Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.

Background: Immune checkpoint inhibitors (ICIs) have improved survival outcomes in melanoma. Studies exploring the correlations between body mass index (BMI), type 2 diabetes (T2DM) and the outcomes of ICI treatment have yielded inconsistent results. In this study, we aim to investigate the effects of BMI and T2DM on survival outcomes of patients with melanoma receiving ICIs. Methods: A retrospective multicenter cohort of patients with melanoma treated with ICIs was analyzed. Overall survival was evaluated with Kaplan-Meier survival analysis, univariate Cox and multivariate Cox proportional hazards model. Propensity-score matching (1:1) analysis between overweight and non-overweight groups was done and survival analyses and Cox analyses were performed again. Subgroup analyses and secondary analyses stratifying patients with different weights and T2DM statuses were also performed. Results: A total of 2,078 patients were included, of whom 1,412 were overweight (BMI≥25 kg/m²) and 666 were non-overweight (BMI<25 kg/m²). Overweight patients had better overall survival compared with non-overweight (median 71.7 vs 36.7 months, p<0.001). Patients with T2DM had worse overall survival compared with patients without T2DM (median 28.5 vs 67.3 months, p<0.001). After propensity-score matching (666 overweight were matched to 666 non-overweight), overweight patients remained to have better overall survival compared with non-overweight (median 67.7 vs 36.7 months, p<0.001). Patients with T2DM had worse survival in univariate Cox (HR 1.71, (95% CI: 1.20 to 2.43)) and multivariate Cox (HR 1.58, (95% CI: 1.08 to 2.31)) analyses. Overweight patients without T2DM had the best survival outcomes compared with other weight and T2DM combinations. Conclusion: In patients with melanoma treated with ICIs, being overweight had better survival outcomes compared with non-overweight. Having T2DM was associated with worse survival compared with those without T2DM. Further studies are needed to investigate the underlying mechanisms of these associations.

PURPOSE: Methylthioadenosine phosphorylase ( MTAP ) loss is a common genomic event in cancer and is associated with an immunologically cold phenotype. Recent research has highlighted a synthetic lethality of MTAP loss when combined with PMRT5 or MAT2A inhibition. Although contemporary somatic genomic testing now routinely includes MTAP status, the clinicogenomic characteristics of MTAP loss in cholangiocarcinoma (CCA) remain largely undefined. In this study, we examine the genomic profiles, clinical features, and survival outcomes of MTAP loss CCA. METHODS: This is a single-center retrospective cohort study of patients with CCA from December 2017 to January 2024. Somatic genomics alterations were assessed using targeted next-generational sequencing with FoundationOne CDx. Patient demographics, tumor characteristics, treatment history, and overall survival (OS) were retrospectively collected. Genomics coalterations were assessed using the Fisher exact test. Multivariate Cox proportional hazards regression analysis was used to assess the relationship between MTAP status and OS. RESULTS: Among 94 CCA samples, 89 were successfully sequenced, uncovering 339 genomic alterations, with MTAP loss identified in 16% of cases. It commonly co-occurred with CDKN2A and B loss (93% and 86%, respectively) and was not associated with FGF2R rearrangement, IDH1 mutation, or human epidermal growth factor receptor 2 ( ERBB2 ) amplification. Tumor mutational burden were similar between MTAP status. MTAP loss was associated with lower OS (hazard ratio, 3.95 [95% CI, 1.43 to 10.9]; P = .008) after adjustment for key covariates including age, Eastern Cooperative Oncology Group performance status, nodal stage, metastatic spread, resectability, histologic, and line of therapy. CONCLUSION: MTAP loss is common CCA, co-occurred with CDKN2A and CDKN2B loss, and was associated with poor OS. Future effort to exploit this therapeutic vulnerability in MTAP -loss CCA is critical to improve the care of this population.