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PubMed2006

DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells.

BACKGROUND: The glucagon-like peptides-1 and -2 (GLP-1 and -2) are co-secreted after food intake from intestinal L cells. Since both peptides are rapidly degraded by dipeptidyl peptidase-IV (DPPIV), research is focused on the development of DPPIV inhibitors or DPPIV resistant. AIMS: In this study we investigated, whether the inhibition of DPPIV activity and the resulting increased half-life of DPPIV substrates may influence cancer development and progression. METHODS: We examined proliferation and migratory activity of two human colon cancer cell lines (SW480, HT29) after stimulation with GLP-2 in combination with or without DPPIV inhibitors. RESULTS: Migratory activity was increased by 25% from 20% matrix induced activity to a maximum of 45% (100 nM GLP-2). In cells expressing CD26, migration was prolonged by addition of DPPIV inhibitors in a concentration dependent manner. After treatment with GLP-2 doubling time decreased from 2.4 to 1.5 days - and addition of DPPIV inhibitors enhanced the effect of GLP-2. CONCLUSIONS: The use of DPPIV inhibitors together with GLP-2 led to increased proliferation as well as elevated migratory activity. Therefore, the use of DPPIV inhibitors could increase the risk of promoting an already existing intestinal tumour and may support the potential of colon cancer cells to metastasize.

Adenosine Deaminase Inhibitors↗

PubMed2002

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds.

Metformin was reported to increase plasma active glucagon-like peptide-1 (GLP-1) in humans. There are two possible mechanisms for this effect: (1) metformin inhibits dipeptidyl peptidase IV (DPPIV), an enzyme degrading GLP-1, and (2) metformin enhances GLP-1 secretion. To elucidate the mechanism(s), we examined (1) IC(50) of metformin for DPPIV inhibition, (2) plasma active GLP-1 changes after oral biguanide (metformin, phenformin, and buformin) treatment in fasting DPPIV-deficient F344/DuCrj rats, and (3) plasma intact GLP-1 excursions after oral administration of metformin and/or valine-pyrrolidide, a DPPIV inhibitor, in fasting DPPIV-positive F344/Jcl rats. Our in vitro assay showed that metformin at up to 30mM has no inhibitory activity towards porcine or rat DPPIV. Metformin treatment (30, 100, and 300mg/kg) increased plasma active GLP-1 levels dose-dependently in DPPIV-deficient F344/DuCrj rats (approximately 1.6-fold at 3 and 5h after administration of 300mg/kg). This treatment had no effect on blood glucose levels. Similarly, phenformin and buformin (30 and 100mg/kg) elevated plasma intact GLP-1 levels in F344/DuCrj rats. In DPPIV-positive F344/Jcl rats, coadministration of metformin (300mg/kg) and valine-pyrrolidide (30mg/kg) resulted in elevation of plasma active GLP-1, but neither metformin nor valine-pyrrolidide treatment alone had any effect. These findings suggest that metformin has no direct inhibitory effect on DPPIV activity and that metformin and the other biguanides enhance GLP-1 secretion, without altering glucose metabolism. Combination therapy with metformin and a DPPIV inhibitor should be useful for the treatment of diabetes.

Animals↗

PubMed2004

Metformin causes reduction of food intake and body weight gain and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats.

