• 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.

• 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.29 no.2
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• pp.154-165
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• 2021

This study aimed to investigate whether the antidiabetic drugs dipeptidyl peptidase 4 (DPP4) inhibitors such as evogliptin and sitagliptin affect the membrane DPP4 (mDPP4) enzymatic activity and immune function of T helper1 (Th1) cells in terms of cytokine expression and cell profiles. The mDPP4 enzymatic activity, cytokine expression, and cell profiles, including cell counts, cell viability, DNA synthesis, and apoptosis, were measured in pokeweed mitogen (PWM)-activated CD4+CD26+ H9 Th1 cells with or without the DPP4 inhibitors, evogliptin and sitagliptin. PWM treatment alone strongly stimulated the expression of mDPP4 and cytokines such as interleukin (IL)-2, IL-10, tumor necrosis factor-alpha, interferon-gamma, IL-13, and granulocyte-macrophage colony stimulating factor in the CD4+CD26+ H9 Th1 cells. Evogliptin or sitagliptin treatment potently inhibited mDPP4 activity in a dose-dependent manner but did not affect either the cytokine profile or cell viability in PWM-activated CD4+CD26+ H9 Th1 cells. These results suggest that, following immune stimulation, Th1 cell signaling pathways for cytokine expression function normally after treatment with evogliptin or sitagliptin, which efficiently inhibit mDPP4 enzymatic activity in Th1 cells.

• The Korean Journal of Pain
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• v.37 no.1
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• pp.26-33
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• 2024

Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods: Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K_ATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT₂) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/K_ATP, 5HT₃ and D₂ pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

• Journal of Embryo Transfer
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• v.31 no.4
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• pp.319-322
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• 2016

CD26, also known as Dipeptidyl peptidase IV (DPP-4), is a cell surface glycoprotein that belongs to the serine protease family and has wide spread organ distribution throughout the body. CD26 was previously characterized in immune cells but also has important metabolic functions which are not yet fully understood. Thus, we investigated the effect of CD26 in porcine parthenogenetic embryos. We attempted CD26 downregulation of porcine embryos by siRNA, and evaluated CD26 suppression of developmental competencies. Although the porcine embryos injected with CD26 siRNA were able to develop to the early stage, these embryos were decreased to form blastocysts. Our results indicated that CD26 is one of factors for the regulation of development of porcine embryos.

• Korean Journal of Pharmacognosy
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• v.52 no.2
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• pp.77-83
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• 2021

The number of people suffering from diabetes have been increased around the world. In this study, we investigated the antidiabetic and antioxidant effects of Anthriscus sylvestris(L.) Hoffm and its main compounds. It was divided into root(R) and aerial part(AP) for comparative analysis. Total polyphenol, total flavonoid content was higher in AP extract, but nodakenin content was higher in R(1169.13 ± 6.00 mg/g) extract. Antioxidant activity was also higher in AP extract. To compare antidiabetic efficacy, we analyzed the effects of R and AP extracts on ɑ-glucosidase inhibition(AGI), dipeptidyl peptidase-4(DPP-4) and protein tyrosine phosphatase(PTP)1B activity. R and AP extracts showed similar effects on AGI and DPP-4 activity in a concentration dependent manner, and there was no effect on PTP1B activation. Glucose uptake(139.51 ± 3.19%) in 3T3-L1 cells was more effective in the AP extract-treated group than the positive control, rosiglitazone, group. Both R and AP extracts were effective in protecting against pancreatic beta cell damage caused by hyperglycemia. These results suggest that Anthriscus sylvestris(L.) Hoffm. could be used as a candidate for diabetes treatment.

