# Project 2 - Georgiades

> **NIH NIH P01** · DUKE UNIVERSITY · 2020 · $183,241

## Abstract

PROJECT 2 - Gene x stress interactions' impacts on pathways to type 2 diabetes
PROJECT SUMMARY
There is a strong association between obesity, in particular central obesity, and risk to develop type 2 diabetes
mellitus (T2DM). However, increased adiposity alone does not explain the prevalence of T2DM, suggesting
that additional factors contribute to the pathophysiology of T2DM. Studies conducted by our group during the
previous project period suggest that levels of post-prandial circulating epinephrine (EPI) predict fasting glucose
in the presence of central obesity. EPI binds to lipolytic β-receptors increasing lipolysis i.e. hydrolysis of
triglycerides into non-esterified fatty acids (NEFA). Our studies show that in the absence of high EPI levels,
centrally obese individuals have normal fasting glucose levels, whereas centrally obese individuals with high
EPI levels show impaired fasting glucose levels. We have also found that obese individuals who show an
acute increase in plasma EPI levels to a glucose challenge have higher fasting NEFA levels, as well as higher
endogenous glucose levels during the glucose challenge than obese individuals showing a decrease in EPI
levels to the glucose challenge. Our work has thus led us to propose that the interaction of sympathoadrenal
activity and central obesity plays an important role in the development of impaired glucose metabolism. Using
a candidate gene approach and multiple studies available within the present PPG, we have showed that SNPs
within the dopamine and beta-adrenergic receptor genes, as well as a SNP within the EBF1 gene are related
to different aspects of our model including central adiposity, epinephrine levels, insulin sensitivity and glucose
levels. The overall aim of this project is to test the effects of specific genotypes to parameters of the minimal
model of glucose kinetics and visceral adiposity as well as to test G x E interactions to assess the moderating
effect of chronic stress in order to further evaluate the mechanisms whereby sympathetic activity contributes to
the development of impaired glucose metabolism in obese individuals. In addition, we plan to assess the
interactive effect of EPI x visceral adiposity on minimal model outcomes and NEFA dynamics during the
IVGTT.

## Key facts

- **NIH application ID:** 9939632
- **Project number:** 5P01HL036587-29
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Anastasia Georgiades
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $183,241
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939632

## Citation

> US National Institutes of Health, RePORTER application 9939632, Project 2 - Georgiades (5P01HL036587-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939632. Licensed CC0.

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