Diabetes promotes the development of both
heart failure with a reduced ejection fraction and
heart failure with a preserved ejection fraction through diverse mechanisms, which are likely mediated through
hyperinsulinemia rather than
hyperglycemia. Diabetes promotes nutrient surplus signaling (through Akt and
mammalian target of rapamycin complex 1) and inhibits nutrient deprivation signaling (through
sirtuin-1 and its downstream effectors); this suppresses autophagy and promotes endoplasmic reticulum and oxidative stress and
mitochondrial dysfunction, thereby undermining the health of diabetic cardiomyocytes. The
hyperinsulinemia of diabetes may also activate
sodium-hydrogen exchangers in cardiomyocytes (leading to injury and loss) and in the proximal renal tubules (leading to
sodium retention). Diabetes may cause epicardial adipose tissue expansion, and the resulting secretion of proinflammatory
adipocytokines onto the adjoining myocardium can lead to coronary microcirculatory dysfunction and myocardial
inflammation and
fibrosis. Interestingly,
sodium-glucose cotransporter 2 (
SGLT2) inhibitors-the only class of
antidiabetic medication that reduces serious
heart failure events-may act to mitigate each of these mechanisms.
SGLT2 inhibitors up-regulate sirtuin-1 and its downstream effectors and autophagic flux, thus explaining the actions of these drugs to reduce oxidative stress, normalize mitochondrial structure and function, and mute proinflammatory pathways in the stressed myocardium. Inhibition of SGLT2 may also lead to a reduction in the activity of
sodium-hydrogen exchangers in the kidney (leading to diuresis) and in the heart (attenuating the development of
cardiac hypertrophy and systolic dysfunction). Finally,
SGLT2 inhibitors reduce the mass and mute the adverse biology of epicardial adipose tissue (and reduce the secretion of
leptin), thus explaining the capacity of these drugs to mitigate myocardial
inflammation, microcirculatory dysfunction, and
fibrosis, and improve ventricular filling dynamics. The pathophysiological mechanisms by which
SGLT2 inhibitors may benefit
heart failure likely differ depending on ejection fraction, but each represents interference with distinct pathways by which
hyperinsulinemia may adversely affect cardiac structure and function.