Post-transplant diabetes mellitus after kidney transplantation: pathogenesis, risk factors, and management strategies.

Post-transplant diabetes mellitus (PTDM) affects 7-39% of kidney transplant recipients and substantially worsens cardiovascular, infectious, and allograft outcomes. Although PTDM shares core pathophysiological features with type 2 diabetes-peripheral insulin resistance and impaired β-cell secretion-its etiology is fundamentally shaped by immunosuppressive therapy. Calcineurin inhibitors suppress insulin gene transcription via NFAT inhibition and exacerbate lipotoxicity; corticosteroids drive hepatic gluconeogenesis and impair GLUT4-mediated glucose uptake; and mTOR inhibitors reduce β-cell mass through mTORC1-dependent mechanisms. Chronic NF-κB/JNK-driven inflammation further amplifies insulin resistance and promotes β-cell apoptosis. Beyond these established mechanisms, we propose a unifying "gut-immune-metabolic axis" in which immunosuppression-induced gut microbiota dysbiosis-characterized by depletion of short-chain fatty acid-producing taxa (Roseburia, Faecalibacterium prausnitzii) and Akkermansia muciniphila-drives intestinal barrier dysfunction, endotoxemia, impaired FXR/TGR5-mediated GLP-1 secretion, and TMAO-associated metabolic inflammation, collectively perpetuating glucose dysregulation. Risk stratification integrates non-modifiable factors (advanced age, African American/Hispanic/South Asian ethnicity, TCF7L2 polymorphisms, autosomal dominant polycystic kidney disease) with modifiable determinants (pre-transplant dysglycemia, obesity, hypomagnesemia, hepatitis C and cytomegalovirus infections, acute rejection, and diuretic use). Diagnosis requires OGTT-centered assessment per the 2024 International Consensus guidelines, with cautious interpretation of HbA1c during the early post-transplant period. Management encompasses personalized immunosuppression (corticosteroid minimization, tacrolimus trough levels <10 ng/mL, and belatacept-based regimens in high-risk patients), structured lifestyle interventions, and emerging pharmacotherapies-particularly SGLT2 inhibitors and GLP-1 receptor agonists-which offer cardiometabolic benefits beyond glycemic control. Microbiome-targeted strategies, including prebiotics, probiotics, and fecal microbiota transplantation, represent a conceptually compelling frontier warranting prospective investigation. This framework reframes PTDM as a multi-hit, immunometabolic syndrome and provides a translational roadmap toward precision prevention and improved long-term transplant outcomes.