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

The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu8/Abu2 (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu8)GLP-1 was completely stable to human plasma (half-life >12 h), GLP-1, GIP, and (Abu2)GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu8)GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu2)GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu8)GLP-1 displayed substantial glucose-lowering and insulin-releasing activities, whereas (Abu2)GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala8/Ala2 substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu8)GLP-1 represents a potential candidate for future therapeutic development.
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PMID:Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid. 1524 69

Inhibitors of the enzyme dipeptidyl peptidase IV (DPP IV) are of increasing interest to both diabetologists and the pharmaceutical industry alike, as they may become established as the next member of the oral antidiabetic class of therapeutic agents, designed to lower blood glucose and, possibly, prevent the progressive impairment of glucose metabolism in patients with impaired glucose tolerance and Type 2 diabetes. DPP IV has become a focus of attention for drug design, as it has a pivotal role in the rapid degradation of at least two of the hormones released during food ingestion, a property that has warranted the design of inhibitor-based drugs. At the molecular level, DPP IV cleaves two amino acids from the N-terminus of the intact, biologically active forms of both so-called incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (formerly known as gastric inhibitory polypeptide), resulting in truncated metabolites, which are largely inactive. Inhibition of the enzyme, therefore, is thought to increase levels of the active forms of both incretin hormones, culminating in an increase in insulin release after a meal, in a fully glucose-dependent manner. DPP IV inhibitors combine several features of interest to the drug design process. They can be readily optimised for their target and be designed as low molecular weight, orally active entities compatible with once-daily administration.
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PMID:Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes? 1533 Jul 41

Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine to lower plasma glucose and reduce glycemic excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation of the peptide.
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PMID:Therapeutic strategies based on glucagon-like peptide 1. 1533 25

Public health efforts and current antiobesity agents have not controlled the increasing epidemic of obesity. Investigational antiobesity agents consist of 1) central nervous system agents that affect neurotransmitters or neural ion channels, including antidepressants (bupropion), selective serotonin 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, and cannabinoid-1 receptor antagonists (rimonabant); 2) leptin/insulin/central nervous system pathway agents, including leptin analogues, leptin transport and/or leptin receptor promoters, ciliary neurotrophic factor (Axokine), neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and cocaine and amphetamine regulated transcript promoters, alpha-melanocyte-stimulating hormone analogues, melanocortin-4 receptor agonists, and agents that affect insulin metabolism/activity, which include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated receptor-gamma receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin; 3) gastrointestinal-neural pathway agents, including those that increase cholecystokinin activity, increase glucagon-like peptide-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors), and increase protein YY3-36 activity and those that decrease ghrelin activity, as well as amylin analogues (pramlintide); 4) agents that may increase resting metabolic rate ("selective" beta-3 stimulators/agonist, uncoupling protein homologues, and thyroid receptor agonists); and 5) other more diverse agents, including melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone sulfate, antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity, corticotropin-releasing hormone agonists, inhibitors of fatty acid synthesis, carboxypeptidase inhibitors, indanones/indanols, aminosterols, and other gastrointestinal lipase inhibitors (ATL962). Finally, an emerging concept is that the development of antiobesity agents must not only reduce fat mass (adiposity) but must also correct fat dysfunction (adiposopathy).
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PMID:Current and investigational antiobesity agents and obesity therapeutic treatment targets. 1534 Jan

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.
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PMID:[Analogs of glucagon-like peptide-1 (GLP-1): an old concept as a new treatment of patients with diabetes mellitus type 2]. 1549 88

Proof-of-concept for the efficacy of a glucagon-like peptide 1 (GLP-1)-based therapy of patients with type 2 diabetes was provided in 2002 by means of prolonged continuous subcutaneous infusion of native GLP-1. Since then, several long-acting analogues of GLP-1, as well as inhibitors of dipeptidyl peptidase IV, the enzyme that rapidly inactivates endogenous GLP-1, have demonstrated efficacy in long term clinical trials.
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PMID:Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. 1552 49

K579 ((S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile), which is a long-acting and a slow binding dipeptidyl peptidase IV inhibitor, preserved the endogenously secreted active forms of glucagon-like peptide-1, augmented the insulin response and ameliorated the glucose excursion during oral glucose tolerance test in rats. In this study, we measured plasma concentrations of K579 after oral administration to rats. However, K579 was eliminated rapidly from plasma after oral administration to rats. Therefore, we postulated that there are active metabolites of K579 in rat plasma. We investigated the effect of K579 on plasma dipeptidyl peptidase IV activity using bile duct-cannulated rats. The duration of inhibitory action of plasma dipeptidyl peptidase IV after the administration of K579 in bile duct-cannulated rats was shorter than that in sham-operated rats. Moreover, we investigated the effect of bile obtained from K579-treated rat on plasma dipeptidyl peptidase IV activity in normal rats. The bile collected from K579-treated rats exhibited tardive and potent inhibitory activity of normal rat plasma. These results suggest that K579 sustained the duration of inhibitory action of plasma dipeptidyl peptidase IV by the character as a slow-binding inhibitor and, as well, by the presence of metabolites of K579, which exhibit the inhibitory activity of dipeptidyl peptidase IV.
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PMID:Involvement of the active metabolites in the inhibitory activity of K579 on rat plasma dipeptidyl peptidase IV. 1555 58

Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and beta-cell growth. Together with the related hormone glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and beta-cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies.
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PMID:The incretin approach for diabetes treatment: modulation of islet hormone release by GLP-1 agonism. 1556 11

Cyclic 3'5'AMP is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet beta-cell, where it is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). These hormones are secreted from the small intestine during and following a meal, and are important in producing a full insulin secretory response to nutrient stimuli. Cyclic AMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet beta-cell differentiation, growth and survival. Cyclic AMP (cAMP) itself is rapidly degraded in the pancreatic islet beta-cell by cyclic nucleotide phosphodiesterase (PDE) enzymes. This review discusses the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired. This could be achieved by the use of GLP-1 or GIP to elevate cAMP in the pancreatic islet beta-cell. However, these peptides are normally rapidly degraded by dipeptidyl peptidase IV (DPP IV). Thus longer-acting analogues of GLP-1 and GIP, resistant to enzymic degradation, and orally active inhibitors of DPP IV have also been developed, and these agents were found to improve metabolic control in experimentally diabetic animals and in patients with type 2 diabetes. The use of selective inhibitors of type 3 phosphodiesterase (PDE3B), which is probably the important pancreatic islet beta-cell PDE isoform, would require their targeting to the islet beta-cell, because inhibition of PDE3B in adipocytes and hepatocytes would induce insulin resistance.
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PMID:Targeting beta-cell cyclic 3'5' adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review. 1556 54

Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.
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PMID:Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents. 1557 61


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