Effect of immunosuppressive drugs on glucose-stimulated insulin secretion: concentration-response studies in dynamic perifusion assays
- 1Diabetes Research Institute, Miller School of Medicine, University of Miami
- 2Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami
Abstract
Immunosuppressive drugs, which are required to maintain graft function in transplant recipients, are associated with many unavoidable side effects including posttransplant diabetes mellitus (PTDM) that involves both peripheral insulin resistance and impairment of insulin secretion. To characterize in detail the concentration-dependency of the effect of well-known immunosuppressive drugs on glucose-stimulated insulin secretion (GSIS), we performed dynamic perifusion studies with human pancreatic islets. The effect on the time-profile of GSIS has been assessed over a wide concentration range for several clinically relevant immunomodulatory therapies, including small-molecule drugs (cyclosporine, sirolimus, tacrolimus, prednisolone acetate, and loteprednol etabonate) and biologics (abatacept and anti-CD40L), plus a prospective β-cell proliferation-inducing agent (harmine). While biologics showed no significant detrimental effects after one-day treatment even at relatively high concentrations (5 µM), all small-molecule drugs inhibited insulin secretion in a concentration-dependent manner, although glucocorticoids showed a distinct response pattern. Calcineurin and mTOR inhibitors preserved GSIS within their therapeutic ranges but progressively distorted its time-profile at higher concentrations and completely suppressed secretion at the highest levels, where they were also cytotoxic. Cyclosporine exhibited the least, only about 35-fold, separation between its therapeutic target ( C targ ) and half-maximal GSIS inhibitory (IC ₅₀ ) concentrations. Glucocorticoids did not alter the shape of the time-profile but inhibited overall insulin secretion even at therapeutic levels without affecting islet viability. Their inhibitory effect only increased slowly with concentration and did not follow a classic sigmoid pattern that has unity Hill slope. These findings establish quantitative benchmarks for immunosuppressant-induced β-cell toxicity and provide a framework for optimizing immunosuppressive regimens to reduce the risk of PTDM.
Related
- Lidocaine modulates interleukin-1β and interferon-α2 secretion in LPS with ATP stimulated human peripheral blood mononuclear cells
- The effect of exercise on plasma soluble IL-6 receptor concentration: a dichotomous response.
- Dose–response association and predictive value of plasma aldosterone concentration for cardiometabolic multimorbidity in patients with hypertension: a retrospective cohort study
- OA17 Improvement in Sjögren’s disease-associated interstitial lung disease following immunosuppressive therapy: a case report
- The Effects of Continuous Venovenous Hemofiltration on Immunosuppressive Drug concentrations in an Ex‐Vivo Model of the critically Ill Adult: (CITRIC) study
BibTeX
@article{chuang2026effect,
title = {{Effect of immunosuppressive drugs on glucose-stimulated insulin secretion: concentration-response studies in dynamic perifusion assays}},
author = {Sung-Ting Chuang and Brandon Watts and Oscar Alcazar and Peter Buchwald},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1947013},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947013/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Effect of immunosuppressive drugs on glucose-stimulated insulin secretion: concentration-response studies in dynamic perifusion assays
AU - Sung-Ting Chuang
AU - Brandon Watts
AU - Oscar Alcazar
AU - Peter Buchwald
PY - 2026
DA - 2026/10/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1947013
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947013/full
AB - Immunosuppressive drugs, which are required to maintain graft function in transplant recipients, are associated with many unavoidable side effects including posttransplant diabetes mellitus (PTDM) that involves both peripheral insulin resistance and impairment of insulin secretion. To characterize in detail the concentration-dependency of the effect of well-known immunosuppressive drugs on glucose-stimulated insulin secretion (GSIS), we performed dynamic perifusion studies with human pancreatic islets. The effect on the time-profile of GSIS has been assessed over a wide concentration range for several clinically relevant immunomodulatory therapies, including small-molecule drugs (cyclosporine, sirolimus, tacrolimus, prednisolone acetate, and loteprednol etabonate) and biologics (abatacept and anti-CD40L), plus a prospective β-cell proliferation-inducing agent (harmine). While biologics showed no significant detrimental effects after one-day treatment even at relatively high concentrations (5 µM), all small-molecule drugs inhibited insulin secretion in a concentration-dependent manner, although glucocorticoids showed a distinct response pattern. Calcineurin and mTOR inhibitors preserved GSIS within their therapeutic ranges but progressively distorted its time-profile at higher concentrations and completely suppressed secretion at the highest levels, where they were also cytotoxic. Cyclosporine exhibited the least, only about 35-fold, separation between its therapeutic target ( C targ ) and half-maximal GSIS inhibitory (IC ₅₀ ) concentrations. Glucocorticoids did not alter the shape of the time-profile but inhibited overall insulin secretion even at therapeutic levels without affecting islet viability. Their inhibitory effect only increased slowly with concentration and did not follow a classic sigmoid pattern that has unity Hill slope. These findings establish quantitative benchmarks for immunosuppressant-induced β-cell toxicity and provide a framework for optimizing immunosuppressive regimens to reduce the risk of PTDM.
SN - 1664-3224
ER -