# Use of SGLT2 inhibition to improve skeletal muscle metabolism in prediabetes

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 2022 · $297,000

## Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are used to treat hyperglycemia in type 2 diabetes (T2D)
due to their ability to increase urinary glucose excretion; however, new evidence suggests SGLT2 inhibition
also improves skeletal muscle insulin action as a mechanism to improve glycemia. Recent studies in humans
and rodent models report SGLT2 inhibitor treatment increases insulin-stimulated glucose disposal, even after
accounting for urinary glucose losses. Despite the clinical significance of these findings, mechanisms to
explain this effect remain unresolved. The current project will test the hypothesis that SGLT2 inhibitor
treatment stimulates changes in skeletal muscle fat metabolism that serve to improve skeletal muscle insulin
action. Our preliminary studies in model systems demonstrate SGLT2 inhibitor treatment alters mitochondrial
function, can induce energetic stress signaling (AMP-activated protein kinase), and even lower accumulation of
bioactive lipids known to negatively regulate insulin signaling. These findings support our hypothesis and
highlight the need to better understand the impact of SGLT2 inhibition on human skeletal muscle given its
critical role in regulating whole-body glucose metabolism. The current project will also test the hypothesis that
SGLT2 inhibition may provide therapeutic benefit (via improved skeletal muscle metabolism) before the onset
of T2D. Treating individuals with prediabetes with SGLT2 inhibitors is an especially attractive option given their
dysglycemia, high risk for advanced cardiometabolic disease and limited current treatment options (i.e.,
lifestyle modification and metformin). Taken together, the overall objectives of the current proposal are to
identify mechanisms of how SGLT2 inhibition improves skeletal muscle insulin action and test the ability of
SGLT2 inhibition to improve skeletal muscle metabolism among individuals with prediabetes. The current
project is a randomized, double-blind, 13-week intervention comparing SGLT2 inhibition with placebo among
overweight and obese adults with prediabetes. Participants will undergo robust metabolic phenotyping before
and in response to the intervention to achieve the following specific aims: Aim 1: Test the hypothesis that
SGLT2 inhibition improves skeletal muscle insulin action and insulin signaling in prediabetes; Aim 2: Determine
mechanisms responsible for increased skeletal muscle fat oxidation during SGLT2 inhibition; Aim 3: Determine
the extent to which SGLT2 inhibition lowers skeletal muscle diacylglycerol and ceramide content in
prediabetes. The proposed studies can be expected to generate new information regarding the mechanisms of
how SGLT2 inhibition can improve skeletal muscle metabolism and provide new understanding of the
therapeutic potential of using SGLT2 inhibitors as a treatment for prediabetes.

## Key facts

- **NIH application ID:** 10420977
- **Project number:** 1R01DK132128-01
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** Sean A. Newsom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $297,000
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420977

## Citation

> US National Institutes of Health, RePORTER application 10420977, Use of SGLT2 inhibition to improve skeletal muscle metabolism in prediabetes (1R01DK132128-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10420977. Licensed CC0.

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