metformin + sitagliptin (Januvia ER / Janumet ER / Janumet XR)

p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans.

Al Hatem Ali A, Balasubramaniam Boopathi B, Villhauer Alissa A, Naji Ali K AK et al.

Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H2O2), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H2O2 production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H2O2. This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections.

Methodological Considerations in Assessing Metformin-Associated Vitamin B12 Deficiency.

Halog Evangeline A EA, Mangaoang Ray L RL, Aban Jomar L JL

Preclinical and limited clinical evidence for metformin in ulcerative colitis: a systematic review and meta-analysis.

Chong Jinchen J, Ding Haoyu H, Ma Jiaze J, Gong Chenkai C et al.

This study systematically evaluated the preclinical efficacy and limited clinical evidence of metformin as a potential repurposed therapy for ulcerative colitis (UC) and explored candidate mechanisms using multi-omics and in silico analyses. Controlled animal studies were quantitatively synthesized using random-effects meta-analysis. Human randomized controlled trials (RCTs) were summarized narratively because of the limited number of trials and heterogeneity in clinical endpoints. Exploratory 3D response surface modeling, network pharmacology, molecular docking, molecular dynamics (MD) simulations, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) were integrated to prioritize potential dose-duration patterns and candidate mechanistic pathways. Eight preclinical animal studies and three human RCTs involving 232 patients were included. In animal models, metformin was associated with improvements in core colitis-related outcomes, including disease activity index, colon length, body weight change, and histopathological score. However, the magnitude of the pooled standardized mean differences should be interpreted cautiously because of small sample sizes, methodological heterogeneity, and potential small-study effects. Exploratory response surface modeling suggested a potential association between low-dose, long-duration regimens and larger preclinical effect estimates, but this pattern should not be interpreted as a validated dosing recommendation. Multi-omics and in silico analyses prioritized Xanthine dehydrogenase (XDH)-associated epithelial inflammatory programs and predicted epithelial-immune-vascular communication as plausible mechanistic hypotheses. The available RCTs provided limited supportive clinical signals but did not establish mechanistic causality. Metformin may ameliorate experimental colitis and shows preliminary supportive clinical signals as an adjunctive therapy in UC. The proposed XDH-associated epithelial inflammatory program remains exploratory and requires direct biochemical, functional, and large-scale clinical validation.

Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.

Breeyear Joseph H JH, House John S JS, Kvale Mark M, Nam Stella S et al.

Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10-8) and suggestive (P < 5.0 × 10-6) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.