An incretin hormone, glucagon-like peptide-1 (GLP-1), has been shown to lower plasma glucose via glucose-dependent insulin secretion and to reduce appetite. We previously found that the biguanide metformin, an antidiabetic agent, causes a significant increase of plasma active GLP-1 level in the presence of dipeptidyl peptidase IV (DPPIV) inhibitor in normal rats. This finding suggested that the combination treatment might produce a greater antidiabetic and anorectic effect, based on enhanced GLP-1 action. In this study, we assessed the effects of subchronic treatment with metformin and a DPPIV inhibitor, valine-pyrrolidide (val-pyr), on glycemic control, food intake, and weight gain using Zucker fa/fa rats, a model of obesity and impaired glucose tolerance. The combination treatment caused a significant increase of GLP-1 level in Zucker fa/fa rats. In a subchronic study, val-pyr, metformin, or both compounds were administered orally b.i.d. for 14 days. The combination treatment significantly decreased food intake and body weight gain, although neither metformin nor val-pyr treatment alone had any effect. In an oral glucose tolerance test on day 1, the coadministration caused a greater improvement of glucose tolerance and a prominent increase of plasma active GLP-1 without marked insulin secretion. The 14-day combination treatment produced a potent reduction of fasting blood glucose and plasma insulin levels. These results demonstrate that the combination therapy of metformin with DPPIV inhibitor leads to reduced food intake and body weight gain, most likely through the significant increase of plasma GLP-1 level. The combination therapy seems to be a good candidate for treatment of type 2 diabetes with obesity.

Animals↗

PubMed2003

Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition.

In type 2 diabetic patients, the administration of glucagon-like peptide-1 (GLP-1), known as an incretin, exerts antidiabetic effects. However, GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV) after its release. DPPIV inhibition is thought to be a rational strategy to treat type 2 diabetes. In this study, using C57BLKS/J-db/db (db/db) mice as a model of type 2 diabetes, we examined the effect of acute DPPIV inhibition on glucose tolerance at the early and later stages of diabetes, determining plasma active GLP-1 and insulin levels. In addition, we investigated changes of plasma DPPIV activity. Compared with normal C57BL6/J (B6) and db/+ mice, significantly increased plasma DPPIV activities were observed in db/db mice. Expression of the proglucagon gene encoding GLP-1 was significantly upregulated in the colon of db/db mice. The administration of valine-pyrrolidide, a DPPIV inhibitor, resulted in potentiated insulin secretion mediated by increased endogenous GLP-1 action, leading to improved glucose tolerance in db/db mice at 6 weeks of age. However, although acute DPPIV inhibition with valine-pyrrolidide resulted in higher plasma active GLP-1 and insulin levels in db/db mice at 23 weeks of age, it did not improve glucose tolerance. The function of the enteroinsular axis is preserved in both stage of diabetes and the DPPIV inhibitor potentiated it, but the progression of insulin resistance appeared to block the improvement of glucose tolerance through DPPIV inhibition. Our results suggest that DPPIV inhibition is a suitable approach for treatment of impaired glucose tolerance (IGT), and type 2 diabetes in the early stage.

Actins↗

PubMed2004

The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight.

Glucagon-like peptide 2 (GLP-2), which has intestinotrophic effects, is secreted from L-cells in the intestine in response to nutrient ingestion and is degraded by dipeptidyl peptidase IV (DPPIV). In this report, we show that biguanides promote GLP-2 release. Plasma GLP-2 levels were significantly increased by 1.4- to 1.6-fold in fasted F344 rats 1 h after oral meformin (300 mg/kg), phenformin (30 and 100 mg/kg) and buformin (100 mg/kg) treatment. In addition, metformin administration (300 mg/kg, p.o.) significantly elevated plasma GLP-2 in fasted CD-1 mice by about 2.0-fold 1 and 3 h after the treatment. Metformin and/or valine-pyrrolidide, a DPPIV inhibitor, was orally given (300 and 30 mg/kg, respectively, p.o., b.i.d., 3 days) to BALB/c mice treated with 5-fluorouracil (5-FU; 60 mg/kg, s.i.d.), which induces gastrointestinal damage leading to a reduction of small intestine wet weight. Metformin and valine-pyrrolidide co-administration prevented the 5-FU-induced reduction of wet weight of the small intestine, whereas metformin or valine-pyrrolidide alone had no effect. These results suggest that GLP-2 is co-secreted with GLP-1 flollowing biguanide stimulation, and that the combination of metformin with a DPPIV inhibitor might a useful oral treatment for gastrointestinal damage, based on GLP-2 actions.

Animals↗

PubMedDate not supplied

Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.

Animals↗

PubMed2006

Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.

A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.

Animals↗

PubMed2001

Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery?

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.

