Cisd2 deficiency impairs glucose-stimulated extracellular Ca2+ influx in beta-cells and causes insulin-dependent diabetes
Shao-Yu Hsiung1,2, Cheng-Heng Kao3 and Ting-Fen Tsai1,2,4 1Program in Molecular Medicine, School of Life Sciences, and 2Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan; 3Center of General Education, Chang Gung University, Taoyuan, Taiwan; 4Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Taiwan
Diabetes is one of age-associated diseases which at least double a person's risk of death. In 2015, diabetes is ranked at the 6th place among the “Top 10 causes of death worldwide” reported by World Health Organization. Diabetes causes serious metabolic complications in clinic and the trends of this disorder suggest that the rate would continue to rise in the future. In humans, CISD2 recessive mutations cause insulin-dependent diabetes in Wolfram syndrome 2 (WFS2) patients. In mice, our preliminary results revealed the followings: (1) Cisd2 pancreas-specific knockout (pKO) mice display glucose intolerance and develop spontaneous diabetes at mid-age of 12-15 months; (2) In the beta-cells of Cisd2 pKO mice at young age, Cisd2 deficiency results in ultrastructural abnormality including mitochondrial degeneration, rough ER dilation and mitochondria-associated ER membrane (MAM) degeneration, and swollen Golgi complex; (3) Increased ER stress is detected in the beta-islets of Cisd2 pKO mice; (4) The numbers of beta-granules are significantly decreased, and there is an impaired extracellular Ca2+ influx in the MIN6-Cisd2 KO beta-cells after glucose stimulation; (5) Cisd2 seems to directly bind to the large (catalytic) subunit of Calpain2 to regulate its activity. Accordingly, we hypothesize that Cisd2 is essential for maintaining the normal function of pancreatic beta-cells, and that Cisd2 deficiency will affect beta-cell function. These studies will provide rigorously validated evidence that Cisd2 as a potential drug target for insulin-dependent diabetes and age-associated beta-cell dysfunction during natural aging.
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