Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of type 2 diabetes, with several inhibitors currently in phase 3 clinical trials. This review will mainly focus on proline-specific dipeptidyl peptidases related to DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase II (DPP II). The biochemical and biological properties of these enzymes will be discussed, as well as the therapeutic potential of their inhibition. The development of potent and selective inhibitors for each of these peptidases will be described.
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PMID:Prolyl peptidases related to dipeptidyl peptidase IV: potential of specific inhibitors in drug discovery. 1735 82

The incretins are peptide hormones produced by special cell types of the intestines, which are secreted following ingestion of foods, indirectly, through a complex mechanism, by decreasing postprandial blood glucose levels participate in the regulation of the glucose homeostasis. The article beside of summarizing the physiological aspects of the two most important incretins, the glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrope polypeptide (GIP), gives a detailed overview of multifaceted effects of GLP-1 and their potential application in the therapy of type 2 diabetes mellitus. The human GLP-1 because of its very short half-life is not suitable for therapeutic use. However, by inhibition its degradation, by suppression of activity of the serine peptidase type enzyme dipeptidyl peptidase (DPP) IV, its effect can be prolonged. Compounds with this effect have been synthetised, as well as drugs resistant to DPP IV, not being identical with the structure of the human GLP-1, but having agonist effect on its receptor could also be manufactured. Members of the first group are called incretin (GLP-1) enhancers, while of the second one incretin mimetics. Two of the enhancers, the sita- and vildagliptin, and one representative of the incretin mimetics, the exenatide after encouraging preclinical and human experiences have also been registered and introduced in the clinical practice. Their potential place in the treatment of type 2 diabetes is not exactly outlined at present. Though there are arguments underlining their early use in the glucose lowering drug treatment of type 2 diabetes, their application as part of a combination therapy seems to be a real indication.
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PMID:[Incretin enhancers, incretin mimetics: from therapeutic concept to clinical application]. 1738 51

Thiazolidinediones (TZDs) are currently the most efficacious class of oral antidiabetics. However, they carry the burden of weight gain and haemodilution, which may lead to cardiovascular complications. The present study was designed to ascertain whether a combination of dipeptidyl peptidase IV (DPP IV) inhibitor with low dose of a thiazolidinedione absolves TZD associated weight gain and oedema without compromising its efficacy. In this study, we examined the efficacy and safety of lower dose (1 mg/kg/day) of rosiglitazone, a thiazolidinedione, in combination with 5 mg/kg/day dose of LAF-237 (vildagliptin), a known DPP IV inhibitor, in aged db/db mice after 14 days of treatment and compared the combination with therapeutic dose (10 mg/kg) of rosiglitazone. The combination therapy showed similar efficacy as that of 10 mg/kg/day rosiglitazone in lowering random blood glucose (53.8%, p<0.001 and 54.3%, p<0.001 respectively), AUC ((0-120) min) during oral glucose tolerance test (OGTT) (38.6 %, p<0.01; 38.3%, p<0.01 respectively) and triglyceride levels (63.9% and 61% respectively; p<0.01). Plasma active glucagon like peptide-1 (GLP-1) and insulin levels were found to be elevated significantly (p<0.01 and p<0.05 respectively) in both LAF-237 and combination treated groups following oral glucose load. LAF-237 alone had no effect on random glucose and glucose excursion during OGTT in severely diabetic db/db mice. Interestingly, the combination treatment showed no significant increase in body weight as compared to the robust weight gain by therapeutic dose of rosiglitazone. Rosiglitazone at 10 mg/kg/day showed significant reduction (p<0.05) in haematocrit, RBC count, haemoglobin pointing towards haemodilution associated with increased mRNA expression of Na(+), K(+)-ATPase-alpha and epithelial sodium channel gamma (ENaCgamma) in kidney. The combination therapy escaped these adverse effects. The results suggest that combination of DPP IV inhibitor with low dose of thiazolidinedione can interact synergistically to represent a therapeutic advantage for the clinical treatment of type 2 diabetes without the adverse effects of haemodilution and weight gain associated with thiazolidinediones.
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PMID:Combination of dipeptidylpeptidase IV inhibitor and low dose thiazolidinedione: preclinical efficacy and safety in db/db mice. 1753 47

Dipeptidyl peptidase IV (DPP IV) is the primary inactivator of glucoregulatory incretin hormones. This has lead to development of DPP IV inhibitors as a new class of agents for the treatment of type 2 diabetes. Recent reports indicate that other antidiabetic drugs, such as metformin, may also have inhibitory effects on DPP IV activity. In this investigation we show that high concentrations of several antidiabetic drug classes, namely thiazolidinediones, sulphonylureas, meglitinides and morphilinoguanides can inhibit DPP IV. The strongest inhibitor nateglinide, the insulin-releasing meglitinide was effective at low therapeutically relevant concentrations as low as 25 micromol/l. Nateglinide also prevented the degradation of glucagon-like peptide-1 (GLP-1) by DPP IV in a time and concentration-dependent manner. In vitro nateglinide and GLP-1 effects on insulin release were additive. In vivo nateglinide improved the glucose-lowering and insulin-releasing activity of GLP-1 in obese-diabetic ob/ob mice. This was accompanied by significantly enhanced circulating concentrations of active GLP-1(7-36)amide and lower levels of DPP IV activity. Nateglinide similarly benefited the glucose and insulin responses to feeding in ob/ob mice and such actions were abolished by co-administration of exendin(9-39) and (Pro(3))GIP to block incretin hormone action. These data indicate that the use of nateglinide as a prandial insulin-releasing agent may partly rely on inhibition of GLP-1 degradation as well as beta-cell K(ATP) channel inhibition.
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PMID:Effects of antidiabetic drugs on dipeptidyl peptidase IV activity: nateglinide is an inhibitor of DPP IV and augments the antidiabetic activity of glucagon-like peptide-1. 1757 70

