Fasting and Post Prandial Monitoring of Dipeptidyl Peptidase-IV (DPP-IV) - A Biomarker to Assess Incretin Response in Type-2 Diabetes

Dipeptidyl peptidase-IV (DPP-IV) could serve as a potential biomarker in monitoring the disease progression and improvement on treatment. To investigate fasting & post prandial response of DPP-IV enzyme as indirect marker of incretin response failure after chronic treatment with metformin in type 2 diabetes. The study included twelve nondiabetic subjects, ten patients with glycosylated hemoglobin values (6-8%) and fifteen patients with glycosylated hemoglobin greater than 8 % of type-2 diabetes patients of either sex with metformin treatment above 3 years were recruited. Fasting and post prandial DPP-IV levels were calculated. HbA1c was used to assess diabetes status. DPP-IV activity (fasting) in type 2 diabetic subjects with HbA1c > 8 % was significantly higher DPP-IV (44.67 ± 2.19 U/l) than in non diabetic subjects (24.39 ± 3.97 U/l). A significant correlation between DPP-IV (fasting / post prandial) and HbA1c (r = 0.821 & r = 0.732, P< 0.01) was observed in both diabetic (HbA1c 6-8, HbA1c < 8) patients. Hyperglycemia induces significant increase in serum DPP-IV activity in fasting condition and might contribute to the reduction in active glucagon like peptide-1(GLP-1) in type 2 diabetic subjects. In normal subjects during post prandial condition, there is sudden increase followed by decrease of GLP-1 due to cleavage of GLP-1 to as substrate of DPP-IV is seen as upsurge of DPP-IV. This response was lacking in diabetic patients with high HbA1c indicates indirectly metformin failure to secrete GLP-1. High fasting level and decreased post prandial of DPP-IV may indicate drug failure in type-2 diabetes mellitus. Key words: Type 2 diabetes; metformin; DPP-IV; HbA1c; GLP-1.DOI: 10.3329/sjps.v2i2.1698Stamford Journal of Pharmaceutical Sciences Vol.2(2) 2009: 81-85

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Comparison of the Effects of Mitiglinide and Glibenclamide Administered in Combination with the Dipeptidyl Peptidase-IV Inhibitor Sitagliptin in Rats with Streptozotocin-Nicotinamide-Induced Type 2 Diabetes

Drug Research ◽

10.1055/s-0043-102951 ◽

2017 ◽

Vol 67 (07) ◽

pp. 396-403 ◽

Cited By ~ 1

Author(s):

Kenji Akahane ◽

Kazuma Ojima ◽

Ayaka Yokoyama ◽

Toshihiro Inoue ◽

Sumiyoshi Kiguchi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Oral Glucose ◽

Diabetic Patients ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Dpp Iv

Abstract We compared the individual effects of mitiglinide and glibenclamide administered in combination with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin on plasma DPP-IV activity and blood glucose levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes (STZ-NA rats). We examined the inhibitory activity of mitiglinide and glibenclamide as well as their combination with sitagliptin on plasma DPP-IV activity in STZ-NA rats. The oral glucose tolerance test (OGTT) was used to compare effects of mitiglinide, glibenclamide, and their combination with sitagliptin on blood glucose levels in STZ-NA rats. Mitiglinide and glibenclamide did not inhibit rat DPP-IV and did not influence the inhibitory effect of sitagliptin on rat plasma DPP-IV activity. In STZ-NA rats, plasma glucose levels were stronger suppressed by a combination of mitiglinide and sitagliptin than by either drug used alone. However, no clear effect of the combination of glibenclamide and sitagliptin was observed. These results indicate that the combination of mitiglinide and sitagliptin has a lower risk of hypoglycemia in the rats with induced type 2 diabetes compared with the combination of glibenclamide and sitagliptin. The combination of mitiglinide and sitagliptin can be a promising combination for the treatment of diabetic patients.

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Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

Acta Endocrinologica ◽

10.1530/eje-09-0547 ◽

2009 ◽

Vol 161 (6) ◽

pp. 877-885 ◽

Cited By ~ 10

Author(s):

Aine M McKillop ◽

Nicola A Duffy ◽

John R Lindsay ◽

Brian D Green ◽

S Patterson ◽

...

Keyword(s):

Dipeptidyl Peptidase ◽

Inhibitory Effect ◽

Dipeptidyl Peptidase Iv ◽

Oral Glucose ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Dpp Iv ◽

Type 2 Diabetic

BackgroundNateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation.Research design and methodsBlood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36±1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design.ResultsPlasma glucose reached 18.2±1.7 and 16.7±1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9±1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9±0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6±163.9 pmol/l (P<0.05) and 11.8±1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1–42) to GIP(3–42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC50 values of 17.1 and 2.1 μM respectively.ConclusionsAlthough considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

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Dipeptidyl-Peptidase-IV Inhibition Augments Postprandial Lipid Mobilization and Oxidation in Type 2 Diabetic Patients

