• MeSH
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases analysis   physiology   MeSH
• Histocytochemistry MeSH
• Transplantation, Homologous MeSH
• Brain MeSH
• Mice MeSH
• Submandibular Gland enzymology   transplantation   MeSH
• Sex Characteristics MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Comparative Study MeSH

• MeSH
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases analysis   physiology   MeSH
• Histocytochemistry MeSH
• Mice MeSH
• Submandibular Gland enzymology   growth & development   MeSH
• Sex Characteristics MeSH
• Developmental Biology MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Comparative Study MeSH

With the increasing prevalence of type 2 diabetes and its complications throughout the world, there is a need for efficient and safe therapeutic strategies. The dipeptidyl peptidase-4 (DPP-4) inhibitors have become important oral glucose lowering drugs for the management of patients with type 2 diabetes. All DPP-4-inhibitors act on the incre - tin system to lower hyperglycemia, have a similar safety profile, are well tolerated, do not cause significant weight gain and have a relatively low risk of hypoglycemia. However, there are clinical differences among the four agents, sitagliptin, vildagliptin, saxagliptin, and linagliptin which are currently approved by the US Food and Drug Admi - nistration or the European Medicines Agency. This review article discusses similarities and differences in efficacy, safety and tolerability of these four DPP-4-inhibitors.

• MeSH
• Diabetes Mellitus, Type 2 * drug therapy   metabolism   MeSH
• Glucagon-Like Peptide 1 * drug effects   MeSH
• Drug Evaluation MeSH
• Hyperglycemia * drug therapy   MeSH
• Hypoglycemia chemically induced   prevention & control   MeSH
• Dipeptidyl-Peptidase IV Inhibitors * administration & dosage   pharmacology   metabolism   MeSH
• Incretins * metabolism   therapeutic use   MeSH
• Humans MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH

Sitagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor that exerts an anti-hyperglycaemic effect by preventing degradation of glucagon-like peptide 1 with subsequent β-cell stimulation and potential regeneration. We tested whether sitagliptin therapy in symptomatic non-obese diabetic (NOD) mice would lead to changes in the immune cell profile, improve β-cell survival and induce diabetes remission. Flow cytometry analysis of immune cells in the spleen and peripheral lymph nodes, immunohistology of the pancreas and DPP-IV activity were investigated in diabetic NOD mice, either treated or non-treated with sitagliptin, at 0, 7, 14 and 28 days after hyperglycaemia onset, and in non-diabetic NOD controls. While compared to diabetic controls sitagliptin prevented increase of the CD8+/CD4+ ratio in pancreatic nodes after four weeks (0.443 ± 0.067 vs. 0.544 ± 0.131; P < 0.05), the population of Tregs in lymph nodes increased from day 0 to 28 in both treated and non-treated diabetic groups (8 ± 1.76 vs. 13.45 ± 5.07 % and 8 ± 1.76 vs. 13.19 ± 5.58 %, respectively). The severity of islet infiltration was similar in both diabetic groups and decreased in parallel with β-cell loss. Surprisingly, sitagliptin blocked the DPP-IV activity only temporarily (on day 7, 277.68 ± 89.2 vs. 547.40 ± 94.04 ng/ml in the diabetic control group) with no apparent effect later on. In conclusion, sitagliptin administered after the onset of overt hyperglycaemia in NOD mice had only a marginal immunological effect and did not lead to diabetes remission. Failure to block DPP-IV over time represents an important finding that requires further explanation.

