Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes. Clin Exp Immunol 2013 Jun;172(3):375-82 PMID: 23600825 PMCID: PMC3646436

Pubmed ID

23600825

DOI

10.1111/cei.12068

Abstract

Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing β cells. Novel experimental therapies for T1D target immunomodulation, β cell survival and inflammation. We examined combination therapy with the dipeptidyl peptidase-IV inhibitor MK-626 and the histone deacetylase inhibitor vorinostat in the non-obese diabetic (NOD) mouse model of T1D. We hypothesized that combination therapy would ameliorate T1D by providing protection from β cell inflammatory destruction while simultaneously shifting the immune response towards immune-tolerizing regulatory T cells (T(regs)). Although neither mono- nor combination therapies with MK-626 and vorinostat caused disease remission in diabetic NOD mice, the combination of MK-626 and vorinostat increased β cell area and reduced the mean insulitis score compared to diabetic control mice. In prediabetic NOD mice, MK-626 monotherapy resulted in improved glucose tolerance, a reduction in mean insulitis score and an increase in pancreatic lymph node T(reg) percentage, and combination therapy with MK-626 and vorinostat increased pancreatic lymph node T(reg) percentage. We conclude that neither single nor combination therapies using MK-626 and vorinostat induce diabetes remission in NOD mice, but combination therapy appears to have beneficial effects on β cell area, insulitis and T(reg) populations. Combinations of vorinostat and MK-626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.

Author List

Cabrera SM, Colvin SC, Tersey SA, Maier B, Nadler JL, Mirmira RG

Author

Susanne M. Cabrera MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




Scopus

2-s2.0-84876719833   16 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Blood Glucose
Diabetes Mellitus, Type 1
Dipeptidyl-Peptidase IV Inhibitors
Drug Evaluation, Preclinical
Drug Synergism
Drug Therapy, Combination
Female
Histone Deacetylase Inhibitors
Hydroxamic Acids
Insulin-Secreting Cells
Mice
Mice, Inbred NOD
T-Lymphocytes, Regulatory
Transforming Growth Factor beta1
Triazoles
jenkins-FCD Prod-321 98992d628744e349846c2f62ac68f241d7e1ea70