Knowledge of the mechanisms that modulate glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells, particularly in the face of insulin resistance, is of paramount importance for understanding the pathogenesis of type 2 diabetes mellitus. Over the previous project period, it has become clear that even small changes in glucokinase (GK) activity in the pancreatic beta cell affect GSIS, that insulin action in the beta cell modulates GSIS, and that insulin affects GK gene expression, both at the transcriptional and post-translational levels. This proposal will explore several aspects of GK regulation and function. We will continue to place an emphasis both on the pancreatic beta cell, since it plays a principal role in most glycemic disorders and serves as a model for other glucose-sensitive cells, and on the generation of novel new mouse models. However, some studies will involve other sites of GK expression, such as the brain, in order to learn more about how the expression of GK in certain neurons contributes to the regulatory feedback loops that control the blood glucose concentration.
In Aim 1 we will determine whether GK is necessary for neural glucose sensing by generating and characterizing brain-specific GK gene knockout mice.
In Aim 2 we will establish true mouse models for PHHI and MODY-2 in order to correlate changes in enzyme kinetics with insuIin secretion and glucose homeostasis.
In Aim 3 we will determine the role of alternate RNA processing the insulin receptor in modulating both GK gene transcription and subcellular localization in the pancreatic beta cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042612-14
Application #
6640219
Study Section
Special Emphasis Panel (ZRG1-PC (01))
Program Officer
Laughlin, Maren R
Project Start
1990-06-01
Project End
2006-05-31
Budget Start
2003-07-01
Budget End
2004-05-31
Support Year
14
Fiscal Year
2003
Total Cost
$302,002
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Dodell, G B; Kotler, D P; Engelson, E S et al. (2009) Intermuscular and subcutaneous adipose tissue distributions differ in HIV+ versus HIV-men and women. Int J Body Compos Res 7:73-78
Gannon, Maureen; Ables, Elizabeth Tweedie; Crawford, Laura et al. (2008) pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis. Dev Biol 314:406-17
Albu, Jeanine B; Kenya, Sonjia; He, Qing et al. (2007) Independent associations of insulin resistance with high whole-body intermuscular and low leg subcutaneous adipose tissue distribution in obese HIV-infected women. Am J Clin Nutr 86:100-6
Engelson, Ellen S; Agin, Denise; Kenya, Sonjia et al. (2006) Body composition and metabolic effects of a diet and exercise weight loss regimen on obese, HIV-infected women. Metabolism 55:1327-36
Jones, Julie R; Barrick, Cordelia; Kim, Kyoung-Ah et al. (2005) Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A 102:6207-12
Moates, J M; Magnuson, M A (2004) The Pal elements in the upstream glucokinase promoter exhibit dyad symmetry and display cell-specific enhancer activity when multimerised. Diabetologia 47:1632-40
Shiota, Chiyo; Larsson, Olof; Shelton, Kathy D et al. (2002) Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem 277:37176-83
Rizzo, Mark A; Magnuson, Mark A; Drain, Peter F et al. (2002) A functional link between glucokinase binding to insulin granules and conformational alterations in response to glucose and insulin. J Biol Chem 277:34168-75
Postic, C; Shiota, M; Magnuson, M A (2001) Cell-specific roles of glucokinase in glucose homeostasis. Recent Prog Horm Res 56:195-217
Jetton, T L; Shiota, M; Knobel, S M et al. (2001) Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition. Int J Exp Diabetes Res 2:173-86

Showing the most recent 10 out of 41 publications