How might dapagliflozin ease diabetic stiff hearts?

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In 30 rabbits, dapagliflozin lessened diabetes-related diastolic dysfunction and fibrosis by downregulating SGK1 and ENaC, with matching H9C2 cell results.

Source

Dapagliflozin attenuates diabetes-induced diastolic dysfunction and cardiac fibrosis by regulating SGK1 signaling

Lee SG, Kim D, Lee JJ, et al. · BMC medicine · 2022

doi.org/10.1186/s12916-022-02485-z Read the full paper ↗45 citationscc by

Study at a glance

Design: Animal / in-vitro — Alloxan-diabetic rabbits randomized to dapagliflozin vs diabetes vs control, plus fibrotic H9C2 SGK1 mechanistic assays
N: N=30 · 30 male New Zealand white rabbits, n=10 per control/diabetes/diabetes+dapagliflozin group; plus H9C2 cells
Population: Male New Zealand white rabbits with alloxan-induced diabetes and fibrosis-induced H9C2 cardiomyoblasts
Outcome: LV diastolic function, myocardial fibrosis, SGK1/ENaC/NHE1 signaling, inflammation, and mitochondrial structure

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What they did

Randomized 30 male NZ white rabbits to control, diabetes (IV alloxan), or diabetes+dapagliflozin (n=10 each); assessed echo, histology, and molecules, and probed SGK1 with siRNA in fibrotic H9C2 cells.

What they found

Diabetes+dapagliflozin attenuated diastolic dysfunction vs diabetes alone. Fibrosis fell via SGK1 and ENaC inhibition in tissue and H9C2 cells. Dapagliflozin was anti-inflammatory and eased mitochondrial disruption; siSGK1 reduced ENaC and NHE1 similarly to the drug.

The limits

What it doesn't show

Alloxan-rabbit and H9C2 data do not prove SGK1 is the only human mechanism or replace large SGLT2i outcome trials.

Key terms

Dapagliflozin: SGLT2 inhibitor studied here for diabetic cardiac effects.
SGK1: Serum/glucocorticoid-regulated kinase 1 implicated in fibrosis signaling.
ENaC: Epithelial sodium channel downstream of SGK1 in this model.
Diastolic dysfunction: Impaired left-ventricular relaxation/filling.
H9C2: Rat cardiomyoblast line used for mechanistic fibrosis assays.

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Rabbits per group:

Common questions

Animal sample?

30 rabbits, 10 per control/diabetes/diabetes+dapagliflozin.

How was diabetes induced?

Intravenous alloxan.

Key signaling axis?

SGK1 and ENaC (and NHE1).

Functional benefit?

Attenuated LV diastolic dysfunction and cardiac fibrosis.