ABSTRACT
Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.
ABSTRACT
BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level.