• Microbiology and Biotechnology Letters
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• v.40 no.3
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• pp.180-185
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• 2012

Type 2 Diabetes Mellitus, a chronic metabolic disorder which results from a high blood glucose level, is one of the most prevalent and costly diseases of our time. Considering increasing rates of obesity and the aging population in Korea, the number of diabetic patients is likely to rise rapidly in the future. There are five conventional diabetic drugs which work through different mechanisms; sulfonylureas, biguanide, meglitinide, alpha-glucosidase inhibitors, and thiazolidinedione. Although they all have antidiabetic effects, some side effects such as hypoglycemia, weight gain and gastrointestinal intolerance are associated with them. Incretin based therapies, utilizing glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which have a lower risk of adverse side effects, have recently been introduced. At present PPAR-targeting drugs are being actively developed. In this research review, particular emphasis has been placed on the current trends and possible biological targets for the new generation of antidiabetic drugs.

• Journal of Microbiology and Biotechnology
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• v.30 no.3
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• pp.427-438
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• 2020

Middle East respiratory syndrome coronavirus (MERS-CoV) infects the lower respiratory airway of humans, leading to severe acute respiratory failure. Unlike human dipeptidyl peptidase 4 (hDPP4), a receptor for MERS-CoV, mouse DPP4 (mDPP4) failed to support MERS-CoV infection. Consequently, diverse transgenic mouse models expressing hDPP4 have been developed using diverse methods, although some models show no mortality and/or only transient and mild-to-moderate clinical signs following MERS-CoV infection. Additionally, overexpressed hDPP4 is associated with neurological complications and breeding difficulties in some transgenic mice, resulting in impeding further studies. Here, we generated stable hDPP4-transgenic mice that were sufficiently susceptible to MERS-CoV infection. The transgenic mice showed weight loss, decreased pulmonary function, and increased mortality with minimal perturbation of overexpressed hDPP4 after MERS-CoV infection. In addition, we observed histopathological signs indicative of progressive pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory monocytes, and macrophage polarization as well as elevated expression of profibrotic molecules and acute inflammatory response in the lung of MERS-CoV-infected hDPP4-transgenic mice. Collectively, we suggest that this hDPP4-transgenic mouse is useful in understanding the pathogenesis of MERS-CoV infection and for antiviral research and vaccine development against the virus.

• IMMUNE NETWORK
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• v.13 no.5
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• pp.194-198
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• 2013

Recent papers have shown that the initial event in the pathogenesis of autoimmune type 1 diabetes (T1D) comprises sensing of molecular patterns released from apoptotic ${\beta}$-cells by innate immune receptors such as toll-like receptor (TLR). We have reported that apoptotic ${\beta}$-cells undergoing secondary necrosis called 'late apoptotic' ${\beta}$-cells stimulate dendritic cells (DCs) and induce diabetogenic T cell priming through TLR2. The role of other innate immune receptors such as TLR7 or TLR9 in the initiation of T1D has also been suggested. We hypothesized that TLR2 blockade could inhibit T1D at the initial step of T1D. Indeed, when a TLR2 agonist, $Pam3CSK_4$ was administered chronically, the development of T1D in nonobese diabetic (NOD) mice was inhibited. Diabetogenic T cell priming by DCs was attenuated by chronic treatment with $Pam3CSK_4$, indicating DC tolerance. For the treatment of established T1D, immune tolerance alone is not enough because ${\beta}$-cell mass is critically reduced. We employed TLR2 tolerance in conjunction with islet transplantation, which led to reversal of newly established T1D. Dipeptidyl peptidase 4 (DPP4) inhibitors are a new class of anti-diabetic agents that have beneficial effects on ${\beta}$-cells. We investigated whether a combination of DPP4 inhibition and TLR2 tolerization could reverse newly established T1D without islet transplantation. We could achieve normoglycemia by TLR2 tolerization in combination with DPP4 inhibition but not by TLR2 tolerization or DPP4 inhibition alone. ${\beta}$-cell mass was significantly increased by combined treatment with TLR2 tolerization and DPP4 inhibition. These results suggest the possibility that a novel strategy of TLR tolerization will be available for the inhibition or treatment of established T1D when combined with measures increasing critically reduced ${\beta}$-cell mass of T1D patients such as DPP4 inhibition or stem cell technology.

• 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.