title: Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes.
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.
authors.affiliation: Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Cabrera
authors.forename: S C
authors.initials: SC
authors.lastname: Colvin
authors.forename: S A
authors.initials: SA
authors.lastname: Tersey
authors.forename: B
authors.initials: B
authors.lastname: Maier
authors.forename: J L
authors.initials: JL
authors.lastname: Nadler
authors.forename: R G
authors.initials: RG
authors.lastname: Mirmira
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage*; D000077337:Vorinostat
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C570834:MK0626; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D000077337:Vorinostat