# Metabolic heterogeneity underlying hypertriglyceridemia in insulin resistance

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $462,908

## Abstract

Project Summary/Abstract
Insulin resistance (IR) is central to the development of type 2 diabetes and dyslipidemia; however, there is no
single phenotype of the insulin resistant patient. This phenotypic heterogeneity is reflected in clinical practice as
variable manifestations of metabolic disease and variable response to both glucose lowering and triglyceride
lowering agents (such as fibrates and fish oil). A precision medicine approach, wherein an understanding of the
heterogeneity of disease is leveraged to target therapies to an individual patient’s pathology, requires an
understanding of this heterogeneity of disease. Notably, among equally obese patients, some are globally insulin
resistant, others insulin sensitive, and some demonstrate tissue specific IR. Thus, the mechanisms driving
increased triglyceride production an any particular patient may depend on the patient’s pattern of tissue specific
insulin resistance, with de novo lipogenesis predominating in the setting of skeletal muscle insulin resistance,
and esterification of preformed fatty acids predominating in the setting of adipose insulin resistance.
The overarching aim of this proposal is to build a mechanistic knowledge base to identify and optimize therapy
for discrete subgroups of IR. To achieve this goal, Dr. Vatner aims to: 1) elucidate the pathways that support
hepatic de novo lipogenesis (DNL) in rodent models of hepatic insulin resistance; 2) quantify the discrete
pathways by which adipose and muscle insulin resistance promote hepatic triglyceride production; and 3) assess
how differences in adipose and muscle insulin resistance in humans impact on the mechanisms underlying
hepatic triglyceride synthesis.
To achieve these goals, studies in both rodents and humans will be critical. Rodent models that exhibit different
tissue specific patterns of insulin resistance will be used, including high fat diet fed mice, insulin receptor T1160A
mutant mice, Tbc1d4p.Arg684Ter mutant mice, Mkr mice (mice with skeletal muscle specific resistance to insulin and
IGF1), and adipose Pde3b knockout mice. Human subjects with different patterns of tissue specific insulin
resistance will be studied. Stable isotope tracer techniques will be used to assess contributions of de novo
lipogenesis and esterification of preformed fatty acids to triglyceride synthesis. Standard and cutting-edge
molecular biology tools, including chromatin immunoprecipitation, quantitative PCR, RNA-Seq, and
immunoblotting, will be used to delineate the molecular pathways playing key roles in the regulation of hepatic
triglyceride production. The key subject of interest in this proposal is the clinical heterogeneity of
hypertriglyceridemia in the setting of insulin resistance; studies using pharmacologic interventions (SGLT2
inhibition, inhibition of adipose lipolysis) and exercise interventions will directly address this clinical
heterogeneity.

## Key facts

- **NIH application ID:** 10134334
- **Project number:** 5R01DK124272-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Daniel Vatner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $462,908
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134334

## Citation

> US National Institutes of Health, RePORTER application 10134334, Metabolic heterogeneity underlying hypertriglyceridemia in insulin resistance (5R01DK124272-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134334. Licensed CC0.

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