there is evidence that PPARg expression in adipose tissue in obese women with GDM is lower than in obese women with an uncomplicated pregnancy (15).…”