Alcohol Oxidoreductases↗

PubMed2001

Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats.

Glucagon-like peptide-1 (GLP-1) is an incretin, which induces glucose-dependent insulin secretion. GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV) after its release. We investigated whether DPPIV-deficient F344/DuCrj rats show improved glucose tolerance when compared with DPPIV-positive F344/Jcl rats. Oral glucose tolerance test indicated improved glucose tolerance in F344/DuCrj rats, but blood glucose levels of the two strains were almost the same 120 min after the glucose bolus. Valine-pyrrolidide, a DPPIV inhibitor, had no effect on the glucose tolerance of F344/DuCrj rats, but improved that of F344/Jcl rats. Enhanced insulin secretion and high plasma active GLP-1 levels were detected in an intraduodenal glucose tolerance test. Glucose tolerance is improved in DPPIV-deficient F344/DuCrj rats via enhanced insulin release mediated by high active GLP-1 levels. Our results suggest that DPPIV inhibition is a rational strategy to treat diabetic patients by improving glucose tolerance with low risk of hypoglycemia.

Animals↗

PubMed2006

The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation-an in vitro superfusion study in rats.

The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH2, and EM2: Tyr-Pro-Phe-Phe-NH2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists beta-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. beta-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

Animals↗

PubMed2004

[Analogs of glucagon-like peptide-1 (GLP-1): an old concept as a new treatment of patients with diabetes mellitus type 2].

Upon ingestion of food, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are synthesised and secreted by specialised gut cells. GLP-1 is also produced in the pancreatic islets and the central nervous system. Both incretins bind to specific G-protein-coupled receptors that are distributed throughout the body. Incretins potentiate meal-induced insulin production and secretion by the beta-cells and lower the blood glucose level in the presence of hyperglycaemia. GLP-1 and GIP stimulate beta-cell proliferation and differentiation, whereas GLP-1 only inhibits gastric emptying and glucagon secretion, reduces food intake and improves insulin sensitivity. Insulin-resistant and type-2 diabetic patients have an impaired incretin response to meal ingestion. However, the insulinotropic action of exogenous GLP-1, but not that of GIP, is preserved in these subjects. After parenteral administration, GLP-1 has an extremely short duration of action because it is rapidly degraded by the ubiquitous enzyme dipeptidyl peptidase IV (DPPIV). To prolong GLP-1 bioactivity, DPPIV-resistant GLP-1 analogues, DPPIV inhibitors and exenatide, a long-acting synthetic GLP-1 receptor agonist derived from the Gila monster hormone exendin-4, have been developed. Enhancement of incretin action seems a rational and promising option for the treatment of type-2 diabetes.

Diabetes Mellitus, Type 2↗

PubMed2005

Atherosclerosis and angiogenesis: what do nerves have to do with it?

Neuropeptide Y (NPY) is a sympathetic neurotransmitter and a stress mediator with pleiotropic activities mediated by multiple receptors, Y1-Y5. Originally known as an appetite stimulant and a vasoconstrictor, NPY has recently emerged as a growth factor for a variety of cells from vascular smooth muscle to neural precursors - implicating the peptide in atherosclerosis and tissue remodeling. NPY is also potently angiogenic, and was hailed as a potential candidate for a nerve-driven ischemic revascularization. To determine if the latter, beneficial activity of the peptide can be separated from its deleterious pro-atherosclerotic action - receptor specificity and mechanisms of this "Janus phenomenon" were studied. Expression of Y2 receptors on the endothelium, and Y1 receptors on vascular smooth muscle, were required for angiogenic and pro-atherosclerotic activities, respectively. Amplification of both activities was provided by co-expression of Y5 receptors. In rodent models, limb ischemia up-regulated the NPY-Y2 system, which contributed to post-ischemic revascularization; exogenous NPY further augmented it and nearly normalized blood flow and function of ischemic tissues. NPY-induced angiogenesis was also dependent on nitric oxide and endothelial dipeptidyl peptidase IV (DPPIV, which converts NPY to Y2/Y5-selective agonist), but resistant to Y1 receptor blockade. Conversely, vascular angioplasty up-regulated the NPY-Y1 system and promoted atherosclerosis and hyperplastic remodeling, and these activities were blocked by Y1 receptor antagonist and augmented by DPPIV inhibitors. Thus, drugs targeting specific NPY receptors may become new therapeutics against atherosclerosis/restenosis (Y1-selective antagonists) or for ischemic revascularization (Y2-selective agonists). Such drugs may be particularly beneficial for patients with elevated circulating NPY levels e.g. by chronic stress.

