The long-term goals of this project are to understand the mechanisms, role and significance of electrical control of insulin secretion and development of diabetes. Much previous work has demonstrated the central role of the K-ATP channel in electrical activity of the pancreatic ?-cell and has revealed how defective K-ATP channel activity can have profound effects on insulin secretion and cause neonatal diabetes. This has led to transfer of these patients from insulin to sulfonylurea therapy, with marked improvements in lifestyle and disease outcome. Based on new preliminary data, we propose that failure of insulin secretion due to altered electrical activity may be more prominent than previously realized, and that multiple unrecognized molecular components are likely to be relevant to excitation-secretion control and the development of diabetes. To pursue these ideas, we will utilize unique animal models to assess quantitative relationships between islet K-ATP activity and insulin secretory control, and we will utilize innovative forward genetic approaches in model organisms to search for novel regulators of metabolism-excitation coupling. In the process, the proposed experiments will test mechanistic hypotheses regarding metabolism-excitation-secretion coupling in islets and in the etiology of different forms of diabetes and will provide mechanistic information that will impact treatment approaches.
Diabetes is a major world health problem, with severe complications. We have generated unique animal models of diabetes due to depressed islet electrical activity and the analysis of these animals led us to correctly predict that this is a maor cause of neonatal diabetes in humans, as well as a risk factor for type 2 diabetes. The project makes use of both animal models and human studies, to understand the role of altered electrical excitability in the diabetic disease process, and thereby help us to develop appropriate therapies to treat the disease.
| Emfinger, Christopher H; Yan, Zihan; Welscher, Alecia et al. (2018) Contribution of Systemic Inflammation to Permanence of KATP-induced Neonatal Diabetes in Mice. Am J Physiol Endocrinol Metab : |
| Zang, Liqing; Maddison, Lisette A; Chen, Wenbiao (2018) Zebrafish as a Model for Obesity and Diabetes. Front Cell Dev Biol 6:91 |
| Borschel, William F; Wang, Shizhen; Lee, Sunjoo et al. (2017) Control of Kir channel gating by cytoplasmic domain interface interactions. J Gen Physiol 149:561-576 |
| Remedi, Maria S; Thomas, Mareen; Nichols, Colin G et al. (2017) Sulfonylurea challenge test in subjects diagnosed with type 1 diabetes mellitus. Pediatr Diabetes 18:777-784 |
| Remedi, Maria S; Friedman, Jonathan B; Nichols, Colin G (2017) Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel. J Gen Physiol 149:75-84 |
| Emfinger, Christopher H; Welscher, Alecia; Yan, Zihan et al. (2017) Expression and function of ATP-dependent potassium channels in zebrafish islet ?-cells. R Soc Open Sci 4:160808 |
