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Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4.

ABSTRACT: Severe periodontitis is known to aggravate diabetes mellitus, though molecular events related to that link have not been fully elucidated. Porphyromonas gingivalis, a major pathogen of periodontitis, expresses dipeptidyl peptidase 4 (DPP4), which is involved in regulation of blood glucose levels by cleaving incretins in humans. We examined the enzymatic characteristics of DPP4 from P. gingivalis as well as two other periodontopathic bacteria, Tannerella forsythia and Prevotella intermedia, and determined whether it is capable of regulating blood glucose levels. Cell-associated DPP4 activity was found in those microorganisms, which was effectively suppressed by inhibitors of human DPP4, and molecules sized 73 kDa in P. gingivalis, and 71 kDa in T. forsythia and P. intermedia were immunologically detected. The kcat/Km values of recombinant DPP4s ranged from 721 ± 55 to 1,283 ± 23 ?M-1s-1 toward Gly-Pro-4-methylcoumaryl-7-amide (MCA), while those were much lower for His-Ala-MCA. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis showed His/Tyr-Ala dipeptide release from the N termini of incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, respectively, with the action of microbial DPP4. Moreover, intravenous injection of DPP4 into mice decreased plasma active GLP-1 and insulin levels, accompanied by a substantial elevation in blood glucose over the control after oral glucose administration. These results are the first to show that periodontopathic bacterial DPP4 is capable of modulating blood glucose levels the same as mammalian DPP4; thus, the incidence of periodontopathic bacteremia may exacerbate diabetes mellitus via molecular events of bacterial DPP4 activities.

SUBMITTER: Ohara-Nemoto Y

PROVIDER: S-EPMC5563571 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4.

Ohara-Nemoto Yuko Y Nakasato Manami M Shimoyama Yu Y Baba Tomomi T TT Kobayakawa Takeshi T Ono Toshio T Yaegashi Takashi T Kimura Shigenobu S Nemoto Takayuki K TK

Infection and immunity 20170818 9

Severe periodontitis is known to aggravate diabetes mellitus, though molecular events related to that link have not been fully elucidated. Porphyromonas gingivalis, a major pathogen of periodontitis, expresses dipeptidyl peptidase 4 (DPP4), which is involved in regulation of blood glucose levels by cleaving incretins in humans. We examined the enzymatic characteristics of DPP4 from P. gingivalis as well as two other periodontopathic bacteria, Tannerella forsythia and Prev ...[more]

PMID: 28630069

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Project description:UnlabelledBecause the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure are controversial, we examined the long-term effects of sitagliptin (80 mg/kg per day) on blood pressure (radiotelemetry) in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats, and Zucker Diabetic-Sprague Dawley rats (metabolic syndrome model). In SHR, chronic (3 weeks) sitagliptin significantly increased systolic, mean, and diastolic blood pressures by 10.3, 9.2, and 7.9 mm Hg, respectively, a response abolished by coadministration of BIBP3226 (2 mg/kg per day; selective Y1-receptor antagonist). Sitagliptin also significantly increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg per day) or enalapril (angiotensin-converting enzyme inhibitor; 10 mg/kg per day). In Wistar-Kyoto rats, chronic sitagliptin slightly decreased systolic, mean, and diastolic blood pressures (-1.8, -1.1, and -0.4 mm Hg, respectively). In Zucker Diabetic-Sprague Dawley rats, chronic sitagliptin decreased systolic, mean, and diastolic blood pressures by -7.7, -5.8, and -4.3 mm Hg, respectively, and did not alter the antihypertensive effects of chronic enalapril. Because DPP4 inhibitors impair the metabolism of neuropeptide Y1-36 (NPY1-36; Y1-receptor agonist) and glucagon-like peptide (GLP)-1(7-36)NH2 (GLP-1 receptor agonist), we examined renovascular responses to NPY1-36 and GLP-1(7-36)NH2 in isolated perfused SHR and Zucker Diabetic-Sprague Dawley kidneys pretreated with norepinephrine (to induce basal tone). In Zucker Diabetic-Sprague Dawley kidneys, NPY1-36 and GLP-1(7-36)NH2 exerted little, if any, effect on renovascular tone. In contrast, in SHR kidneys, both NPY1-36 and GLP-1(7-36)NH2 elicited potent and efficacious vasoconstriction.In conclusion(1) The effects of DPP4 inhibitors on blood pressure are context dependent; (2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to DPP4’s most important substrates (NPY1–36 and GLP-1(7–36)NH2) [corrected]; (3) Y1 receptor antagonists may prevent the prohypertensive and possibly augment the antihypertensive effects of DPP4 inhibitors.

Project description:BackgroundThe dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.MethodsIn ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.ResultsTwo weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal.ConclusionsWe find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

Dataset Information

Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4.

Publications

Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4.

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