The Effect of SGLT2 Inhibition on Immunometabolism

Obesity and diabetes significantly increase the risk of cardiovascular events, yet modest weight loss or strict glucose control with older diabetes therapies fail to reduce this risk. Inflammation resulting from obesity and hyperglycemia plays a pivotal role in these adverse outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2is), a newer class of diabetes drugs, have modest effects on glucose and weight but have been shown to significantly reduce cardiovascular events, heart failure, and liver and kidney disease through unclear mechanisms. SGLT2is are anti-inflammatory in animal models and human cells in vitro, but whether their cardiometabolic benefits in humans are mediated by anti-inflammatory effects is unknown. In addition, the mechanisms by which SGLT2is modulate inflammation remain poorly understood. In this pilot, we will test the central hypothesis that SGLT2is modulate inflammation by (Aim 1) generating ketones; and (Aim 2) inhibiting sodium/hydrogen exchanger-1 (NHE-1) to reduce intracellular calcium. To test this hypothesis, we will use monocyte-derived macrophages (MDMs) generated from human peripheral blood mononuclear cells, as macrophages are tissue-resident immune cells central to obesity- and hyperglycemia-associated inflammation. First, SGLT2is induce a mild systemic ketosis by increasing hepatic ketogenesis, and ketones are known to exert anti-inflammatory effects. In Aim 1, we will culture MDMs with SGLT2is and manipulate the production, availability, transport, and receptor binding of ketones to determine whether ketone-mediated modulation of macrophage activation underlies SGLT2is’ anti-inflammatory effects. Second, SGLT2is have an off-target effect of inhibiting NHE-1 and reducing intracellular calcium, which is a critical regulator of immune activation. In Aim 2, we will culture MDMs with SGLT2is and manipulate NHE-1 using specific inhibitors and siRNA while measuring intracellular calcium, downstream signaling pathways, and macrophage activation. This will test whether NHE-1 blockade and reduced intracellular calcium mediate the anti-inflammatory effects of SGLT2is. In summary, while SGLT2is have transformed clinical care, the precise mechanisms underlying their cardiometabolic benefits and anti-inflammatory effects are unknown. This pilot will provide critical insights into these mechanisms, which can guide future drug discovery efforts. The data generated from this pilot will form the foundation for my first R01 submission within 1-2 years as I continue to expand my expertise in the field of immunometabolism.