# Impact of Modulated Exocyst Activity on Glut4 Trafficking in Metabolic Tissues

> **NIH NIH P20** · UNIVERSITY OF HAWAII AT MANOA · 2020 · $222,967

## Abstract

Abstract
Type-2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, relative insulin
deficiency and insulin resistance. Insulin resistant cells show defects in insulin-induced exocytosis of the
glucose transporter GLUT4, affecting glucose uptake. The exocyst, a highly conserved eight protein trafficking
complex was identified in cultured adipocytes as a key regulator of GLUT4 trafficking in response to insulin.
However, it is not known if the molecular mechanisms through which the exocyst orchestrates exocytosis of
this glucose transporter in adipocytes are conserved in other, insulin-responsive tissues, such as the skeletal
muscle. Skeletal muscle cells are responsible for the vast majority of insulin-induced glucose uptake, therefore
investigating glucose transporter trafficking in these cells will be key to better understanding the mechanism of
glucose homeostasis. Sec10 is a central subunit of the exocyst complex, and its overexpression can lead to
overall increased exocyst activity, while its knockdown leads to protein degradation of several of the other
subunits. We have recently generated a new transgenic mouse to analyze exocyst-regulated cellular trafficking
in vivo: the first mouse strain with a conditional Sec10 allele. This unique model enables us to investigate the
consequences of tissue-specific Sec10 inactivation by facilitating generation of adipose and muscle-specific
conditional Sec10 knockout animals. We hypothesize that in vivo modulation of the exocyst complex can
independently regulate GLUT4 exocytosis and glucose uptake in insulin-responsive cells and tissues, affecting
the diabetic phenotype. To test this hypothesis, we propose the following Specific Aims: (1) Determine if the
exocyst mediated regulatory mechanism of insulin-induced GLUT4 exocytosis is conserved in skeletal muscle
cells. (2) Test for defects in glucose homeostasis in vivo using adipocyte and skeletal muscle-specific Sec10
knockout mouse strains. (3) Determine T2DM-associated metabolic defects in mice can be ameliorated by
increasing GLUT4 exocytosis with a novel tissue-specific in vivo gene delivery system. The anticipated
outcome of this project is the first in vivo evidence of the exocyst's role in regulating insulin-induced glucose
uptake, and verification whether this regulatory mechanism is conserved in muscle tissues as well. These
studies will also show if the exocyst, and other molecules that directly control GLUT4 exocytosis, are potential
therapeutic targets for insulin resistance and diabetes.

## Key facts

- **NIH application ID:** 10013269
- **Project number:** 5P20GM113134-04
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Noemi Polgar
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,967
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013269

## Citation

> US National Institutes of Health, RePORTER application 10013269, Impact of Modulated Exocyst Activity on Glut4 Trafficking in Metabolic Tissues (5P20GM113134-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10013269. Licensed CC0.

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