scholarly journals Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4

2019 ◽  
Vol 20 (3) ◽  
pp. 530 ◽  
Author(s):  
Po-Kai Huang ◽  
Shian-Ren Lin ◽  
Jirawat Riyaphan ◽  
Yaw-Syan Fu ◽  
Ching-Feng Weng
Keyword(s):  
Single Dose ◽  
Natural Compounds ◽  
Dipeptidyl Peptidase ◽  
Antidiabetic Activity ◽  
Drug Candidate ◽  
Diabetic Patients ◽  
Dose Administration ◽  
Dipeptidyl Peptidase 4

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

scholarly journals Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Minyoung Lee ◽  
Eugene Shin ◽  
Jaehyun Bae ◽  
Yongin Cho ◽  
Ji-Yeon Lee ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dipeptidyl Peptidase ◽  
Trail Receptor ◽  
Dipeptidyl Peptidase 4 ◽  
Alcoholic Steatohepatitis ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Group 2 ◽  
Induced Apoptosis

Abstract Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

scholarly journals Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

Diabetes Care ◽  
2013 ◽  
Vol 36 (12) ◽  
pp. 4083-4090 ◽  
Author(s):  
H. Sell ◽  
M. Bluher ◽  
N. Kloting ◽  
R. Schlich ◽  
M. Willems ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4

Glucagon-like peptide-1 response to whey protein is less diminished by dipeptidyl peptidase-4 in comparison with responses to dextrin, a lipid and casein in rats

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Yuki Shimizu ◽  
Hiroshi Hara ◽  
Tohru Hira
Keyword(s):  
Whey Protein ◽  
Dipeptidyl Peptidase ◽  
Dietary Proteins ◽  
Sprague Dawley ◽  
Dipeptidyl Peptidase 4 ◽  
Sprague Dawley Rats ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Although glucose is the best-known nutrient to stimulate glucagon-like peptide-1 (GLP-1) secretion, dietary peptides also potently stimulate GLP-1 secretion. Certain peptide fragments derived from dietary proteins possess dipeptidyl peptidase-4 (DPP-4) inhibitory activity in vitro. Hence, we hypothesised that dietary peptides protect GLP-1 from degradation through attenuating DPP-4 activity in vivo. Here, we compared GLP-1 responses with dietary proteins, a carbohydrate and a lipid (Intralipos) in rats having or not having plasma DPP-4 activity. Plasma GLP-1 concentrations clearly increased by oral administration of whey protein (2–4 g/kg), but not by that of dextrin (2–4 g/kg), in control rats (untreated Sprague–Dawley rats and F344/Jcl rats), having DPP-4 activity. In contrast, dextrin administration increased the plasma GLP-1 concentrations as the whey protein administration did, in rats having reduced or no DPP-4 activity (a DPP-4 inhibitor, sitagliptin-treated Sprague–Dawley rats or DPP-4-deficient F344/DuCrl/Crlj rats). DPP-4 inhibition by sitagliptin treatment also enhanced GLP-1 response to Intralipos, and casein, but the treatment did not further enhance GLP-1 response to whey protein. Intestinal GLP-1 content and gastric emptying rate were not associated with differences in GLP-1 responses to test nutrients. The luminal contents from rats administered whey protein decreased DPP-4 activity in vitro. These results suggest that GLP-1 released by dextrin, Intralipos and casein was immediately degraded by DPP-4, while GLP-1 released by whey protein was less degraded. Our study provides novel in vivo evidence supporting the hypothesis that dietary peptides not only stimulate GLP-1 secretion but also inhibit DPP-4 activity to potentiate GLP-1 response.

scholarly journals The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo

2017 ◽  
Vol 135 (3) ◽  
pp. 126-130 ◽  
Author(s):  
Masako Uchii ◽  
Mariko Sakai ◽  
Yuhei Hotta ◽  
Satoshi Saeki ◽  
Naoya Kimoto ◽  
...  
Keyword(s):  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4

scholarly journals The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Na-Hyung Kim ◽  
Taeyang Yu ◽  
Dae Ho Lee
Keyword(s):  
Randomized Clinical Trials ◽  
Cardiovascular Effects ◽  
Dipeptidyl Peptidase ◽  
Protective Effects ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Stimulation Of

A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreaticβ-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in bothin vitroandin vivoexperiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

scholarly journals Antidiabetic Activity ofRuellia tuberosaL., Role ofα-Amylase Inhibitor:In Silico,In Vitro, andIn VivoApproaches

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Dyah Ratna Wulan ◽  
Edi Priyo Utomo ◽  
Chanif Mahdi
Keyword(s):  
Single Dose ◽  
In Silico ◽  
Amylase Activity ◽  
Alternative Therapy ◽  
Antidiabetic Activity ◽  
Diabetic Rat ◽  
Control Group ◽  
Folk Remedy

