Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A(1c) (HbA(1c)) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA(1c) reduction with DPP-IV inhibitors depends upon the pretreatment HbA(1c) values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.
 ...
PMID:Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug. 1730 May 91

Novel therapeutic strategies for type 2 diabetes are needed, since the current treatment options neither address all pathophysiological mechanisms nor achieve the glycemic target goals. A general islet-cell dysfunction including insulin- and glucagon-secretion defects contributes to the pathophysiology of type 2 diabetes. Improving islet function by incretin hormone action is a novel therapeutic approach. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are important incretin hormones contributing to 50-70% of the stimulation of insulin secretion after a meal. Dipeptidyl-peptidase IV (DPP-4) inhibitors inhibit the degradation of GLP-1 and GIP as well as that of other regulatory peptides. Sitagliptin, a DPP-4 inhibitor, is orally active and has been shown to be efficacious and safe in clinical studies. Sitagliptin has received approval in Mexico, the United States and other countries. Like other DPP-4 inhibitors, sitagliptin reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause a higher rate of hypoglycemia in comparison to metformin or placebo. This article gives an overview of the mechanisms of action, pharmacology and clinical trial results of sitagliptin.
 ...
PMID:Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. 1731 49

Sitagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, improves glycaemic control by inhibiting DPP-4 inactivation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This increases active incretin and insulin levels, and decreases glucagon levels and post-glucose-load glucose excursion. In large, well designed phase III trials in patients with type 2 diabetes mellitus, sitagliptin 100 or 200mg once daily alone or in combination with other antihyperglycaemics was associated with significant improvements relative to placebo in overall glycaemic control and indices for insulin response and beta-cell function. Improvements from baseline in mean glycosylated haemoglobin (HbA(1c)) were significantly greater with sitagliptin monotherapy than with placebo in patients with type 2 diabetes. As add-on therapy in patients with suboptimal glycaemic control despite oral antihyperglycaemic treatment, sitagliptin improved HbA(1c) to a significantly greater extent than placebo when added to metformin or pioglitazone and was noninferior to glipizide when added to metformin. Sitagliptin was well tolerated when administered alone or in combination with other antihyperglycaemics, with an adverse event profile similar to that shown with placebo. The incidence of hypoglycaemia with sitagliptin was similar to that with placebo and, in combination with metformin, lower than that with glipizide. Sitagliptin had a generally neutral effect on bodyweight.
 ...
PMID:Sitagliptin. 1735 16

Type 2 diabetes is a chronic metabolic disease characterized by the presence of both fasting and postprandial hyperglycemia which is a result of pancreas beta-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. More recently, the role of other glucoregulatory hormones, including glucagon, amylin, and the gut peptide glucagon-like peptide (GLP)-1, and an increase in the rate of postmeal carbohydrate absorption have also been included as important pathophysiologic defects. Existing anti-diabetes medications are often unefficient at achieving sustained glycemic control because they predominantly address only a single underlying defect. A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of 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 inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 diabetic patients. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion, peripheral insulin sensitization and important effects on beta-cell differentiation and survival can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetic patients. The present article focuses on the preclinical and clinical data of DPP-IV inhibitors that make it unique therapeutic agents representing the next generation of antidiabetes drugs.
 ...
PMID:Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes. 1735 76

The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an alpha-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective beta-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.
 ...
PMID:Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. 1735 77

This article describes how the discovery of a protein almost 100 years ago led to a clinical treatment for type 2 diabetes. Food intake, but also stimulation of the sympathetic nervous system (for example physical exercise), stimulates the secretion of glucagon-like-peptide-1 (GLP-1), derived from the glucagon precursor proglucagon in the small intestine. GLP-1 stimulates the production and secretion of insulin, the release of somatostatin, glucose utilisation by increasing insulin sensitivity and in animal studies also beta-cell function and expansion (proliferation). It inhibits glucagon release, gastric emptying, appetite and food intake via the central nervous system and in animal experiments also apoptosis of beta-cells. Since GLP-1 has to be administered parenterally and its half-life is short, a long-acting GLP-1 receptor agonist (exenatide) and a long-acting GLP-1 analogue (liraglutide) have been developed as well as an inhibitor of DPP-IV (the enzyme that breaks down endogenous GLP-1). Clinical studies with exenatide and liraglutide as monotherapy show a significant increase in the postprandial insulin concentration as well as a smaller increase in the postprandial glucose values. Adding these drugs to standard oral glucose-lowering medication shows improvement in glucose and insulin concentrations and HbA1c compared with adding placebo. The effect of exenatide on HbA1c is the same as adding a long-acting insulin analogue (glargine), but the increase in weight after adding insulin is not seen after exenatide, where even a small decrease in weight is found. This is an important advantage, because most type 2 patients are already obese. Whether less beta-cell apoptosis and maintenance of beta-cell function occurs, as has been shown in animal studies, has to be awaited. Clinical studies with the oral DPPIV inhibitors sitagliptin and vildagliptin show promising results, but are only published as abstracts at scientific meetings.
 ...
PMID:Incretins: a new treatment option for type 2 diabetes? 1737 30