Current type 2 diabetes therapies are mainly targeted at stimulating pancreatic beta-cell secretion and reducing insulin resistance. A number of alternative therapies are currently being developed to take advantage of the actions of the incretin hormones Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). These hormones are released from the small intestine in response to nutrient ingestion and stimulate insulin secretion in a glucose-dependent manner. One approach to potentiating their actions is based on inhibiting dipeptidyl peptidase IV (DPP IV), the major enzyme responsible for degrading the incretins in vivo. DPP IV exhibits characteristics that have allowed the development of specific orally administered inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes. A number of clinical trials have demonstrated that DPP IV inhibitors are effective in improving glucose disposal and reducing hemoglobin A1c levels in type 2 diabetic patients and one inhibitor, sitagliptin, is now in therapeutic use, with others likely to receive FDA approval in the near future. Studies aimed at elucidating the mode of action of the inhibitors are still ongoing. Both enhancement of insulin secretion and reduction in glucagon secretion, resulting from the blockade of incretin degradation, are believed to play important roles in DPP IV inhibitor action. Preclinical studies indicate that increased levels of incretins improve beta-cell secretory function and exert effects on beta-cell mitogenesis and survival that can preserve beta-cell mass. Roles for other hormones, neuropeptides and cytokines in DPP IV inhibitor-medicated responses are also possible.
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PMID:Dipeptidyl peptidase IV inhibitors and diabetes therapy. 1798 65

Insulinotropic gut-derived hormones (incretins) play a significant role in the regulation of glucose homeostasis in healthy subjects and are responsible for 50-70% of insulin response to a meal. The main mediators of the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). However, in patients with type 2 diabetes the effect of incretins action is to a large extent impaired, which seems to explain disturbed secretional activity of beta cells in pancreatic islets. Detailed analysis of incretin defect proved that GIP secretion remains within physiological limits, whereas GLP-1 secretion is significantly decreased. Nevertheless, GLP-1 insulinotropic effect is preserved and GIP effect is significantly impaired. In consequence, substitutional GLP-1 administration aiming at the reduction of its deficiency, seems to be logical therapeutic management, because despite a physiologically retained quantity response from GIP, resistance to this peptide is frequently found. Therefore, particularly promising are the results of clinical studies with the use of GLP-1 analogues , GLP-1 receptors activation, as well as the inhibitors of dipeptidyl peptidase-IV (DPP IV), the enzyme responsible for incretin proteolysis, which restores the proper function of the intestinal-pancreatic axis in subjects with type 2 diabetes and creates new possibilities of a glycaemia reducing therapy and improvement in quality of life in this group of patients.
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PMID:[Incretin hormones in the treatment of type 2 diabetes. Part I: influence of insulinotropic gut-derived hormones (incretins) on glucose metabolism]. 1820 9

Takeda San Diego Inc is developing alogliptin, a small-molecule, orally available dipeptidyl peptidase IV (DPP IV) inhibitor, for the potential treatment of type 2 diabetes. In January 2008, Takeda announced that an NDA for alogliptin had been submitted to the FDA.
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PMID:Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. 1839 7

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.
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PMID:Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes. 1850 62

Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue. Thus the biological importance of prolyl-specific peptidases points to a high potential for drug discovery for this family of enzymes. Panels of inhibitors have been synthesized and their effects, determined in biological models, suggest the inhibition of families of enzymes with similar activities. Prolyl-specific aminodipeptidases include dipeptidyl-aminodipeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protease-alpha (FAP-alpha)/seprase, able to release X-Pro dipeptides from the N-terminus of peptides. DPP IV inhibitors are in clinical use for type 2 diabetes. In this review, the expression and the potential functions of prolyl-aminodipeptidases are reviewed in diseases, and the inhibitors developed for these enzymes are discussed, with a specific focus on inhibitors able to discriminate between DPP IV and fibroblast activation protease-alpha (FAPalpha)/seprase as potential leads for the treatment of fibrogenic diseases.
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PMID:The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders. 1920 26

ASP4000 ((2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride) is a novel, potent and selective dipeptidyl peptidase 4 (DPP IV, EC 3.4.14.5) inhibitor (Keiko Tanaka-Amino et al. in Eur J pharmacol 59:444-449, 2008). The aim of the present study was to characterize the kinetic profile of and identify the long duration effect of the antihyperglycemic activity of ASP4000. ASP4000 was found to inhibit human recombinant DPP4 activity with a K(i) of 1.05 nM, a k(on) value of 22.3 x 10(5) M(-1) s(-1), and a k (off) of 2.35 x 10(-3) M(-1) s(-1), with higher affinity than that of vildagliptin. The kinetic studies indicate that both the formation and dissociation of ASP4000/DPP4 complex were faster than those of vildagliptin, and that ASP4000 slow-bindingly inhibits DPP4 with a different mode of inhibition than vildagliptin. In addition, ASP4000 augmented the insulin response and ameliorated the glucose excursion during the oral glucose tolerance test in Zucker fatty rats at 4 h post dosing. ASP4000 is expected to be a promising, long duration DPP4 inhibitor for type 2 diabetes.
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PMID:ASP4000, a slow-binding dipeptidyl peptidase 4 inhibitor, has antihyperglycemic activity of long duration in Zucker fatty rats. 1923 12


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