Ruellia tuberosaL. is a folk remedy in the treatment of diabetes mellitus. However, its hypoglycemic activity has not been investigated so far. In the present study, the antidiabetic mechanism of the n-hexane fraction of methanolic extract (HFME) of this plant was investigatedin silico,in vitro, andin vivo.In silicostudy was performed using AutoDock4.2 software.In vitro  α-amylase inhibitory activity was investigated by starch-iodine method. A single dose of 450 mg/kg HFME for 14 days was subjected to an antidiabetic screeningin vivoby a multiple low dose streptozotocin (MLD-STZ) induced rats. Molecular modeling results show that Betulin exhibited noncompetitiveα-amylase inhibitory activities. The effect of HFME elicited significant reductions of diabetic rat blood glucose. A single dose administration of HFME inhibitedα-amylase activityin vivo(P<0.01) compared to a diabetic control group. Moreover, this extract strongly inhibited theα-amylase activityin vitro(IC500.14 ± 0.005 mg/mL). It is concluded that HFME exerted an antidiabetic effect viaα-amylase inhibitor. Our findings provide a possible hypoglycemic action ofR. tuberosaL. as an alternative therapy in the management of diabetes.

scholarly journals Dipeptidyl Peptidase 4: A New Link between Diabetes Mellitus and Atherosclerosis?

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Wellington Santana da Silva Júnior ◽  
Amélio Fernando de Godoy-Matos ◽  
Luiz Guilherme Kraemer-Aguiar
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Function ◽  
Dipeptidyl Peptidase ◽  
Noncommunicable Diseases ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dipeptidyl Peptidase 4 ◽  
Increased Risk ◽  
Increase Insulin Secretion

Type 2 diabetes mellitus (T2DM) has become one of the most prevalent noncommunicable diseases in the past years. It is undoubtedly associated with atherosclerosis and increased risk for cardiovascular diseases. Incretins, which are intestinal peptides secreted during digestion, are able to increase insulin secretion and its impaired function and/or secretion is involved in the pathophysiology of T2DM. Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins and consequently is related to the pathophysiology of T2DM. DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. In T2DM, the activity of DPP4 seems to be increased and there are a growing number ofin vitroandin vivostudies suggesting that this enzyme could be a new link between T2DM and atherosclerosis. Gliptins are a new class of pharmaceutical agents that acts by inhibiting DPP4. Thus, it is expected that gliptin represents a new pharmacological approach not only for reducing glycemic levels in T2DM, but also for the prevention and treatment of atherosclerotic cardiovascular disease in diabetic subjects. We aimed to review the evidences that reinforce the associations between DPP4, atherosclerosis, and T2DM.

Design and Discovery of Novel 1,3,5-Triazines as Dipeptidyl Peptidase-4 Inhibitor against Diabetes

Pharmacology ◽  
2019 ◽  
Vol 103 (5-6) ◽  
pp. 273-281 ◽  
Author(s):  
Yu Wang ◽  
Xialian Tang ◽  
Lianghong Yi
Keyword(s):  
Glucose Tolerance ◽  
Wistar Rats ◽  
Defense Mechanism ◽  
Density Lipoprotein ◽  
Dipeptidyl Peptidase ◽  
Antidiabetic Activity ◽  
Control Group ◽  
Oral Glucose ◽  
Dipeptidyl Peptidase 4

This study aims at synthesizing novel di-morpholine 1,3,5-triazine derivatives as antidiabetic agent via inhibition of dipeptidyl peptidase-4 (DPP-4). The molecules were developed via sequential nucleophilic reaction to afford target derivatives 5(a–f) and subsequently tested for inhibitory potency against DPP iso-enzymes, such as DPP-4, DPP-8, and DPP-9. The in vitro inhibition assay suggested that these derivatives prominently and selectively inhibit DPP-4 over ­DPP-8 and DPP-9. These molecules also showed no presence of cardiotoxicity, as confirmed by no activity against human Ether-à-go-go related gene channel. The study disclosed compound 5c as the most potent inhibitor of DPP-4 with IC50 of 1.10 nmol/L as compared to the standard. Compound 5c was further evaluated for oral glucose tolerance test (OGTT) and antidiabetic activity in ICR mice and Wistar rats, respectively. In OGTT, compound 5c showed dose-dependent ­improvement of glucose tolerance with a maximum at 30 mg/kg. It also showed reduction in area under the curve from 0 to 120 min, similar to alogliptin (standard). In Wistar rats, compound 5c causes reduction in the blood glucose level, total cholesterol, triglyceride, low density lipoprotein (LDL) and very LDL level as compared to the diabetic control group, whereas the level of high-density lipoprotein was found to be increased. Compound 5c causes improvement in antioxidant defense mechanism, as confirmed via improving superoxide dismutase, catalase, glutathione peroxidase and reducing the malondialdehyde level as compared to normal control group rats.

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