• Korean Circulation Journal
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• v.53 no.12
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• pp.795-810
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• 2023

Background and Objectives: Myocarditis is a potentially fatal disease, but curative treatments have not yet been established. Myocardial inflammation is an important pathogenesis of this disease, and immunosuppressants such as methylprednisolone and immunoglobulin have been used for treatment; however, the effectiveness needs to be improved. Thalidomide and dipeptidyl peptidase (DPP) 4 inhibitors were recently investigated regarding their immunomodulatory properties. This study aimed to test whether thalidomide or a DPP4 inhibitor (evogliptin) can improve the effectiveness of myocarditis treatment using a rat model of experimental autoimmune myocarditis (EAM). Methods: Rats with or without myocarditis were administered thalidomide at 100 mg/kg/day and DPP4 inhibitor at 10 mg/kg/day orally. Measurement of echocardiography, serum inflammatory cytokines, myocardial histopathological examination, and immunohistochemical staining for leukocytes, macrophages, CD4+ T cells, and cytoskeleton were performed after 3 weeks, and the fibrosis area was measured after 3 and 6 weeks. Results: Thalidomide and DPP4 inhibitor did not reduce the severity of myocarditis compared with the EAM without treatment rats by comparing the echocardiographic data, myocardial CD4⁺, macrophages, neutrophil infiltrations, and the heart weight/body weight ratio in 3 weeks. The levels of inflammatory cytokines were not lower in the thalidomide and DPP4 inhibitor-treated group than in the untreated group in 3 weeks. In 6 weeks, thalidomide and DPP4 inhibitors did not reduce the fibrosis area compared to untreated groups. Conclusions: Although thalidomide and the DPP4 inhibitor had an immunomodulatory effect and are used against inflammatory diseases, they did not ameliorate myocardial inflammation and fibrosis in this rat model of EAM.

• BMB Reports
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• v.51 no.12
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• pp.636-641
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• 2018

DPP4 (dipeptidyl peptidase-4), a highly conserved transmembrane glycoprotein with an exo-peptidase activity, has been shown to contribute to glucose metabolism, immune regulation, signal transduction, and cell differentiation. Here, we show that DPP4 is involved in control of activin/nodal signaling in Xenopus early development. In support of this, gain of function of DPP4 augmented Smad2 phosphorylation as well as expression of target genes induced by activin or nodal signal. In addition, Dpp4 and Xnr1 showed synergistic effect on induction of ectopic dorsal body axis, when co-injected at suboptimal doses in early embryos. Conversely, saxagliptin, a DPP4 inhibitor repressed activin induction of Smad2 phosphorylation. Notably, overexpression of Dpp4 disrupted specification of dorsal body axis of embryo, leading to malformed phenotypes such as spina bifida and a shortened and dorsally bent axis. Together, these results suggest that DPP4 functions as a potentiator of activin/nodal signaling pathway.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.713-719
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• 2018

Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are antidiabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by $1{\mu}M$ gemigliptin while not by saxagliptin and sitagliptin up to $10{\mu}M$. The ACh-EDR of SHR MA was also improved by $1{\mu}M$ gemigliptin while similar recovery was observed with higher concentration ($10{\mu}M$) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endothelium-denuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with $30{\mu}M$ pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.

• YAKHAK HOEJI
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• v.56 no.2
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• pp.136-143
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• 2012

Type 2 Diabetes Mellitus (T2DM) is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and dietary modification. As the condition progresses, medications may be needed such as oral sulfonylurea or others. Recently, dipeptidyl peptidase 4 (DPP- 4) Inhibitor is new drug which can control blood glucose by increasing the active levels of incretin hormone in the body. However, researches have been carried out for mostly Caucasian and Japanese, not for Koreans at all. Therefore, this study was to evaluate the efficacy and safety of DPP-4 inhibitor (Sitagliptin, Vildagliptin) in patients with T2DM in Koreans. This study was carried out retrospectively with reviewing of medical records from the 141 patients who received sitagliptin or vildagliptin over 24 week periods from January 2009, to December 2009. Information including demographics, concomitant medication, disease duration, and exercise was evaluated. $HbA_{1c}$, random blood glucose, post prandial 2 hour glucose, blood pressure, AST, ALT, serum creatinine, total cholesterol, triglyceride levels were also collected at baseline and endpoint (at 24 weeks). In each post-treatment group, $HbA_{1c}$, random blood glucose and post prandial 2 hour glucose levels were decreased significantly from baseline in the sitagliptin group (-0.82%, -28.76 mg/dl, -46.65 mg/dl) and vildagliptin group(-1.22%, -27.96 mg/dl, -67.2 mg/dl). Greater $HbA_{1c}$ mean reductions from baseline to 24 weeks were seen in patients with higher baseline values (>7.0%), with shorter disease durations (${\leq}1$ year) compared with those with lower baseline values (<7.0%), with longer disease durations (>1 year) in both sitagliptin and vildagliptin groups. The incidences of hypoglycemia, headache and upper respiratory infection were 0%, 8.7%, 5.8% in sitagliptin group and 2.8%, 8.3%, 6.9% in vildagliptin group. In conclusion, our results showed DPP-4 inhibitor provided similar efficacy compared with sulfonylurea after 24 weeks of treatment and were safer than sulfonylurea in hypoglycemia for Korean T2DM. Also vildagliptin was associated with significant improvement in $HbA_{1c}$ reduction in Korean patient with subgroup (body mass index<25 $kg/m^2$, metformin dose${\geq}$1000 mg, p<0.05) compared to sitagliptin. Therefore, even though DPP-4 inhibitor use for Korean needs to be studied more consistently in the future, DPP-4 inhibitor is a safe and effective drug for Korean T2DM based on our result.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.5
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• pp.329-334
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• 2019

Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.6
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• pp.459-466
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• 2019

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.