Animals↗

PubMed2005

Sulphostin, a novel inhibitor of dipeptidyl peptidases IV (DPPIV) that stimulates hematopoiesis in mice.

CD26, a membrane-bound ectopeptidase, is known as an activated T cell marker with dipeptidyl peptidase IV (DPPIV) activity that has diverse functional roles in the regulation of peptide hormones, neuropeptides, chemokines and growth factors. We recently isolated a novel inhibitor of DPPIV, sulphostin, from culture broth of Streptomyces sp. MK251-43F3. We investigated herein the hematopoietic effect of sulphostin in mice and found that sulphostin induced the production of granulocyte colony-stimulating factor (G-CSF), stimulated myeloblasts in bone marrow, and increased neutrophil numbers in peripheral blood in both normal mice and mice with cyclophosphamide-induced leucopenia. Sulphostin desulfonate, in addition to sulphostin, has a similar inhibitory effect on DPPIV and stimulatory effect on neutrophils. These results suggest that DPPIV/CD26 might be a novel target for hematopoietic stimulation and DPPIV inhibitors including sulphostin and derivatives may be candidates for further development.

Alkylating Agents↗

PubMed2004

Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells.

We recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) in renal brush-border membranes. To examine the possible role of DPPIV in modulating NHE3 activity, we evaluated whether specific competitive inhibitors that bind to the active site of DPPIV affect NHE3 activity in the OKP line of opossum kidney proximal tubule cells. The DPPIV inhibitors diprotin A and P32/98 significantly reduced NHE3 activity, whereas the inactive isomer P34/98 had no effect. DPPIV inhibitors did not reduce the activity of another brush-border transport process, Na-phosphate cotransport. Effects of DPPIV inhibitors on NHE3 activity were not associated with detectable changes in amount or apparent molecular weight of NHE3 or in NHE3 surface expression. To investigate the signaling mechanisms involved in modulation of NHE3 activity by DPPIV, we used inhibitors of protein kinase pathways known to regulate NHE3. Whereas the PKA inhibitor H-89 failed to block the effect of DPPIV inhibitors, the tyrosine kinase inhibitor genistein alone caused a decrement in NHE3 activity very similar in magnitude to that caused by P32/98. We also found that the effects of genistein and P32/98 on NHE3 activity were not additive. In contrast, forskolin/IBMX and P32/98 had additive inhibitory effects on NHE3 activity. These findings suggested that the effect of DPPIV inhibitors to reduce NHE3 activity results from inhibition of a tyrosine kinase signaling pathway rather than by activation of PKA. We conclude that DPPIV plays an unexpected role in modulating Na+/H+ exchange mediated by NHE3 in proximal tubule cells.

Animals↗

PubMed2003

The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed beta-propeller fold.

Dipeptidyl peptidase IV (DPPIV) is a serine protease, a member of the prolyl oligopeptidase (POP) family, and has been implicated in several diseases. Therefore, the development of DPPIV selective inhibitors, which are able to control the biological function of DPPIV, is important. We determined the crystal structure of human DPPIV at 2.6A resolution. The molecule consists of a unique eight-bladed beta-propeller domain in the N-terminal region and a serine protease domain in the C-terminal region. Also, the large "cave" structure, which is thought to control the access of the substrate, is found on the side of the beta-propeller fold. Comparison of the overall amino acid sequence between human DPPIV and POP shows low homology (12.9%). In this paper, we report the structure of human DPPIV, especially focusing on a unique eight-bladed beta-propeller domain. We also discuss the way for the access of the substrate to this domain.

