The overall goals of this project are to understand the role of electrical signaling in insulin secretion. We have demonstrated dramatic consequences of genetic modification of beta-cell KATP channel activity on insulin secretion and glucose tolerance: Animals with underactive KATP channels show a complex progression from hypersecretion to undersecretion and diabetes. In contrast overactive KATP channels cause undersecretion that can be severe enough to cause neonatal lethality. These animal models have both predicted and paralleled findings in humans: underactive KATP channels cause persistent hypoglycemic hyperinsulinemia, overactive KATP channels have now been shown to cause permanent neonatal diabetes. These models will allow us to examine mechanistically how imbalance in beta-cell electrical activity leads to secretory defects. This proposal will utilize a wide array of electrophysiological, transgenic, genomic and cellular biological approaches to address questions about the in vivo consequences of alterations of beta-cell electrical excitability for glucose tolerance and disease progression, both intrinsically and in response to dietary manipulations. The proposed experiments will test mechanistic hypotheses of the involvement of ion channels in stimulus-secretion coupling in beta-cells and in the etiology of hyperinsulinemia and diabetes. The results of this project will provide mechanistic information that may impact the development of new treatment approaches to both diabetes and hyperinsulinemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069445-05
Application #
7653785
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$310,731
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Zhiyu; York, Nathaniel W; Nichols, Colin G et al. (2014) Pancreatic ? cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab 19:872-82
Tatulian, Suren A (2014) Molecular-scale GPS: positioning a biosensor peptide on RyR. Biophys J 107:2003-5
Silva, Jonathan R; Cooper, Paige; Nichols, Colin G (2014) Modeling K,ATP--dependent excitability in pancreatic islets. Biophys J 107:2016-26
Lin, Yu-Wen; Li, Anlong; Grasso, Valeria et al. (2013) Functional characterization of a novel KCNJ11 in frame mutation-deletion associated with infancy-onset diabetes and a mild form of intermediate DEND: a battle between K(ATP) gain of channel activity and loss of channel expression. PLoS One 8:e63758
Nichols, C G; Remedi, M S (2012) The diabetic ?-cell: hyperstimulated vs. hyperexcited. Diabetes Obes Metab 14 Suppl 3:129-35
Battaglia, Domenica; Lin, Yu-Wen; Brogna, Claudia et al. (2012) Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation. Pediatr Diabetes 13:656-60
Finol-Urdaneta, Rocio K; Remedi, Maria S; Raasch, Walter et al. (2012) Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion. EMBO Mol Med 4:424-34
Lin, Yu-Wen; Akrouh, Alejandro; Hsu, YeouChing et al. (2012) Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits. Channels (Austin) 6:133-8
Loechner, Karen J; Akrouh, Alejandro; Kurata, Harley T et al. (2011) Congenital hyperinsulinism and glucose hypersensitivity in homozygous and heterozygous carriers of Kir6.2 (KCNJ11) mutation V290M mutation: K(ATP) channel inactivation mechanism and clinical management. Diabetes 60:209-17
Remedi, Maria Sara; Agapova, Sophia E; Vyas, Arpita K et al. (2011) Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes. Diabetes 60:2515-22

Showing the most recent 10 out of 30 publications