# Skeletal muscle diacylglycerol and sphingolipids: Impact of localization and species on insulin resistance in humans

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $610,269

## Abstract

Abstract
Accumulation of bioactive lipids such as diacylglycerol (DAG) and sphingolipids are one mechanism proposed
to promote muscle insulin resistance. Recent data indicate these lipids are located in membranes, but the
distribution and signaling of DAG and sphingolipids in specific cellular organelles which regulate insulin
sensitivity is not known. There is a critical need to address these gaps in knowledge to design appropriate
interventions to prevent and treat lipid-induced insulin resistance. The overall objective of this project is to
determine the impact of changes in subcellular DAG and sphingolipid species, signaling, and metabolic
function before and after insulin sensitizing lifestyle interventions. Our central hypothesis is that DAG and
sphingolipids in muscle promote insulin resistance via mechanisms that are unique to location, type of lipid,
and species. The rationale for the proposed research is that elucidating changes in localized DAG and
sphingolipid species that predict insulin sensitivity will reveal specific localized lipids to target in therapeutics
for type 2 diabetes. To attain our overall objective, we propose three specific aims: 1. Identify the influence of
sarcolemmal DAG and sphingolipids on cell signaling and insulin sensitivity before and after insulin sensitizing
lifestyle interventions. Strong preliminary data shape our hypothesis that sarcolemmal 1,2-disaturated DAG
and C18:0 ceramide species will decrease after insulin sensitizing lifestyle interventions, leading to less PKC
and PP2A activation, and enhanced insulin signaling. Skeletal muscle DAG and sphingolipid isomers, species,
localization, and de novo synthesis will be measured before and after diet-induced weight loss or exercise
training interventions in obese men and women. Insulin sensitivity will be measured using insulin clamps, and
muscle lipids using LC/MS. 2. Determine the impact of mitochondrial/ER DAG and sphingolipids on
mitochondrial function and ER stress in vivo, before and after insulin sensitizing lifestyle interventions. We
hypothesize, again based on preliminary data, that mitochondrial/ER sphingolipids will decrease, yet DAG will
increase after insulin sensitizing lifestyle interventions, and each will associate with increased insulin
sensitivity. Changes in sphingolipids will relate to increased mitochondrial function, less ER stress, ROS, and
acyl-carnitine formation, while changes in DAG will relate to increased mitochondrial content and dynamics. 3.
Identify the effect of exogenous DAG and sphingolipids on mitochondrial function in vitro, before and after
insulin sensitizing lifestyle interventions. Our working hypothesis is that DAG and sphingolipids will reduce
mitochondrial respiration and increase ROS and acyl-carnitine content, but will be attenuated after endurance
exercise training. The proposed research is innovative because it represents a substantive departure from the
status quo by addressing cellular compartmentalizat...

## Key facts

- **NIH application ID:** 9850244
- **Project number:** 5R01DK111559-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** BRYAN C BERGMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,269
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850244

## Citation

> US National Institutes of Health, RePORTER application 9850244, Skeletal muscle diacylglycerol and sphingolipids: Impact of localization and species on insulin resistance in humans (5R01DK111559-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850244. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*