Abstract
Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.
Highlights
Type 2 diabetes (T2D) is a complex metabolic disorder characterised by elevated blood glucose levels
Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 that displays β-cell mitochondrial dysfunction and reduced insulin secretion in humans
Given these similarities in β-cell dysfunction in T2D and DS, we developed a trisomy 21 screening method to identify genes that may be important in T2D
Summary
Type 2 diabetes (T2D) is a complex metabolic disorder characterised by elevated blood glucose levels. Pancreatic β-cell dysfunction and reduced insulin output in the presence of insulin resistance is the primary cause of T2D. Alternative pathways exist to drive β-cell dysfunction and reduced glucose-stimulated insulin secretion (GSIS). Oxidative stress is increased in human T2D β-cells and negatively correlates with GSIS impairment [2]. T2D β-cells display marked mitochondrial dysfunction; characterised by a reduced respiratory response to glucose [3] in association with lower ATP levels [4]. Given that mitochondrial function is central to oxidative stress, ATP production and GSIS in β-cells, and that these are major defects in T2D β-cells, identifying the genes responsible for β-cell mitochondrial dysfunction is essential to further our understanding of the mechanisms controlling β-cell function
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