Abstract

The applicant states that the expression of GLUT4, the insulin responsive glucose transporter, found specifically in the heart, skeletal muscle, and adipose tissue, has been shown to be down regulated in metabolically altered states such as diabetes and obesity. According to the applicant, GLUT4 null mice (genetically altered mice which do not make GLUT4) exhibit modified glucose and fat metabolism, and exhibit significant cardiac hypertrophy independent of increased arterial blood pressure. The precise mechanisms controlling the development of this hypertrophy are not well understood. The GLUT4 null mice and GLUT4 null mice complemented with a transgene specifically engineered to express GLUT4 in the heart only (HO mice) will be used in in vivo and in vitro experiments to study the consequences of altered substrate availability on cardiac structure and function. Experiments employing these mouse models will answer the following questions: 1. What changes occur in structure and function in the heart of GLUT4 null mice as hypertrophy develops, and does putting GLUT4 back into the heart of the HO mouse to make glucose uptake more normal affect the development of this hypertrophy? In vitro 31P nuclear magnetic resonance (NMR) spectroscopy and in vivo 1H magnetic resonance imaging (MRI) will be used at various time points to evaluate bioenergetic status, myocardial morphology (mass, dimensions) and function (ejection fraction). 2. What is the substrate utilization profile in the GLUT4 null and HO hearts as compared to control mice, and do alterations in these profiles affect function? Isolated perfused hearts of GLUT4 null and HO mice will be used to determine changes in substrate utilization and function at different time points in the development of hypertrophy. 3. How does the hypertrophic heart of the GLUT4 null mouse and the complemented heart of the HO mouse respond to metabolic and hemodynamic stress? Several methods will be used to assess what effect the lack of GLUT4 and its consequent effect on cardiac glucose uptake has on the ability of the GLUT4 null and HO heart to withstand stress conditions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL058119-01
Application #
2031331
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1997-04-01
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Charron, Maureen J; Vuguin, Patricia M (2015) Lack of glucagon receptor signaling and its implications beyond glucose homeostasis. J Endocrinol 224:R123-30
Vuguin, Patricia M; Hartil, Kirsten; Kruse, Michael et al. (2013) Shared effects of genetic and intrauterine and perinatal environment on the development of metabolic syndrome. PLoS One 8:e63021
Ouhilal, Sophia; Vuguin, Patricia; Cui, Lingguang et al. (2012) Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance. Am J Physiol Endocrinol Metab 302:E522-31
Vuguin, P M; Charron, M J (2011) Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models. Diabetes Obes Metab 13 Suppl 1:144-50
Hartil, Kirsten; Vuguin, Patricia M; Kruse, Michael et al. (2009) Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero. Pediatr Res 66:368-73
Gelling, Richard W; Vuguin, Patricia M; Du, Xiu Quan et al. (2009) Pancreatic beta-cell overexpression of the glucagon receptor gene results in enhanced beta-cell function and mass. Am J Physiol Endocrinol Metab 297:E695-707
Kedees, Mamdouh H; Guz, Yelena; Vuguin, Patricia M et al. (2007) Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling. Dev Dyn 236:1126-33
Ranalletta, Mollie; Du, Xiu Quan; Seki, Yoshinori et al. (2007) Hepatic response to restoration of GLUT4 in skeletal muscle of GLUT4 null mice. Am J Physiol Endocrinol Metab 293:E1178-87
Goldman, Noah A; Katz, Ellen B; Glenn, Alan S et al. (2006) GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma. Mod Pathol 19:1429-36
Vuguin, Patricia M; Kedees, Mamdouh H; Cui, Lingguang et al. (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147:3995-4006

Showing the most recent 10 out of 35 publications