# Glucose Transporter Regulation in Obesity and Diabetes

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $494,237

## Abstract

Abstract
The overall goal of this grant is to understand the molecular mechanisms for insulin resistance in Type 2
diabetes and, in particular, how changes in adipose biology contribute to diabetes risk, with the long-term goal
of finding new therapeutic targets for T2D. Since our discovery in 2005 that Retinol Binding Protein 4 (RBP4) is
elevated in serum and white adipose tissue in many insulin-resistant states in humans, RBP4 elevation causes
insulin resistance, and lowering serum RBP4 levels improves insulin sensitivity, many studies worldwide have
extended these observations to show that elevated RBP4 is a biomarker and a potential cause of insulin
resistance and metabolic syndrome. A breakthrough in the last grant cycle was our discovery that RBP4
causes insulin resistance by inducing a proinflammatory state in adipose tissue mediated by Toll Like Receptor
4. We also showed that overexpression of RBP4 selectively in adipose tissue has detrimental systemic
metabolic effects and causes hepatic steatosis. In the next grant cycle, we will investigate novel mechanisms
by which RBP4 induces adipose tissue inflammation and systemic insulin resistance including the role of
lipolysis. Using “omics” approaches in adipose tissue from the same adipose-Glut4 overexpressing and
knockout mice in which we found RBP4, we discovered a novel class of endogenous lipids with anti-diabetic
and anti-inflammatory effects - Branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). Since a subclass
of FAHFAs, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), are low in insulin-resistant people and in
RBP4-overexpressing mice and our new data show that PAHSAs can block the actions of RBP4 at the cellular
level and improve insulin sensitivity in RBP4-overexpressing mice, we will investigate a possible mechanistic
relationship between RBP4 and PAHSAs. We will also build on our studies to determine the molecular
mechanisms for increased RBP4 retention in serum in insulin-resistant states by investigating the role of post-
translational modifications of transthyretin, the serum binding partner for RBP4.
Significance: These studies will provide novel insights into the mechanisms by which adipose tissue regulates
systemic insulin sensitivity and glucose homeostasis. Discovering the interactions among these molecules will
lead to a more comprehensive understanding of the cellular and tissue networks by which Glut4
downregulation in adipocytes increases Type 2 diabetes risk. Since RBP4 is elevated in many insulin-resistant
people, understanding the mechanisms underlying RBP4-induced insulin resistance and retention of RBP4 in
serum may lead to new strategies to lower RBP4 levels to prevent and treat Type 2 diabetes.

## Key facts

- **NIH application ID:** 9957042
- **Project number:** 5R01DK043051-28
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** BARBARA B. KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,237
- **Award type:** 5
- **Project period:** 1992-02-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957042

## Citation

> US National Institutes of Health, RePORTER application 9957042, Glucose Transporter Regulation in Obesity and Diabetes (5R01DK043051-28). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9957042. Licensed CC0.

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