• Korean Journal of Clinical Pharmacy
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• v.25 no.2
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• pp.74-79
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• 2015

Objective: Treatment with sulfonylureas in combination with metformin improves glycemic control in type 2 diabetes mellitus (T2DM), but is associated with hypoglycemia and weight gain. This retrospective study aims to compare the effectiveness of dipeptidylpeptidase-4 (DPP-4) inhibitors and sulfonylureas as an add-on therapy to metformin in patients with T2DM. Methods: Data from medical records of 355 T2DM patients received therapy either DPP-4 inhibitors (DPP-4 inhibitor group) or sulfonylurea (SU group) in combination with metformin from 1 March 2009 to 30 September 2011 were retrospectively reviewed. Of total 355 patients, 231 patients were in DPP-4 inhibitor group and 124 patients were in SU group. Baseline Hemoglobin $A_{1c}$ ($HbA_{1c}$) level in SU group was higher than DPP-4 inhibitor group with a statistically significant difference (8.6% vs. 7.8%). Comparative analysis between DPP-4 inhibitor group and SU group was performed for $HbA_{1c}$ values, amounts of $HbA_{1c}$ changes, and rates of $HbA_{1c}$ changes from baseline at 6-month intervals and incidence rates of major cardiocerebral events. Results: SU group showed larger $HbA_{1c}$ changes in both amounts and rates compared to DPP-4 inhibitor group, although statistical significance was not found in all study periods. Proportions of patients with stable $HbA_{1c}$ <6.5% or 7% were significantly higher in DPP-4 inhibitor group than SU group (<6.5%: 30.4% vs. 13.4%, <7%: 72.3% vs. 41.2%). Time to achieve stable $HbA_{1c}$ <6.5% was not significantly different, but time to achieve stable $HbA_{1c}$ <7% was shorter in DPP4 inhibitor group than SU group with a significant difference. The incidence rate of cardiocerebral events in group of patients with or without previous events was 1.7%, not significantly lower than that in DPP-4 inhibitor group (4.0%). For newly encountered cardiocerebral events during the treatment, incidence rates of two groups did not differ significantly. Conclusion: DPP-4 inhibitors were as effective as sulfonylureas in achieving the $HbA_{1c}$ goal of less than 6.5% or 7% and cardiocerebral event rates did not differ between the two drugs.

• International journal of advanced smart convergence
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• v.7 no.2
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• pp.101-111
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• 2018

Celiac disease (CD) is an immune-mediated enteropathy of small intestine diagnosed in both childhood and adulthood. CD is caused by gluten, which produces gliadorphin during its digestion. The enzyme dipeptidyl peptidase-4 (DPP4) breaks gliadorphin down nevertheless the last tripeptide remains and eventually inhibits DPP4, thus slowing down its process. Therefore, the idea is to produce an additional DPP4 enzyme which is crucial. Consequently, the functional DPP4 gene was cloned into pCDNA3 intermediate (FLAG+DPP4) vector and finally a recombinant plasmid pSB1C3 (Andersons promoters+FLAG+DPP4) was constructed using synthetic biology. Normally, a DPP4 inhibitor is used as a cure for diabetes. Another important concern was overexpression of DPP4, which might lead to diabetes, accordingly the work was also performed for the regulation of the DPP4 gene expression. In this regard, three types of Anderson promoters (strong, moderate and weak) were utilized to study the control overexpression. This is the first report of idealistic trial for control the exogenous DPP4 gene-expression by molecular biologic tools.

• Food Science and Industry
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• v.51 no.4
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• pp.302-312
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• 2018

Bioactive peptides generated from milk proteins play an important role in the prevention and alleviation of diabetes. Whey proteins possess direct insulinotropic effect by amino acids (especially branch chain amino acids) produced through its gastrointestinal digestion. Additionally, blood glucose level can be lowered by gut hormone which called incretin [glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)]. However, physiological effects of incretin readily disappeared by dipeptidyl peptidase-4 (DPP-4) causing degradation of GLP-1. Several DPP-4 inhibitors are currently used as therapeutic medicines for the treatment of type II diabetes. More than 60 natural peptide (2-14 amino acids) DPP-4 inhibitors were identified in milk proteins. Peptide DPP-4 inhibitors act as substrate inhibitor and delay breakdown of GLP-1 both in vitro and in vivo. This review summarizes nutritional quality of milk proteins, absorption and mode of action of bioactive peptides, and finally up-to-dated knowledge on DPP-4 inhibitory peptides derived from milk proteins.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.201-209
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• 2018

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.