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 micromol/mouse daily) to female mice with beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located alpha-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with beta-cell specific transgenic overexpression of human IAPP.
 ...
PMID:DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide. 1748 89

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase IV (DPP-IV) inhibitor. Since the target of both DPP-IV inhibitors and alpha-glucosidase inhibitors is the lowering of postprandial hyperglycemia, we compared antihyperglycemic effects for E3024 and alpha-glucosidase inhibitors in various oral carbohydrate and meal tolerance tests using normal mice. In addition, we investigated the combination effects of E3024 and voglibose on blood glucose levels in a meal tolerance test using mice fed a high-fat diet. ER-235516-15 (the trifluoroacetate salt form of E3024, 1 mg/kg) lowered glucose excursions consistently, regardless of the kind of carbohydrate loaded. However, the efficacy of acarbose (10 mg/kg) and of voglibose (0.1 mg/kg) varied with the type of carbohydrate administered. The combination of E3024 (3 mg/kg) and voglibose (0.3 mg/kg) improved glucose tolerance additively, with the highest plasma active glucagon-like peptide-1 levels. This study shows that compared to alpha-glucosidase inhibitors, DPP-IV inhibitors may have more consistent efficacy to reduce postprandial hyperglycemia, independent of the types of carbohydrate contained in a meal, and that the combination of a DPP-IV inhibitor and an alpha-glucosidase inhibitor is expected to be a promising option for lowering postprandial hyperglycemia.
 ...
PMID:Comparison of efficacies of a dipeptidyl peptidase IV inhibitor and alpha-glucosidase inhibitors in oral carbohydrate and meal tolerance tests and the effects of their combination in mice. 1748 17

Orally ingested glucose leads to a greater insulin response compared to intravenously administered glucose leading to identical postprandial plasma glucose excursions, a phenomenon referred to as the "incretin effect". The incretin effect comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. One of the very important gastrointestinal hormones promoting this effect is glucagon-like peptide 1 (GLP-1). It only stimulates insulin secretion and normalizes blood glucose in humans under hyperglycemic conditions, therefore it does not cause hypoglycemia. Other important physiological actions of GLP-1 are the inhibition of glucagon secretion and gastric emptying. It further acts as a neurotransmitter in the hypothalamus stimulating satiety. In vitro and animal data demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. In humans, the improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity after GLP-1 infusions. GLP-1 represents an attractive therapeutic principle for type 2 diabetes. However, native GLP-1 is degraded rapidly upon exogenous administration and is therefore not feasible for routine therapy. The first long-acting GLP-1 analog ("incretin mimetic") Exenatide (Byetta) has just been approved for type 2 diabetes therapy. Other compounds are being investigated in clinical trials (e.g. liraglutide, CJC1131). Dipeptidyl-peptidase IV inhibitors (DPP-IV inhibitors; e.g. Vildagliptin, Sitagliptin) that inhibit the enzyme responsible for incretin degradation are also under study.
 ...
PMID:New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins. 1749 80

Dipeptidyl peptidase IV is a serine protease with an indirect role in antihyperglycaemia via degradation of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide. Inhibition of the DPP-IV is thus a potential therapeutic strategy for type 2 diabetes. In this study, we have investigated upon selectivity of dipeptidyl peptidase IV compared to two other members of the S9b family, dipeptidyl peptidase 8 and 9, based on kinetic analyses of the pancreatic peptide hormones neuropeptide Y and peptide YY. We report a striking 250-fold preference for cleavage of neuropeptide Y compared to peptide YY observed for DPP-8/-9, but not for DPP-IV. This difference appears to be linked to differences in the S1' pocket within the active site, particularly via flexibility of the oxyanion stabilizing residue Y547. These aspects are discussed in relation to available protein structures of DPP-IV and data on DPP-IV selective inhibitors.
 ...
PMID:Selectivity among dipeptidyl peptidases of the S9b family. 1754 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>