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)

Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
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PMID:Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review. 1576 27

Glucagon-like peptide 1 (GLP-1) was discovered as an insulinotropic gut hormone, suggesting a physiological role as an incretin hormone, i.e., being responsible, in part, for the higher insulin secretory response after oral as compared to intravenous glucose administration. This difference, the incretin effect, is partially lost in patients with Type 2 diabetes. The actions of GLP-1 include (a) a stimulation of insulin secretion in a glucose-dependent manner, (b) a suppression of glucagon, (c) a reduction in appetite and food intake, (d) a deceleration of gastric emptying, (e) a stimulation of beta-cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) an in vitro inhibition of beta-cell apoptosis induced by different toxins. Intravenous GLP-1 can normalize and subcutaneous GLP-1 can significantly lower plasma glucose in the majority of patients with Type 2 diabetes. GLP-1 itself, however, is inactivated rapidly in vivo and thus does not appear to be useful as a therapeutic agent in the long-term treatment of Type 2 diabetes. Other agents acting on GLP-1 receptors have been found (like exendin-4) or developed as GLP-1 derivatives (like liraglutide or GLP-1/CJC-1131). Clinical trials with exenatide (two injections per day) and liraglutide (one injection per day) have shown reductions in glucose concentrations and HbA1c by more than 1%, associated with moderate weight loss (2-3 kg), but also some nausea and, rarely, vomiting. It is hoped that this new class of drugs interacting with the GLP-1 or other incretin receptors, the so-called "incretin mimetics", will broaden our armamentarium of antidiabetic medications in the nearest future.
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PMID:Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. 1578 Apr 33

Alcoholic ketoacidosis is an often overlooked disorder, which affects chronic ethanol abusers who have usually had a binge culminating in severe vomiting with resulting hypovolemia, acute starvation and then a beta-hydroxybutyrate dominated ketoacidosis (due to the conjonction of enhanced Glucagon/Insuline and NADH/NAD ratios). Although the pathophysiology is complex, the syndrome is quickly reversible with the administration of saline and glucose solutions along with the correction of electrolyte disturbances, often unmasked during the treatment. Insuline and bicarbonates are not indicated. The prognosis, which is excellent, depends mainly on the coexisting acute disorders, which should be purchased and treated appropriately.
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PMID:[Alcoholic ketoacidosis: not rare cause of metabolic acidosis]. 1623 32

In 2003, U.S. poison control centers were consulted after 9650 ingestions of calcium channel blockers (CCBs), including 57 deaths. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System database that were associated with cardiovascular drugs and emphasizes the importance of developing a guideline for the out-of-hospital management of calcium channel blocker poisoning. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of calcium channel blockers alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. The panel's recommendations follow. The grade of recommendation is in parentheses. 1) All patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately regardless of the amount ingested (Grade D). 2) Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D). 3) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see Table 5), would warrant consideration of referral to an emergency department (Grade D). 4) Do not induce emesis (Grade D). 5) Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D). 6) For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D). 7) Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).
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PMID:Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. 1644 May 9