Amino Acid Sequence↗

PubMed2002

Involvement of dipeptidyl peptidase IV in extravillous trophoblast invasion and differentiation.

Previously, we reported that dipeptidyl peptidase IV (DPPIV), a membrane-bound peptidase, was expressed on human placental cytotrophoblasts. In the present study, we focused on DPPIV expression on extravillous trophoblasts (EVTs). In the first trimester, DPPIV was expressed in the proximal part of the cell column and some EVTs located in the deep portion of the decidua and myometrium. EVTs migrating in the decidua from the cell column were negative for DPPIV. In the second and third trimesters, almost all EVTs were positive for DPPIV. Because negative DPPIV expression was associated with migration or the invasive phenotype of EVTs, using JEG-3 cells (choriocarcinoma cell line) that endogenously produce DPPIV, the influence of DPPIV on the invasive activity was examined. When a competitive inhibitor of DPPIV, diprotin A, was added in Matrigel invasion assay system, JEG-3 cells exhibited a significant enhancement of invasion. Because hypoxia is reported to reduce trophoblastic invasion, the effect of hypoxia was examined on JEG-3 cells. JEG-3 cells became less invasive with increased expression of DPPIV when cultured under hypoxic conditions (1% O(2)). These results suggest that DPPIV is important for the noninvasive EVT phenotype and the down-regulation of this enzyme was strongly associated with migration or invasive EVT phenotype.

Base Sequence↗

PubMed2003

Gut peptides and type 2 diabetes mellitus treatment.

The gut expresses peptide hormones in endocrine cells and neuropeptides in autonomic nerves. Several of these peptides have the ability to stimulate insulin secretion. Gut hormones that are released after meal ingestion and stimulate insulin secretion postprandially are called incretins. In humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the most important incretins. The potential use of these insulinotropic gut peptides for the treatment of diabetes has been considered. This has been most successful for GLP-1, which exerts antidiabetogenic properties in subjects with type 2 diabetes by stimulating insulin secretion, increasing beta-cell mass, inhibiting glucagon secretion, delaying gastric emptying, and inducing satiety. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV), making it unattractive as a therapeutic agent because of a very short half-life. Successful strategies to overcome this difficulty are the use of DPPIV-resistant GLP-1 receptor agonists, such as NN2211 or exendin-4, and the use of inhibitors of DPPIV, such as NVPDPP728 and P32/98. These two approaches are explored in clinical investigations.

Diabetes Mellitus, Type 2↗

PubMed2002

Loss of dipeptidylpeptidase IV activity in chronic rhinosinusitis contributes to the neurogenic inflammation induced by substance P in the nasal mucosa.

In this study, we have found that dipeptidylpeptidase IV (DPPIV) plays in vivo an active role in the modulation of the inflammatory response of chronic rhinosinusitis. Human nasal mucosa expresses DPPIV-like immunoreactivity in submucosal seromucus glands, leukocytes, and endothelial cells of blood vessels. DPPIV enzymatic activity in nasal tissue biopsies taken from patients suffering from chronic rhinosinusitis was correlated inversely with the density of inflammatory cells in the nasal mucosa, and the DPPIV activity rose when chronic rhinosinusitis was treated. By using a pig animal model, we have shown that the intranasal administration of recombinant DPPIV decreased the vasodilatation induced by exogenous substance P (SP), a proinflammatory peptide released by sensory nerves. In contrast, an inhibitor of DPPIV enhanced the vasodilatatory effect at low doses of SP. SP5-11 was 100- to 1000-fold less potent than SP as a vasodilator of the nasal mucosa. The vasodilatatory effect of SP was abolished by a NK1 receptor antagonist. In conclusion, these results suggest a new pathophysiological pathway for rhinitis based on clinical observations in humans, indicating the involvement of an enzyme to modulate non-adrenergic and non-cholinergic substrate that occurred during nasal dysfunctions.

Animals↗