Our long-term objective is to understand the regulation of insulin secretion via coordination of ionic and hormonal pathways. To help understand the ionic path, we cloned and expressed the high-affinity sulfonylurea receptor, SUR1, the regulatory subunit of Beta-cell SUR1/klR6.2 KATP channels. Mutations in SUR1 and KIR6.2 cause a recessive form of persistent hyperinsulinemic hypoglycemia of infancy, HI, characterized by excess insulin secretion despite severe hypoglycemia. Paradoxically, Sun null (Sur 1 KO) mice are normoglycemic, although they share the electrophysiologic phenotype seen in HI Beta-cells Our recent work on SurIKO mice identify two 'compensatory' responses: 1) they retain a 'basal' glucose-dependent, Ca2+-dependent regulation of insulin release, albeit with altered release kinetics, and 2) unexpectedly Sur 1KO islets show no response to the incretins, GLP- 1 and GIP. This defect is secondary to an impaired response to elevated cAMP and serves to disrupt the enteroinsular axis, effectively removing a potent stimulus for insulin secretion in the Sur1 KO animals. We have shown that potentiation of glucose-induced insulin secretion by incretins occurs via a PKA independent pathway. Our results imply SUR1 interacts with non-PKA dependent pathway which we hypothesize involves the cAMP-GEF or Epac family of guanine-nucleotide exchange factors and that loss of this pathway disrupts cAMP sensing. We will test this hypothesis by directly measuring and characterizing SURI -Epac interactions. We will identify the affected cAMP effector pathway(s) by comparing activation of several kinase cascades and the Rab3A/Rim path, of known importance for exocytosis, in control vs Sur1KO islets. We will test the hypothesis that the dramatic difference in glucose homeostasis between HI neonates vs Sur1KO mice is the result of the latter completely lacking SURI by making transgenic mice expressing mutant SUR1 on the Sur1KO background. These studies will provide insight into sulfonylurea receptor function, understanding of how cAMP potentiates secretion, a deeper understanding of how insulin secretion is regulated and the importance of the enteroinsular axis in this regulation, and may suggest novel therapeutic strategies for HI and targets for the design of novel drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052771-08
Application #
6873647
Study Section
Endocrinology Study Section (END)
Program Officer
Blondel, Olivier
Project Start
1997-09-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
8
Fiscal Year
2005
Total Cost
$301,471
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Munoz, Alvaro; Hu, Min; Hussain, Khalid et al. (2005) Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement. Endocrinology 146:5514-21
Sieg, Andrea; Su, Jiping; Munoz, Alvaro et al. (2004) Epinephrine-induced hyperpolarization of islet cells without KATP channels. Am J Physiol Endocrinol Metab 286:E463-71

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