Recognizing that type 1 diabetes was characterized not only by insulin deficiency, but also by amylin deficiency, Cooper (Cooper, 1991) predicted that certain features of the disease could be related thereto, and he proposed amylin/insulin co-replacement therapy. Although the early physiological rationale was flawed, the idea that glucose control could be improved over that attainable with insulin alone without invoking the ravages of worsening insulin-induced hypoglycemia was vindicated. The proposal spawned a first-in-class drug development program that ultimately led to marketing approval by the U.S. Food and Drug Administration of the amylinomimetic pramlintide acetate in March 2005. The prescribers' package insert (Amylin Pharmaceuticals Inc., 2005), which includes a synopsis of safety and efficacy of pramlintide, is included as Appendix 1. Pramlintide exhibited a terminal t1/2, in humans of 25-49 min and, like amylin, was cleared mainly by the kidney. The dose-limiting side effect was nausea and, at some doses, vomiting. These side effects usually subsided within the first days to weeks of administration. The principal risk of pramlintide co-therapy was an increased probability of insulin-induced hypoglycemia, especially at the initiation of therapy. This risk could be mitigated by pre-emptive reduction in insulin dose. Pramlintide dosed at 30-60 microg three to four times daily in patients with type 1 diabetes, and at doses of 120 microg twice daily in patients with type 2 diabetes, invoked a glycemic improvement, typically a decrease in HbA1c of 0.4-0.5% relative to placebo, that was sustained for at least 1 year. This change relative to control subjects treated with insulin alone typically was associated with a reduction in body weight and insulin use, and was not associated with an increase in rate of severe hypoglycemia other than at the initiation of therapy. Effects observed in animals, such as slowing of gastric emptying, inhibition of nutrient-stimulated glucagon secretion, and inhibition of food intake, generally have been replicated in humans. A notable exception appears to be induction of muscle glycogenolysis and increase in plasma lactate.
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PMID:Clinical studies. 1649 55

Liraglutide is a once-daily glucagon-like peptide-1 analogue being developed for the treatment of type 2 diabetes. The aim of this study was to investigate the effect of age and gender on the pharmacokinetics of liraglutide. Eight male and 8 female subjects were recruited from an 18- to 45-year-old group and an over-65-year-old group, respectively. All subjects received a single subcutaneous dose of 1.0 mg liraglutide. The area under the liraglutide plasma concentration curve from time 0 to last quantifiable concentration adjusted for body weight (significant covariate; P = .001) was found to be equivalent in young and elderly subjects (primary end point), with an estimated ratio of 0.94 (90% confidence interval, 0.84-1.06; P = .39). No significant impact of gender was observed (P = .38; estimated ratio, 1.08; 90% confidence interval, 0.93-1.26). Adverse events were of mild or moderate severity. The most frequently reported events were headache, vomiting, and nausea. When adjusted for body weight, no effect of gender or age was found on the pharmacokinetics of liraglutide.
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PMID:An open-label, parallel group study investigating the effects of age and gender on the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide. 1670 10

Maintaining glycemic control is the primary goal for preventing macrovascular and microvascular complications associated with type 2 diabetes. Currently available antidiabetic drugs work in different ways to lower blood glucose levels; unfortunately, each of them has its tolerability and safety concerns. Exenatide is the first drug in a new class known as the incretin mimetic agents. It improves glucose control by mimicking the effects of glucagon-like peptide-1, a natural mammalian incretin hormone secreted during food intake. Exenatide was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in conjunction with metformin and/or sulfonylurea. The recommended dosage is 5 mug to 10 mug twice daily subcutaneously before breakfast and dinner. In randomized, placebo-controlled, 30-week clinical studies, exenatide improved glycemic control and promoted weight loss of up to 2.8 kg. The most common adverse effects were nausea (44%), vomiting (13%), diarrhea (13%), and hypoglycemia (5-36%). Hypoglycemia occurred in a dose-dependent fashion. Patients should be closely monitored for hypoglycemia, especially when exenatide is added to sulfonylurea therapy. Overall, exenatide provides a treatment option for patients with type 2 diabetes who fail to obtain glycemic control while on a maximum dose of metformin and/or sulfonylurea therapy. It is also an alternative therapy for those patients who cannot tolerate other antidiabetic drugs.
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PMID:Exenatide: a novel incretin mimetic agent for treating type 2 diabetes mellitus. 1678 34

