Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin

Abstract

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors (i) reduce cardiovascular and renal events in patients with and without type 2 diabetes (T2D). However, the underlying mechanisms are debated. Low-grade inflammation (LGI) is a key driver of vascular complications, suggested to be attenuated by SGLT-2i in animal models. Based on a specific working hypothesis, here we investigated the net effect of SGLT-2i on LGI in patients with T2D and the possible underlying mechanism. We enrolled patients with T2D treated either with a stable therapy with SGLT-2i or with other glucose-lowering drugs (GLD) (n = 43 per group after matching for a range of pro-inflammatory variables), and tested hs-CRP and interleukin (IL)-6 as primary variables of interest. Patients treated with SGLT-2i had lower circulating levels of IL-6, a prototypical marker of LGI, but also of uric acid and fasting insulin, compared with patients treated with other GLD. Then, to explore whether uric acid and insulin might mediate the effect of SGLT-2i on IL-6, we tested physiologically pertinent doses of these two molecules (i.e. 0.5 mM uric acid and 1 nM insulin) in two in vitro models of LGI, i.e. monocytes (THP-1) treated with LPS and endothelial cells (HUVEC) exposed to hyperglycaemia. Results from in vitro models supported a pro-inflammatory role for uric acid and its combination with insulin in monocytes and for uric acid alone in hyperglycaemia-stimulated endothelial cells. On the contrary, we observed no drug-intrinsic, anti-inflammatory effect for dapagliflozin, empagliflozin, and canagliflozin in the same models. Overall, these results suggest that SGLT-2i possess a tangible activity against LGI, an effect possibly mediated by their ability to lower uric acid and insulin concentrations and that juxtaposes other proposed mechanisms in explaining the observed benefit of this class on cardiovascular and renal endpoints.

New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure

“…However, recent studies report that in some specific circumstances, insulin can trigger the pro-inflammatory pattern of macrophages, thereby contributing to a climb in IL-β mediated by activated inflammasome and overproduction of ROS ( 121 , 122 ). Such a function of insulin has been validated in a clinical setting by other research conducted by La Grotta et al ( 123 ). Likewise, given the glucose-lowering function of SGLT2i, the insulin shows a decrease along with the dropped levels of blood glucose correspondingly, contributing to the avoidance of progressed inflammation and increased inflammasome.…”

Serum uric acid to creatinine ratio is associated with higher prevalence of NAFLD detected by FibroScan in the United States

“… 37 UA induced pro‐inflammatory endocrine imbalance in adipose tissue and acted as pro‐oxidant, leading to oxidant stress. 38 , 39 The intracellular and mitochondrial oxidative stress caused by UA induces disturbances in the Krebs cycle, leading to increased fat synthesis and impaired fatty acid oxidation. Moreover, oxidant stress may be a critical factor in the pathogenesis of NAFLD.…”

“…Exposure to UA resulted in mitochondrial dysfunction and lipogenesis increase in hepatocytes 37 . UA induced pro‐inflammatory endocrine imbalance in adipose tissue and acted as pro‐oxidant, leading to oxidant stress 38,39 . The intracellular and mitochondrial oxidative stress caused by UA induces disturbances in the Krebs cycle, leading to increased fat synthesis and impaired fatty acid oxidation.…”

A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

“…Purine is a heterocyclic bicyclic aromatic organic molecule, which includes DNA, RNA, nucleosides and nucleotides, AMP, ADP, ATP, GMP, GDP, GTP, and cyclic forms of cAMP and cGMP, and participates in various metabolic pathways and cell signal transduction ( La Grotta et al, 2022 ; Xiao et al, 2022 ). Uric acid is the product of purine metabolism.…”