• MeSH
• Time Factors MeSH
• Diabetes Mellitus, Type 1 drug therapy   immunology   pathology   MeSH
• Dipeptidyl Peptidase 4 drug effects   MeSH
• Dipeptidyl-Peptidase IV Inhibitors blood   pharmacology   therapeutic use   MeSH
• Islets of Langerhans immunology   pathology   MeSH
• Lymph Nodes drug effects   immunology   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred NOD MeSH
• Mice MeSH
• Pyrazines pharmacology   therapeutic use   MeSH
• Spleen immunology   pathology   MeSH
• T-Lymphocyte Subsets drug effects   immunology   pathology   MeSH
• Triazoles pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Srdeční selhání je častou komplikací u pacientů s diabetes mellitus 2. typu (DM2) a je asociováno se špatnou dlouhodobou prognózou. Porozumění potenciálním vedlejším efektům antidiabetik se jeví kriticky důležitým. Studie SAVOR-TIMI 53 DPP-4 inhibitorem saxagliptinem u pacientů ve vysokém kardiovaskulárním riziku prokázala zvýšení rizika srdečního selhání s nutností hospitalizace. Přibližně 50 % pacientů s DM2 má prokázané diabetické onemocnění ledvin, které je spojeno se signifikantním zvýšením rizika progrese do selhání ledvin a je také spojeno se zvýšením rizika předčasného úmrtí. Studie CARMELINA s DPP-4 inhibitorem linagliptinem prokázala non-inferioritu ve srovnání s placebem pro primární sdružený cíl (smrt z kardiovaskulárních příčin, nefatální infarkt myokardu, nefatální cévní mozková příhoda), v případě druhotného renálního sdruženého cíle nebylo mezi linagliptinem a placebem dosaženo statisticky signifikantního rozdílu. V červnu tohoto roku jsou očekávány výsledky další studie s kardiovaskulárními cíli, studie CAROLINA. Léčba linagliptinem je zde srovnávána s aktivní komponentou sulfonylureou (glimepiridem), která doplní výsledný obraz kardiovaskulární bezpečnosti léčby DPP-4 inhibitory.

Heart failure is a common complication in patients with DM2, and is associated with poor long-term prognosis. Understanding the potential adverse effects of antidiabetic drugs is critical. The SAVOR-TIMI 53 trial with DPP-4 inhibitor saxagliptin in patients at high cardiovascular risk showed an increased risk of heart failure (HF) requiring hospitalization. Approximately 50% of patients with DM2 have proven diabetic kidney disease, which is associated with a significant increase of the risk of progression to end-stage kidney disease and an increased risk of premature death. The CARMELINA study with DPP-4 inhibitor linagliptin proved non-inferiority for the primary outcome (the time to the first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke). CARMELINA was also designed to evaluate renal outcomes of linagliptin treatment; there was no significant difference between linagliptin and placebo for composite renal outcome. In June this year we should receive the results of a further study with CV objectives, CAROLINA, where linagliptin treatment is compared with the active component sulphonylurea (glimepiride). We should soon receive a full image of cardiovascular safety of treatment with DPP-4 inhibitors.

• Keywords
• kardiovaskulární bezpečnost, saxagliptin,
• MeSH
• Diabetes Mellitus, Type 2 * drug therapy   complications   MeSH
• Dipeptidyl-Peptidase IV Inhibitors adverse effects   therapeutic use   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Kidney Diseases MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Heart Failure * chemically induced   MeSH
• Check Tag
• Humans MeSH