We report a rare case of symptomatic hypoglycemia in a patient with intra-abdominal recurrence of a previously resected gastrointestinal stromal tumor (GIST). The patient is a 65-year-old woman who underwent resection of a large abdominal mass arising from the stomach, histologically diagnosed as a high-grade leiomyosarcoma. She was lost to follow up. Five years later, the mass recurred; core biopsy demonstrated a CD 117-positive, spindle-cell tumor, consistent with a GIST. She was placed on Gleevec, as there was evidence of multifocal disease, but imaging revealed only mild improvement. Subsequently, her clinical status deteriorated, and she was hospitalized for dehydration, vomiting, and mental status changes. Her blood glucose on admission was 22 mg/dL, and a dextrose infusion (50%) was necessary to maintain adequate blood glucose levels. Measurements of insulin, proinsulin, c-peptide, beta-hydroxybutyrate, and thyroid-stimulating hormone were normal, as were cosyntropin stimulation and glucagon response tests. Suspicions arose for tumor-secreted insulin-like factor. She underwent resection of the dominant 44-cm recurrence, with immediate rebound hyperglycemia, followed by complete normalization of her blood glucose levels. She was discharged on postoperative Day 5 without symptoms or insulin, and is alive with disease at 20 months. Paraneoplastic syndromes occur in only 15 per cent of patients with known malignancies (e.g., lung cancer and metastatic carcinoid), and are rarely reported in the setting of GIST. Hypoglycemia is most often observed in presence of insulinoma and only isolated case reports in GIST patients exist. Overexpression of insulin-like growth factor II is thought to be the mechanism of action. Supportive management and palliative resection or debulking is recommended when possible.
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PMID:Hypoglycemia in the setting of advanced gastrointestinal stromal tumor. 1721 25

Exenatide is the first drug in the incretin mimetic class and is indicated for treatment of type 2 diabetes mellitus. Although structurally similar to the native glucagon-like peptide, this synthetic form has a much longer duration of action. Randomized trials have shown exenatide to be efficacious in improving glycemic control when combined with either metformin or a sulfonylurea. The dose is initially 5 mcg subcutaneously twice daily and may be titrated to 10 mcg subcutaneously twice daily to achieve better diabetes management. Nausea, vomiting, and diarrhea were the most common adverse events reported with exenatide therapy. Exenatide is not associated with hypoglycemia, which may provide advantages over adding insulin to a sulfonylurea or metformin.
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PMID:Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. 1725 50

This article describes a newly recognized highly malignant neoplastic entity in young bearded dragons (Pogona vitticeps), gastric neuroendocrine carcinomas, which readily metastasize. Ten bearded dragons with histories of anorexia (8), vomiting (3), hyperglycemia (2), and anemia (3) were included in this study. All animals had neoplastic masses in their stomach, with metastasis to the liver. Microscopically, 6 of these neuroendocrine carcinomas were well-differentiated and 4 were poorly differentiated. For further characterization, immunohistochemistry for protein gene product 9.5, neuron-specific enolase, endorphin, chromogranins A and B, synaptophysin, somatostatin, insulin, glucagon, gastrin, pancreatic polypeptide, and vasoactive intestinal peptide was performed on 5 animals. Because only immunolabeling for somatostatin was consistently observed in all neoplasms, a diagnosis of somatostatinoma was made for these 5 bearded dragons. Some neoplasms also exhibited multihormonal expression. Electron microscopy performed on 1 tumor confirmed the presence of neuroendocrine granules within neoplastic cells. Gastric neuroendocrine carcinomas, and specifically somatostatinomas, have not been previously reported in bearded dragons, or other reptiles, and may be underdiagnosed due to inconsistent, ambiguous clinical signs. In humans, pancreatic somatostatinomas are associated with a syndrome of hypersomatostatinemia, which includes hyperglycemia, weight loss, and anemia, as observed in some of these bearded dragons. Somatostatinomas in humans are commonly associated with neurofibromatosis type 1 (Von Recklinghausen's disease), caused by a mutation in the tumor suppressor gene NF1, which results in decreased expression of neurofibromin. In all 5 animals examined, neoplasms exhibited decreased neurofibromin expression compared with control tissues, suggesting that decreased functional neurofibromin may play a role in the pathogenesis of somatostatinomas in bearded dragons.
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PMID:Gastric neuroendocrine carcinomas in bearded dragons (Pogona vitticeps). 1960 3


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