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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CADO-B (09))
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Appel, Michael C
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Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
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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
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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

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