Animals with reduced KATP channel activity (KATP loss-of-function, LOF) are hyperexcitable and initially hypersecrete insulin, but secondarily progress, either spontaneously or in response to dietary stress, to undersecretion and glucose- intolerance. In contrast, animals with overactive KATP channels (KATP gain-of-function, GOF) are underexcitable and initially undersecrete insulin, and then secondarily progress to profound loss of pancreatic insulin content, resulting in diabetes that can be severe enough to cause neonatal lethality. Based on our initial studies we predicted that KATP GOF mutations could underlie human neonatal diabetes (NDM) and this has been dramatically confirmed over the last five years: not only have KATP GOF mutations been shown to be the major cause of human NDM, but many patients have since successfully switched from injected insulin treatments to oral sulfonylureas, which act to block the KATP channel, thereby treating the molecular defect directly. Our second generation KATP GOF transgenic mice provide temporal and tissue-specific control of transgene expression and thereby provide a tractable experimental model of NDM (xNDM). In explaining and informing the response to ?-cell underexcitability, our preliminary findings with these mice have potentially broad implications for fundamental mechanisms in both human NDM and type 2 diabetes. To pursue the implications, we will utilise our inducible transgenic KATP GOF animals to determine the response to ?-cell underexcitability at the cellular and islet level using a combination of imaging and electrophysiological techniques. We will determine the treatability of experimental NDM at different stages, informing otherwise unaddressable issues in human NDM. We will determine the potential involvement of environmental and genetic modulators in the ?-cell response to inexcitability at the whole animal level, and the role of electrical activity in modulating islet sensitivity to glucotoxicity in isolated islets from hyperexcitable (Kir6.2-/-, SUR1-/-) and underexcitable (tamoxifen-induced Pdx-DTG) animals. The proposed experiments will test mechanistic hypotheses of the role of electrical excitability in stimulus-secretion coupling in ?-cells and in the etiology of different forms of diabetes and will provide mechanistic information that will impact treatment approaches to both neonatal and type 2 diabetes.

Public Health Relevance

Diabetes is a major world health problem, characterized by a hyperglycemic state caused by depressed secretion of insulin, unresponsivity to circulating insulin, or a combination of both. We have generated unique mouse models of diabetes due to depressed secretion and the analysis of these animals led us to correctly predict that this is a major cause of neonatal diabetes in humans, as well as a risk factor for type 2 diabetes. The project makes use of these animals to understand the disease process in a way that is impossible in humans, and thereby helps us to develop appropriate therapies to treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069445-09
Application #
8485589
Study Section
Special Emphasis Panel (ZRG1-CADO-B (09))
Program Officer
Appel, Michael C
Project Start
2005-09-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$294,056
Indirect Cost
$100,598
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
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
Finol-Urdaneta, Rocio K; Remedi, Maria S; Raasch, Walter et al. (2012) Block of K(v) 1.7 potassium currents increases glucose-stimulated insulin secretion. EMBO Mol Med 4:424-34
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
Benninger, R K P; Remedi, M S; Head, W S et al. (2011) Defects in beta cell Caýý+ signalling, glucose metabolism and insulin secretion in a murine model of K(ATP) channel-induced neonatal diabetes mellitus. Diabetologia 54:1087-97
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 S; Koster, Joseph C (2010) K(ATP) channelopathies in the pancreas. Pflugers Arch 460:307-20
Wambach, Jennifer A; Marshall, Bess A; Koster, Joseph C et al. (2010) Successful sulfonylurea treatment of an insulin-naive neonate with diabetes mellitus due to a KCNJ11 mutation. Pediatr Diabetes 11:286-8
Remedi, Maria Sara; Nichols, Colin G (2009) Hyperinsulinism and diabetes: genetic dissection of beta cell metabolism-excitation coupling in mice. Cell Metab 10:442-53
Villareal, Dennis T; Koster, Joseph C; Robertson, Heather et al. (2009) Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance. Diabetes 58:1869-78

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