Endocrine Abstracts

Metabolic and inflammatory insults contribute to beta-cell failure and apoptosis, in part via the generation of reactive oxygen species (ROS). The pancreatic β-cell acquires sensitivity to the damaging actions of pro-inflammatory cytokines during differentiation, but the mechanisms underlying the differentiation-dependent sensitisation is unknown. By mRNA microarray of a cell-model of β-cell differentiation exposed to cytokines we identified a cluster of transcripts involved in metal-ion handling, including the divalent metal transporter DMT-1¹. Cytokines up-regulated DMT-1 expression and iron import in β-cell-lines and islets. DMT-1 knock-down prevented cytokine-induced β-cell apoptosis. We generated an inducible β-cell specific DMT-1 knock-out (KO) mouse. Islets from these mice were protected from cytokine-toxicity in vitro, and glucose intolerance caused by both low-dose streptozotocin causing an autoimmune islet response but also by high-fat feeding was attenuated in DMT-1 KO mice. For this reason we have investigated whether FFA regulate β-cell and islet DMT-1 expression, iron import and ROS formation, and if DMT-1 KO prevented FFA induced islet secretory failure and apoptosis. The results of these studies will be presented. Elevated iron saturation conferred risk of diabetes development in large population studies². This evidence suggests that pathways regulating iron handling may harbour novel therapeutic targets for anti-diabetic drugs.

References: 1. Hansen JB, Tonnesen MF, Madsen AN, Hagedorn PH, Friberg J, Grunnet LG, Heller RS, Nielsen AØ, Størling J, Bayens L, Anker-Kitai L, Quortrup K, Bouwens L, Efrat S, Aalund M, Andrews N, Billestrup N, Karlsen E, Holst B, Pociot F, Mandrup-Poulsen T. Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic β-cell fate in response to cytokines. Cell Metab 2012; 16: 1-13.

2. Ellervik C, Mandrup-Poulsen T, Andersen HU, Tybjærg-Hansen A, Frandsen M, Birgens H, Nordestgaard BG. Elevated transferrin saturation and risk of diabetes mellitus – three population-based studies. Diabetes Care 2011;34: 2256-2258.