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NORCH Bulletin April 2019

Research Spotlight: SGLT2 Inhibition Reprograms Systemic Metabolism via FGF21-Dependent and – Independent Mechanisms 

Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of antidiabetic medications that inhibit renal glucose reabsorption, increasing glucosuria and lowering serum glucose. More recently, SGLT2 inhibitors have been shown to cause modest weight loss, improve cardiovascular risk, and reduce mortality – effects that are not adequately explained by increased glucosuria. Drs. Patti, Gerszten, and colleagues used an integrated transcriptomic-metabolomics approach to identify molecular mediators of the SGLT2 inhibitor canagliflozin in obese, non-diabetic mice. Results demonstrate that SGLT2 inhibitors modulate key nutrient-sensing pathways, activating 5’ AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR), and inducing transcriptional programming that activates catabolic pathways and increases hepatic and plasma levels of FGF21.

Osataphan S, Macchi C, Singhal G, Chimene-Weiss J, Sales V, Kozuka C, Dreyfuss JM, Pan H, Tangcharoenpaisan Y, Morningstar J, Gerszten R, Patti ME. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. 2019 Mar 7;4(5). pii: 123130. doi: 10.1172/jci.insight.123130. eCollection 2019 Mar 7. PMID: 30843877

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