Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

Lee YH, et al. J Korean Med Sci. 2017 Jan;32(1):60-69. https://doi.org/10.3346/jkms.2017.32.1.60

Senescent T cells have been implicated in chronic inflammatory and cardiovascular diseases. Here, we explored the relationship between senescent T cells and glycemic status in a cohort of 805 participants by investigating the frequency of CD57⁺ or CD28^null senescent T cells in peripheral blood. Normal glucose tolerance (NGT) participants with follow-up data (N = 149) were included to determine whether hyperglycemia (prediabetes or type 2 diabetes) developed during follow-up (mean 2.3 years). CD8⁺CD57⁺ and CD8⁺CD28^null T cell frequencies were significantly higher in prediabetes and type 2 diabetes compared with NGT. Increased CD57⁺ or CD28^null cells in the CD8⁺ T cell subset was independently associated with hyperglycemia. Furthermore, among participants with baseline NGT, the frequency of CD8⁺CD57⁺ T cells was an independent predictor of hyperglycemia development. Immunofluorescent analyses confirmed that CD8⁺CD57⁺ T cell infiltration was increased in visceral adipose tissue of patients with prediabetes or type 2 diabetes compared to those with NGT. Our data suggest that increased frequency of senescent CD8⁺ T cells in the peripheral blood is associated with development of hyperglycemia.

Recently, several renal tubular damage markers have gained considerable attention because of their clinical implications as sensitive and specific biomarkers for early stage diabetic kidney disease. However, little is known about the demographic and glucometabolic factors affecting levels of urinary N-acetyl-β-D-glucosaminidase (NAG), a marker of proximal tubular damage, in type 2 diabetes mellitus (T2DM).The aim of this study was to investigate the clinical relevance of urinary NAG with regard to demographic and glucometabolic parameters, as well as nephropathic parameters, by comparing the glomerulopathic marker of albuminuria.In this retrospective cross-sectional study, we enrolled a total of 592 patients with either prediabetes (N = 29) or T2DM (N = 563). Glucometabolic parameters (glucose, hemoglobin A1c, glycated albumin [GA], insulin, C-peptide, homeostasis model assessment [HOMA] of insulin resistance, HOMA-β, postprandial C-peptide-to-glucose ratio [PCGR], and urinary glucose-to-creatinine ratio) and nephropathic parameters (urinary NAG, albumin-to-creatinine ratio [ACR], and estimated glomerular filtration rate) were measured.The levels of urinary NAG showed moderate positive correlation with the levels of urinary ACR in T2DM (r = 0.46). In correlation analysis, urinary NAG was more strongly correlated with body mass index (BMI) (r = -0.22; P < 0.001 vs. r = -0.02; P = 0.74), plasma stimulated glucose (r = 0.25; P < 0.001 vs. r = 0.08; P = 0.10), GA (r = 0.20; P < 0.001 vs. r = 0.13; P = 0.01), PCGR (r = -0.17; P = 0.001 vs. r = -0.09; P = 0.11), and HOMA-β (r = -0.10; P = 0.05 vs. r = -0.02; P = 0.79) than urinary ACR. In multiple regression analysis, age, lower BMI, stimulated glucose, GA, and urinary ACR predicted increased urinary NAG.In conclusion, increase in urinary NAG may be related to glycemic parameters reflecting glucose fluctuation and decreased insulin secretory capacity in patients with T2DM. Further longitudinal, prospective studies are needed to investigate a causal relationship between glucose fluctuations, renal tubular damage, and other vascular complications of diabetes.