Preliminary data suggest the presence of the delta-to-beta cell endocrine axis within the islet in which intraislet somatostatin inhibits insulin secretion. The purpose of this competitive renewal project is to prove the following hypotheses: 1) intraislet somatostatin inhibits secretion via a delta-to-beta cell endocrine axis in the human, rat and mouse pancreas and that the effect is glucose-dependent, 2) the somatostatin receptor subtype responsible for the inhibition of insulin is species-specific, and 3) genetic ablation of the somatostatin receptor subtype 5 will alter insulin secretion and glucose homeostasis in the mouse. The effect of intraislet somatostatin will be determined by examining the insulin response to immunoneutralization of intraislet somatostatin with antibodies and FAb fragments of antibodies directed against somatostatin in isolated perfused human, rat and mouse pancreas models. Electron microscopy will help to determine the compartment of immunoneutralization. The somatostatin receptor subtype responsible for the inhibition of insulin will be determined by examining the response of insulin secretion to infusions of specific somatostatin receptor subtype agonists in these models. Immunohistochemistry will be performed using polyclonal antibodies directed against SSTR 1-5 to determine which receptor subtypes are present in the human, rat and mouse pancreas. It appears that the somatostatin receptor subtype 5 is responsible for inhibition of mouse insulin secretion, therefore two models will be developed using state-of-the-art transgenic techniques: the first is a total somatostatin receptor subtype 5 gene ablation model and the second is a beta cell-specific somatostatin receptor subtype 5 gene ablation model. In vivo and in vitro physiology studies will be performed in these mice to determine the effect of genetically altering the delta-to-beta cell endocrine axis on insulin secretion and glucose homeostasis. The pancreas of the gene-ablated mice will be studied using immunohistochemistry with antibodies directed against the somatostatin receptor subtypes to determine if the somatostatin receptor subtypes are altered in the islets of the gene ablated mice. These studies will help elucidate physiologic mechanisms regulating insulin secretion and will determine whether there are species differences in this regulation. Furthermore, it will be determined whether there are pathophysiologic consequences to genetically altering these mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK046441-10S1
Application #
6606408
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Laughlin, Maren R
Project Start
1993-05-01
Project End
2004-04-30
Budget Start
2001-05-01
Budget End
2004-04-30
Support Year
10
Fiscal Year
2002
Total Cost
$75,250
Indirect Cost
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Yu, Juehua; Liu, Shi-He; Sanchez, Robbi et al. (2016) PDX1 associated therapy in translational medicine. Ann Transl Med 4:214
Zhou, G; Yu, J; Wang, A et al. (2016) Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma. Curr Mol Med 16:83-90
Wu, James X; Liu, Shi-He; Nemunaitis, John J et al. (2015) Liposomal insulin promoter-thymidine kinase gene therapy followed by ganciclovir effectively ablates human pancreatic cancer in mice. Cancer Lett 359:206-10
Zhou, G; Wang, H; Liu, S-H et al. (2013) p38 MAP kinase interacts with and stabilizes pancreatic and duodenal homeobox-1. Curr Mol Med 13:377-86
Liu, Shi-He; Rao, Donald D; Nemunaitis, John et al. (2012) PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. PLoS One 7:e40452
Zhou, Guisheng; Liu, Shi-He; Shahi, Kelly M et al. (2012) Negative regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5. Mol Endocrinol 26:1225-34
Brunicardi, F Charles; Gibbs, Richard A; Wheeler, David A et al. (2011) Overview of the development of personalized genomic medicine and surgery. World J Surg 35:1693-9
Zhou, Guisheng; Gingras, Marie-Claude; Liu, Shi-He et al. (2011) The hypofunctional effect of P335L single nucleotide polymorphism on SSTR5 function. World J Surg 35:1715-24
Liu, Shi-He; Smyth-Templeton, Nancy; Davis, Alan R et al. (2011) Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice. Surgery 149:484-95
Nemunaitis, John; Rao, Donald D; Liu, Shi-He et al. (2011) Personalized cancer approach: using RNA interference technology. World J Surg 35:1700-14

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