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)

ASP4,000, (2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4,000 inhibited human recombinant DPP4 with an IC(50) value of 2.25 nM, and the enzyme-kinetic curve indicated that the inhibition type was competitive. In addition, ASP4,000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10(-9) M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4,000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4,000 at doses of 0.03-1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4,000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.
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PMID:ASP4,000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity. 1858 61

Sitagliptin (brand name Januvia) the first of a new class of oral agents, the DPP4 inhibitors, which lower blood glucose in type 2 diabetes has recently been launched in UK. Another DPP4 inhibitor vildagliptin is due to be launched soon, and there are several others in the pipeline. This article gives an overview of this new class of medications.
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PMID:New treatments for type 2 diabetes--the DPP4 inhibitors. 1863 49

This review tries to delineate how to insert the GLP-1 based agents, DPP4-inhibitors (sitagliptin and vildagliptin) and GLP-1 analogues (exenatide and liraglutide), in the guidelines and the daily practice for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors reduce HbA(1c) by 0.5-1.1%, without hypoglycaemic events and no weight gain. The subcutaneous injected GLP-1 analogues show larger reductions in HbA(1c) by 0.8-1.7% and a weight loss (1.75-3.8 kg) with most gastrointestinal common adverse events contributing to a significant treatment interruption. Regarding the efficacy, the cost and the safety of these drugs they will no challenge the use of metformin as the initial therapy of T2DM. In patients'not tolerating metformin or in older patients, DPP-4 inhibitors seem to be an excellent alternative monotherapy. Several studies argue in favour of the use of DPP-4 inhibitors in combination with metformin as a promising second line treatment. This combination offers advantages when compared to others currently used, particularly if one considers the more stringent guidelines with a higher risk of hypoglycaemic events in patient receiving sulfonylureas and mild hyperglycaemia or weight gain with thiazolidinedione (TZD). Oral triple therapy, metformin + TZD + incretin-based drug, has several theoretical advantages but is not supported by any published trial. Finally, obtaining the acceptance of injections once to twice daily vs. oral administration of OADs will probably remain difficult during the first years of treatment in many patients. Nevertheless a long-acting release exenatide formulation (i.e. once weekly), for subcutaneous injection in patients with type 2 diabetes under development shows promising preliminary results. If confirmed, the use of this new class of drugs should be largely developed from monotherapy to combinations (bitherapy or tritherapy), and even instead of insulin or in association with insulin. The long-term effect of GLP-1 based agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are required and will allow progressively determining the use of incretin-based agents in T2DM treatment strategy. Their efficacy, safety and their cost vs. older strategies, will be really evaluated by physicians in the real daily practice and by large and long term systematic surveys, as recently shown in other therapeutic fields.
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PMID:DPP-4 inhibitors and GLP-1 analogues: for whom? Which place for incretins in the management of type 2 diabetic patients? 1864 May 91

With vildagliptin and sitagliptin on the market for the treatment of type 2 diabetes, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5) research has entered a new era. Scientists aim to uncover the broader pharmacological profile of DPP4 inhibitors and search for therapeutic opportunities outside diabetes. During the pre-clinical and clinical evaluation of vildagliptin and sitagliptin, there has been a growing awareness of the presence of other DPP4-like peptidases in various cells and tissues. This fuelled the development of more inhibitors with defined selectivity for DPP2, 8 and 9 that were used to investigate the expression, distribution and regulation of these peptidases. In turn, these studies increased the insights in the role of DPP4 in the body's response to various insults.
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PMID:DPP4 inhibitors for diabetes--what next? 1875 55

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

This review article focuses on the therapeutic potential of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in treating type 2 diabetes mellitus (T2DM). T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for T2DM are often unsatisfactory at getting patients to glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. Therefore, the actions of GLP-1 and GIP, which include potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new drug classes based on the actions of the incretin hormones have recently been approved for therapy of T2DM; injectable long-acting stable analogues of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation of GLP-1 and GIP), the so-called incretin enhancers. This review article focuses on these two new classes of antidiabetic agents and will outline the scientific basis for the development of incretin mimetics and incretin enhancers, review clinical experience gathered so far and discuss future expectations for incretin-based therapy.
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PMID:Incretin-based therapy of type 2 diabetes mellitus. 1927 72

Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research.
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PMID:Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme. 1968 75

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, gastric inhibitory peptide) are secreted from intestinal L and K cells and stimulate insulin secretion from pancreatic beta cells. However, they are immediately inactivated mainly via N-terminal degradation by dipeptidyl peptidase IV (DPP IV, CD26), a specialised enzyme located on the cell surface enzyme of endothelial, epithelial and some other cell types. Cleavage by neprilysin (neutral endopeptidase) is a minor degradation route, and renal clearance eliminates incretin/fragments, but appears of less importance for regulating incretin bioactivities. Based on these observations two novel types of drugs for the treatment of type 2 diabetes have been developed: DPP IV inhibitors and DPP IV-resistant incretin analogues. Both have distinct advantages and disadvantages. Potential side effects of DPP IV inhibitors may result from affecting the bioactivity of other hormones, neuropeptides or chemokines and also by their cross-reactivity with DPP IV-related enzymes.
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PMID:Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP. 1974 62

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.
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PMID:Neurogenin 3-specific dipeptidyl peptidase-2 deficiency causes impaired glucose tolerance, insulin resistance, and visceral obesity. 1981 73


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