The long-term objective of this grant has been to determine the role of glucose transport in adipose tissue and muscle in whole body glucose homeostasis and insulin sensitivity, with the goal of finding new therapeutic targets for type 2 diabetes. We demonstrated an important role for adipocytes in insulin sensitivity and the pathogenesis of type 2 diabetes. We showed that the down regulation of Glut4 in adipocytes that occurs in obesity and type 2 diabetes plays an important role in the insulin resistance in these states. We discovered that adipose expression and serum levels of retinol binding protein 4 (RBP4) are increased in insulin resistant states in humans and rodents In the next cycle, the overall goals will continue to be to determine 1) the physiologic, cellular and molecular mechanisms by which RBP4 causes insulin resistance and 2) whether increased retention of RBP4 is an important mechanism for its serum elevation in insulin resistant states, and the mechanisms underlying this.
Aim 1 is to determine the mechanisms for RBP4-induced insulin resistance. Using complementary in vivo and in vitro approaches, we will investigate the intracellular signaling pathways that appear to be involved and the """"""""inflammatory"""""""" effects.
Aim 2 is to determine whether the mechanism(s) by which elevation of RBP4 causes insulin resistance are retinoid-dependent or retinoid-independent.
Aim 3 is to determine the role of STRA6 in RBP4-induced metabolic effects.
Aim 4 is to determine whether increased retention of RBP4 is an important mechanism for RBP4 elevation in serum in insulin-resistant states and whether this results from post-translational modifications of transthyretin. Understanding the mechanisms by which elevated RBP4 contributes to insulin resistance, metabolic syndrome and risk of diabetes and cardiovascular disease could lead to new insights into the pathogenesis of these disorders. In addition, understanding the mechanisms by which RBP4 becomes elevated in these states could lead to new therapeutic approaches. These studies will elucidate novel mechanisms underlying the inter-tissue communication that plays an important role in the pathogenesis of type 2 diabetes.

Public Health Relevance

Fat cells are important regulators of metabolism and diabetes risk. Fat cells and liver secrete retinol binding protein 4 (RBP4) which carries vitamin A in the blood. RBP4 is elevated in serum of insulin resistant people with obesity and type 2 diabetes. This may contribute to the insulin resistance and risk for diabetes. We will investigate the mechanisms by which RBP4 regulates insulin/glucose balance and diabetes risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK043051-23
Application #
8724474
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Laughlin, Maren R
Project Start
1992-02-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
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