# Metabolic architecture of insulin action in Southwest American Indians

> **NIH NIH U01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $594,728

## Abstract

Project Summary
Southwest American Indians (SWAI) suffer from the highest lifetime risk of type 2 diabetes (T2D) and its
adverse health consequences of any ethnic group. Over the last two decades, our collaborators (led by Dr. C.
Bogardus; NIDDK-Phoenix) have pioneered longitudinal studies of SWAls in the Gila River Indian Community
in Phoenix, Arizona, to characterize clinical and genetic predictors of T2D in this at-risk population. Through
careful integrative metabolic studies (e.g. measurement of insulin action using hyperinsulinemic-euglycemic
clamp), they have defined insulin resistance (IR) and reduced acute insulin secretion (IS) as significant
predictors of T2D. Of note, while these physiologies are linked to T2D in other ethnicities, SWAls have a
greater degree of IR and IS at a similar level of obesity relative to other Americans, the mechanisms of which
are elusive. While studies have found small molecule metabolites proximal and specific to metabolic
dysfunction may presage T2D, these studies (1) do not identify precise biologic mechanisms of IR/IS due to
lack of mechanistic measures of IR/IS (e.g., via clamp); (2) are focused on Caucasians, whose clinical risk and
severity of T2D is lower relative to SWAls. Furthermore, pilot studies in Indians suggest that metabolites linked
to T2D may not be the same as those found in Caucasians. Here, we identify metabolic pathways linked to
T2D via their effect on IR/IS by measuring circulating metabolites in high-risk SWAls alongside exquisite
characterization of in vivo insulin physiology and molecular genetics. We collaborate with the NIDDK-Phoenix
Epidemiology/Clinical Research Branch to measure metabolites in SWAI adults to define the molecular
architecture of metabolism, focused on insulin physiology. Our central hypothesis is that circulating metabolites
will identify mechanisms of IR and IS in SWAls. We will study two different populations: (1) the Gila River
Indian Cohort Study, a prospective cohort study of >650 SWAls with baseline measures of body composition
and insulin physiology and longitudinal follow-up for T2D; (2) the Phoenix Cohort Study, a longitudinal study of
>650 SWAls with oral glucose tolerance testing (OGTT) and ongoing clinical surveillance. In Aim 1, we will use
measures of IR and IS based on the euglycemic-hyperinsulinemic- 3H-glucose clamp (HEC) and oral or IV
glucose tolerance testing in the Gila River Indian Study to identify metabolic pathways linked to IR/IS in SWAls
without T2D. In Aim 2, we will identify the genetic architecture of metabolism in SWAls via (1) association of
metabolite patterns with >500,000 directly genotyped SNP variants and >4.5m imputed variants to identify
quantitative trait loci for metabolism (mQTLs), with verification of derived genetic risk scores with T2D in a
separate, large population of SWAls (N=6936) to demonstrate a causal role ininstrumental variables analysis;
(2) studying relationship between IR and expression of genes implica...

## Key facts

- **NIH application ID:** 10544900
- **Project number:** 7U01DK123013-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Venkatesh Locharla Murthy
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $594,728
- **Award type:** 7
- **Project period:** 2020-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544900

## Citation

> US National Institutes of Health, RePORTER application 10544900, Metabolic architecture of insulin action in Southwest American Indians (7U01DK123013-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10544900. Licensed CC0.

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