Dipeptidylpeptidáza 4 (DPP-4, identická s CD26) je multifunkční enzym, významný pro řadu imunoregulačních pochodů. U pacientů s diabetem mellitem 2. typu léčených inhibitory DPP-4 budou sledovány důsledky inhibice tohoto enzymu na aktivitu a koncentraci DPP-4, koncentraci eosinofilního katonického proteinu a vybraných cytokinů v krevní plasmě. Dále budou zjištěny poměry populací a exprese CD26 na CD4 a CD8 lymfocytech a jejich DPP-4 aktivita, stanovení Treg (CD4+CD25+CD127-/FoxP3+) a CD86+ monocytů, případně NK (zastoupení a aktivace) a kvantifikace intracelulárních cytokinů v CD4+ IFNgamma/ IL4/ IL17 (Th1/Th2/Th17) doplněné o IL2 a event. TGFbeta a IL10. Vyšetření budou provedena před a po 4 týdnech a 12 měsících léčby DPP-4 inhibitory. Výsledky umožní posoudit vliv inhibice DPP-4 na navození imunosuprese pozorované u experimentálních zvířat a posoudit její mechanismus. To může přispět k racionalizaci indikace s přihlédnutím k případným komorbiditám, zejména autoimunitním a neoplastickým.; Dipeptidyl peptidase 4 (DPP-4, identical to CD26) is multifunctional enzyme, participating on a number of immunoregulatory processes. In patients with the diabetes mellitus type 2 treated by DPP-4 inhibitors, changes DPP-4 activity and concentration, concentration of eosinophyllic cationic protein and selected cytokines in blood plasma will be followed. In parallel, proportion of CD26 expressing cells within the CD4 and CD8 cells, together with the relevant enzymatic activity, Treg (CD4+CD25+CD127-/FoxP3+) and CD86+ monocytic cells and alternatively NK cells (presence and activation) and intracellular cytokines in CD4+ IFNgamma/ IL4/ IL17 (Th1/Th2/Th17) supplemented with IL2 and eventually TGFbeta and IL10 will be investigated. The results might help to assess causality of DPP-4 inhibitors' induced immunosupression observed in animals. The results also should help to better define indications of the treatment, namely respective to the autoimmune and oncological comorbidities.

• MeSH
• Amylases analysis   MeSH
• Autoimmune Diseases MeSH
• Diabetes Mellitus, Type 2 drug therapy   immunology   MeSH
• Eosinophil Cationic Protein analysis   MeSH
• Immunosuppression Therapy MeSH
• Dipeptidyl-Peptidase IV Inhibitors immunology   therapeutic use   MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• T-Lymphocytes, Regulatory MeSH
• Th1 Cells MeSH

• Conspectus
• Farmacie. Farmakologie
• NML Fields
• farmakoterapie
• diabetologie
• NML Publication type
• závěrečné zprávy o řešení grantu IGA MZ ČR

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.

• Publication type
• Journal Article MeSH
• Review MeSH

AIM: To assess intraindividually the effects of DPP-IV inhibition on the subpopulations of immune cells in type 2 diabetes mellitus (DM2) patients during the course of treatment with sitagliptin. METHODS: In this open label non-randomized observational study with a control group DM2 patients were examined before the initiation of the DPP-IV inhibitor administration (sitagliptin 100mg once daily) and then after 4weeks and 12months. Inhibition of the blood plasma DPP-IV enzymatic activity was determined by a chromogenic assay, the immunophenotyping of the blood cell subpopulations was performed using flow cytometry and blood plasma cytokine concentrations were quantified using an array-based multiplex ELISA. All parameters were evaluated in relation to the entry values in individual patients. RESULTS: The blood plasma DPP-IV enzymatic activity was effectively inhibited during the sitagliptin treatment. A significant decrease of the proportion of Treg cells (to 86±31% (median±SD) of entry values, p=0.001) and an increase of Th1 cells (to 120±103% (median±SD) of entry values, p=0.004) were observed after 4weeks but not after one year of the sitagliptin treatment. No changes were observed in the ratio of CD4(+)/CD8(+) cells, in the quantity of NK and Th2 cells and blood plasma cytokine levels. CONCLUSIONS: Sitagliptin treatment may cause temporary changes of the proportion of lymphocyte subpopulations in patients with DM2. The consequent deregulation of the immune system should be considered as a possible cause of the eventual side effects of long term DPP-IV inhibition.

• MeSH
• Diabetes Mellitus, Type 2 blood   drug therapy   immunology   MeSH
• Adult MeSH
• Dipeptidyl-Peptidase IV Inhibitors administration & dosage   MeSH
• Humans MeSH
• Lymphocyte Count MeSH
• T-Lymphocytes, Regulatory drug effects   immunology   MeSH
• Sitagliptin Phosphate administration & dosage   MeSH
• Th1 Cells drug effects   immunology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH

• Publication type
• Meeting Abstract MeSH

• Publication type
• Meeting Abstract MeSH