Recent advances in understanding the mechanisms in skeletal muscle of interaction between exercise and frontline antihyperglycemic drugs

Abstract

Regular exercise and antihyperglycemic drugs are front-line treatments for type-2 diabetes and related metabolic disorders. Leading drugs are metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists. Each class has strong individual efficacy to treat hyperglycemia, yet the combination with exercise can yield varied results, some of which include blunting of expected metabolic benefits. Skeletal muscle insulin resistance contributes to the development of type-2 diabetes while improvements in skeletal muscle insulin signaling are among key adaptations to exercise training. The current review identifies recent advances into the mechanisms, with an emphasis on skeletal muscle, of the interaction between exercise and these common antihyperglycemic drugs. The review is written toward researchers and thus highlights specific gaps in knowledge and considerations for future study directions.

Keywords: aerobic; glucagon‐like peptide 1 receptor agonist; metformin; mitochondria; resistance; sodium‐glucose cotransporter‐2 inhibitor.

FIGURE 1

Metformin lowers glycemia through combined actions to lower hepatic glucose production (HGP) and possible complementary improvements to skeletal muscle insulin action. The combination of metformin with exercise can blunt several positive adaptations to aerobic and resistance training. Underlying mechanisms appear to be related to mitochondrial energetics. Image created with Biorender.com.

FIGURE 2

Future questions for metformin and exercise. Gaps include regulation of substrate metabolism across fiber types, separating resistance versus aerobic training adaptations, and cross‐talk with signals from other tissues. Image created with Biorender.com.

FIGURE 3

SGLT2i have primary actions to lower glucose resorption in kidneys that combine with off‐target actions on nonrenal tissues to lower plasma glucose. SGLT2i treatment during aerobic training can promote fat oxidation without limiting gains in performance. Resistance training may prevent loss of muscle mass with SGLT2i. Image created with Biorender.com.

FIGURE 4

Future questions for SGLT2i and exercise. Fundamental questions are rooted in how SGLT2i have off‐target effects in muscle and other tissues that do not express SGLT2 protein. Image created with Biorender.com.

FIGURE 5

GLP1 receptor agonists provide longer term GLP1 signaling and incretin effect, with downstream impact on lowering blood glucose and weight loss. The combination with exercise can further promote weight loss while maintaining muscle mass. Image created with Biorender.com.

FIGURE 6

Future questions for GLP1 receptor agonists and exercise. Gaps include separating direct drug actions on skeletal muscle, including regulation of mass and function, versus indirect effects through cardiovascular regulation or decreased fat mass. Image created with Biorender.com.