Post-transplant diabetes mellitus and COVID-19-related dysglycemia increasingly overlap in clinical practice. Nonetheless, their shared mechanistic roots remain incompletely synthesized. We performed a focused mechanistic review of preclinical and clinical evidence linking calcineurin inhibitor (CNI) immunosuppression and SARS-CoV-2 infection to β-cell injury and systemic insulin resistance. Both CNIs (particularly tacrolimus) and SARS-CoV-2 converge on common diabetogenic processes. These processes include inhibition of calcineurin–NFAT/CREB signaling with reduced insulin gene transcription; mitochondrial bioenergetic failure and oxidative stress; loss of β-cell maturity with apoptosis or reversible dedifferentiation; and activation of stress-kinase and inflammatory pathways that promote peripheral insulin resistance. SARS-CoV-2 additionally exerts direct tropism for pancreatic β-cells and triggers integrated stress responses that can impair β-cell identity. Moreover, systemic inflammation and infection-related downregulation of CYP3A can also raise tacrolimus exposure, potentiating drug-mediated β-cell toxicity. These overlapping insults support a “two-hit” model in which background CNI-related vulnerability is amplified by viral, inflammatory, and pharmacokinetic perturbations. These factors together increase the risk of persistent dysglycemia. Translational priorities include prospective risk-stratification tools, pharmacologic studies of CNIs during infection, and randomized trials of β-cell-protective or anti-inflammatory strategies in transplant populations. Better integration of transplant, infectious disease, and endocrine care is essential to mitigate long-term metabolic complications in this group.
Afrooghe et al. (2026) studied this question.