Endocrinology ◽

10.1210/endo.150.2.9997 ◽

2009 ◽

Vol 150 (2) ◽

pp. 1069-1069

Author(s):

Michael Boschmann ◽

Stefan Engeli ◽

Kerstin Dobberstein ◽

Petra Budziarek ◽

Anke Strauss ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Standardized Test ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Diabetic Patients ◽

Lipid Mobilization ◽

Postprandial Lipid

Abstract Context: Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extra-pancreatic mechanisms. Objective: We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism. Design: Randomized, double blind, crossover study. Setting: Academic clinical research center. Patients: Twenty patients with type 2 diabetes, body mass index between 28 and 40 kg/m2. Intervention: Seven days treatment with the selective DPP-4 inhibitor vildagliptin or placebo. Standardized test meal on day seven. Main Outcome Measures: Venous DPP-4 activity, catecholamines, free fatty acids, glycerol, glucose, (pro)insulin; dialysate glucose, lactate, pyruvate, glycerol. Results: Fasting and postprandial venous insulin, glucose, glycerol, triglycerides and free fatty acid concentrations were not different with vildagliptin and with placebo. Vildagliptin augmented the postprandial increase in plasma norepinephrine. Furthermore, vildagliptine increased dialysate glycerol and lactate concentrations in adipose tissue while suppressing dialysate lactate and pyruvate concentration in skeletal muscle. The respiratory quotient increased with meal ingestion but was consistently lower with vildagliptin. Conclusions: Our study is the first to suggest that DPP-4 inhibition augments postprandial lipid mobilization and oxidation. The response may be explained by sympathetic activation rather than a direct effect on metabolic status.

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Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0310529 ◽

2003 ◽

Vol 31 (3) ◽

pp. 529-540 ◽

Cited By ~ 23

Author(s):

BD Green ◽

VA Gault ◽

MH Mooney ◽

N Irwin ◽

CJ Bailey ◽

...

Keyword(s):

Type 2 Diabetes ◽

Biological Activities ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Glucose Lowering ◽

Dpp Iv ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

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Generation of Dipeptidyl Peptidase-IV-Inhibiting Peptides fromβ-Lactoglobulin Secreted byLactococcus lactis

BioMed Research International ◽

10.1155/2014/393598 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Suguru Shigemori ◽

Kazushi Oshiro ◽

Pengfei Wang ◽

Yoshinari Yamamoto ◽

Yeqin Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Expression System ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Delivery Vehicle ◽

Dpp Iv

Previous studies showed that hydrolysates ofβ-lactoglobulin (BLG) prepared using gastrointestinal proteases strongly inhibit dipeptidyl peptidase-IV (DPP-IV) activityin vitro. In this study, we developed a BLG-secretingLactococcus lactisstrain as a delivery vehicle andin situexpression system. Interestingly, trypsin-digested recombinant BLG fromL. lactisinhibited DPP-IV activity, suggesting that BLG-secretingL. lactismay be useful in the treatment of type 2 diabetes mellitus.

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A Novel Dipeptidyl Peptidase IV Inhibitory Tea Peptide Improves Pancreatic β-Cell Function and Reduces α-Cell Proliferation in Streptozotocin-Induced Diabetic Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20020322 ◽

2019 ◽

Vol 20 (2) ◽

pp. 322 ◽

Cited By ~ 3

Author(s):

Yating Lu ◽

Peng Lu ◽

Yu Wang ◽

Xiaodong Fang ◽

Jianming Wu ◽

...

Keyword(s):

Mass Spectrometry ◽

Type 2 Diabetes ◽

Inhibitory Activity ◽

Black Tea ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Inhibitory Peptides ◽

Dpp Iv

Dipeptidyl peptidase IV (DPP-IV) inhibitors occupy a growing place in the drugs used for the management of type 2 diabetes. Recently, food components, including food-derived bioactive peptides, have been suggested as sources of DPP-IV inhibitors without side effects. Chinese black tea is a traditional health beverage, and it was used for finding DPP-IV inhibitory peptides in this study. The ultra-filtrated fractions isolated from the aqueous extracts of black tea revealed DPP-IV inhibitory activity in vitro. Four peptides under 1 kDa were identified by SDS-PAGE and LC-MS/MS (Liquid Chromatography-Mass Spectrometry-Mass Spectrometry) from the ultra-filtrate. The peptide II (sequence: AGFAGDDAPR), with a molecular mass of 976 Da, showed the greatest DPP-IV inhibitory activity (in vitro) among the four peptides. After administration of peptide II (400 mg/day) for 57 days to streptozotocin (STZ)-induced hyperglycemic mice, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increased from 9.85 ± 1.96 pmol/L to 19.22 ± 6.79 pmol/L, and the insulin level was increased 4.3-fold compared to that in STZ control mice. Immunohistochemistry revealed the improved function of pancreatic beta-cells and suppressed proliferation of pancreatic alpha-cells. This study provides new insight into the use of black tea as a potential resource of food-derived DPP-IV inhibitory peptides for the management of type 2 diabetes.

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