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)

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.
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PMID:Sitagliptin. 1735 16

There is a progressive deterioration in beta-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in beta-cell mass of about 60% was shown at necropsy. The reduction of beta-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of beta-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired beta-cell function and possibly beta-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased beta-cell mass has probably not been passed. Among the interventions to preserve or "rejuvenate" beta-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve beta-cell function, usually leading to a temporary remission time. Another intervention is the induction of beta-cell "rest" by selective activation of ATP-sensitive K+ (K(ATP)) channels, using drugs such as diazoxide. A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human beta-cell function. The TZDs improve insulin secretory capacity, decrease beta-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on beta-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor gamma activation in pancreatic islets, with TZDs consistently improving basal beta-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic beta-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on beta-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating beta-cell proliferation, induction of islet neogenesis, and inhibition of beta-cell apoptosis, thus promoting expansion of beta-cell mass, as observed in rodent diabetes and in cultured beta-cells. Exenatide and liraglutide enhanced postprandial beta-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted beta-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial beta-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on beta-cells in humans, and there is no clinical evidence that these drugs really have protective effects on beta-cells.
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PMID:beta-cell failure in diabetes and preservation by clinical treatment. 1735 95

Sitagliptin is a once-daily, orally active, competitive and fully reversible inhibitor of dipeptidyl peptidase 4, the enzyme that is responsible for the rapid degradation of the incretin hormone glucagon-like peptide-1. It is the first in this new class of antihyperglycaemic agents to gain regulatory approval for the treatment of Type 2 diabetes, both as a monotherapy and for use in combination with metformin or a thiazolidinedione. In clinical trials of < or = 1-year duration, sitagliptin improves glycaemic control by reducing both fasting and postprandial glucose concentrations, leading to clinically meaningful reductions in glycosylated haemoglobin levels. It is safe and well tolerated, with a side-effect profile that is similar to that of the placebo, a low incidence of hypoglycaemia and body weight neutrality. Further clinical experience with sitagliptin will reveal its long-term durability, safety and efficacy.
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PMID:Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes. 1737 Dec

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

The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.
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PMID:The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. 1740 88

Nardilysin is a metalloendopeptidase that in vitro cleaves peptides such as dynorphin-A, somatostatin-28, alpha-neoendorphin and glucagon at the N-terminus of arginine and lysine residues in dibasic moieties. The enzyme is highly expressed in many endocrine tissues. Nardilysin has also been found in the brain. Previously, we have detected that nardilysin interacts with brain-specific proteins, i.e. p42(IP4)/centaurin-alpha1 [Stricker R, Chow KM, Walther D, Hanck T, Hersh LB, Reiser G (2006) Interaction of the brain specific protein p42(IP4)/centaurin-alpha1 with the peptidase nardilysin is regulated by the cognate ligands of p42(IP4), PtdIns(3,4,5)P(3) and Ins(1,3,4,5)P(4), with stereospecificity. J Neurochem 98:343-354]. However, very little is known about the distribution of nardilysin in the brain. The aim of the present study was to reveal its regional distribution and cellular localization in developing and adult human brain. Using immunohistochemistry and Western blot analysis we demonstrate that the enzyme is widely, but unevenly, expressed in the human brain. We found high staining intensity in the hypothalamus, neocortex and brain stem nuclei. The cellular localization is almost exclusively confined to neurons. In pre- and perinatal human brain cortex, most neurons express the enzyme. In cortical neurons nardilysin protein was found to be partially co-localized with parvalbumin but not calretinin. No co-expression was seen with somatostatin-28 immunoreactivity. A considerable overlap was revealed between p42(IP4) and nardilysin. Our data support the hypothesis that nardilysin might possibly play a role in brain development, whereas its putative function in brain peptide metabolism remains to be clarified further.
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PMID:Histochemical evidence for wide expression of the metalloendopeptidase nardilysin in human brain neurons. 1744 99

This randomized, open-label, placebo-controlled, 7-period crossover study assessed dose-response relationships following single oral doses (10-400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase-4 activity, glucose, insulin, and glucagon were measured during 75-g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The t(max) for parent drug was observed between 0.5 and 1.5 hours postdose. Both C(max) and AUC(0-8 h) increased dose proportionately. Both onset and duration of dipeptidyl peptidase-4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for >/=4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed-meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.
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PMID:Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. 1744 88

Type 2 diabetes mellitus affects 9.6% of the adults in the United States and more than 200 million people worldwide. Diabetes can be a devastating disease, but it can now be treated with nine classes of approved drugs (insulins, sulfonylureas, glinides, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide 1 mimetics, amylin mimetics, and dipeptidyl peptidase 4 inhibitors), in addition to diet and exercise regimens. Choosing which drug to give a patient is based on efficacy and also availability, cost, safety, tolerability, and convenience. Personalized medicine promises a path for individually optimized treatment choices, but realizing this promise will require a more comprehensive characterization of disease and drug response. In this issue of the JCI, Shu et al. make significant progress by integrating diverse data supporting the hypothesis that genetic variation in organic cation transporter 1 (OCT1) affects the response to the widely used biguanide metformin (see the related article beginning on page 1422). We discuss metformin, OCT1, pharmacogenetics, and how the integrative genomics revolution is likely to change our understanding and treatment of diabetes.
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PMID:Pharmacogenetics of metformin response: a step in the path toward personalized medicine. 1747 61

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.
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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

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.
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PMID:Biology of incretins: GLP-1 and GIP. 1749 8


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