Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is available that exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist acutely stimulates hypothalamo-pituitary-adrenal (HPA) axis in the rat. EX4 is a potent insulinotropic agent, which is currently under clinical trial for treatment of type 2 diabetes. Since diabetes is known to affect adrenal function, we investigated the effects of the prolonged administration of EX4 and/or the GLP-1R antagonist EX4(9-39) (EX4-A) (daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A, for 7 days) on the HPA axis of normoglycemic and streptozotocin (STZ)-induced diabetic rats. In STZ-untreated rats, chronic EX4 treatment did not change the blood level of ACTH. In contrast, it evoked a marked rise in the plasma concentrations of aldosterone and corticosterone, these effects being reversed by EX4-A. In STZ-induced diabetic rats, prolonged EX4 administration increased the plasma levels of ACTH, aldosterone and corticosterone. EX4-A did not prevent the first two effects of EX4, and annulled the latter one. These findings allow us to draw the following conclusions: i) EX4 prolonged exposure desensitizes hypothalamo-hypophyseal GLP-1R in normal rats, and exerts an ACTH-independent GLP-1R-mediated aldosterone and corticosterone secretagogue effect; and ii) experimental diabetes induces the expression of EX4 receptors other than the classic GLP-1R, whose activation mediate the ACTH and aldosterone, but not corticosterone, secretagogue effects. Our study provides evidence that metabolic dysregulations occurring in STZ-induced diabetic rats are able to profoundly affect the response of the HPA axis to GLP-1.
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PMID:Prolonged exendin-4 administration stimulates pituitary-adrenocortical axis of normal and streptozotocin-induced diabetic rats. 1296 40

The gut expresses peptide hormones in endocrine cells and neuropeptides in autonomic nerves. Several of these peptides have the ability to stimulate insulin secretion. Gut hormones that are released after meal ingestion and stimulate insulin secretion postprandially are called incretins. In humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the most important incretins. The potential use of these insulinotropic gut peptides for the treatment of diabetes has been considered. This has been most successful for GLP-1, which exerts antidiabetogenic properties in subjects with type 2 diabetes by stimulating insulin secretion, increasing beta-cell mass, inhibiting glucagon secretion, delaying gastric emptying, and inducing satiety. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV), making it unattractive as a therapeutic agent because of a very short half-life. Successful strategies to overcome this difficulty are the use of DPPIV-resistant GLP-1 receptor agonists, such as NN2211 or exendin-4, and the use of inhibitors of DPPIV, such as NVPDPP728 and P32/98. These two approaches are explored in clinical investigations.
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PMID:Gut peptides and type 2 diabetes mellitus treatment. 1297 25

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
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PMID:Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. 1452 86

Achieving normoglycemia is the goal of diabetes therapy. Potentially, there are many ways to achieve this goal, including transplantation of cells exhibiting glucose-responsive insulin secretion. However, to be applicable to the large number of people who might benefit from beta cell replacement, an unlimited supply of beta cells must be found. To address this problem, we have been developing cell lines from the human endocrine pancreas. In one case, a cell line, betalox5, has been developed from human islets that can be induced under some circumstances to differentiate into functional beta cells exhibiting appropriate glucose-responsive insulin secretion. Inducing differentiation is complex, requiring the activation of multiple signaling pathways, including those downstream of those involved in cell-cell contact and the glucagon-like peptide-1 receptor. In addition, transfer of the PDX-1 gene is also necessary to render the cells competent for differentiation. However, it is clear that many other genes are involved in maintaining the commitment of betalox5 cells towards the beta cell lineage. Understanding the complement of genes required to establish and maintain a beta cell lineage commitment would be enormously helpful in efforts to develop a cell line that can be used for beta cell replacement therapies. Here, we provide further information on the characteristics of cell lines that we have developed from the human pancreas that are relevant to the development of a beta cell replacement therapy for diabetes.
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PMID:Cell-based therapies for diabetes: progress towards a transplantable human beta cell line. 1467 48

Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic beta-cell. Although GLP-1 is established to be a cAMP-elevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). Two variants of Epac (Epac1 and Epac2) are expressed in beta-cells, and downregulation of Epac function diminishes stimulatory effects of GLP-1 on beta-cell Ca(2+) signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples beta-cell cAMP production to the stimulation of fast Ca(2+)-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca(2+) from intracellular Ca(2+) stores. This is a process of Ca(2+)-induced Ca(2+) release (CICR), and it generates an increase of [Ca(2+)](i) that may serve as a direct stimulus for mitochondrial ATP production and secretory granule exocytosis. This article summarizes new findings concerning GLP-1 receptor-mediated signal transduction and seeks to define the relative importance of Epac and PKA to beta-cell stimulus-secretion coupling.
Diabetes 2004 Jan
PMID:Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. 1469 91

Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like peptides secreted mainly by L cells in the small and large intestine in response to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on beta-cells and can increase islet neogenesis and beta-cell mass. It is not clear whether the transmission of information from the gut to islet beta-cells by messengers such as GLP-1 is different in individuals who develop autoimmune diabetes. In the present study the expression of bioactive GLP-1 protein in the gut and its receptor in the pancreas was examined in diabetes-prone BioBreeding (BBdp) rats in the period before overt diabetes and in age-matched control, non-diabetes-prone BB (BBc) rats. An N-terminal directed antibody specific for the bioactive forms of GLP-1 (GLP-1(7-37) and GLP-1(7-36amide)) was used to mea-sure GLP-1 by radioimmunoassay in proximal, median, and distal gut. Pancreas GLP-1R area fraction, GLP-1R gene expression, and insulin content were analyzed, as were plasma GLP-1, glucose, and insulin. The concentration of GLP-1 protein in the jejunum and ileum of BBdp rats was lower than in BBc rats. Although these animals maintained normal blood glucose, there was impaired pancreatic endocrine function, characterized by low baseline insulin concentration in plasma and pancreas. GLP-1R mRNA expression was threefold less in islets isolated from BBdp rats, and GLP-1R+ islet area fraction in pancreas sections was decreased. When injected iv with GLP-1, BBdp rats displayed lower second-phase insulin response (and insulin/glucose ratios) compared with BBc rats. Thus, young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum, reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1 than controls. The decrease in insulinogenic and islet beta-cell mass-promoting signal from GLP-1 in BBdp rats may contribute to impaired glucoregulation and ineffective maintenance of normal islet mass that shifts islet homeostasis in favor of development of diabetes.
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PMID:Bioactive GLP-1 in gut, receptor expression in pancreas, and insulin response to GLP-1 in diabetes-prone rats. 1503 99

Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.
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PMID:Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. 1504 56

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.
Diabetes 2004 May
PMID:Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. 1511 3

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of beta-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.
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PMID:Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. 1514 Jul 55

Glucagon-like peptide-1 (GLP-1) is a peptide hormone from the gut that stimulates insulin secretion and protects beta-cells, inhibits glucagon secretion and gastric emptying, and reduces appetite and food intake. In agreement with these actions, it has been shown to be highly effective in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation, therefore, appears very promising.
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PMID:Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. 1515 41


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