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)

(1) Liraglutide is a long-acting GLP-1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and beta-cell mass in rat models of beta-cell deficiencies, studies were performed in male Zucker diabetic fatty (ZDF) rats and in 60% pancreatectomized rats. (2) When liraglutide was dosed s.c. at 150 microg kg-1 b.i.d. for 6 weeks in ZDF rats 6-8 weeks of age at study start, diabetes development was markedly attenuated. Blood glucose was approximately 12 mm lower compared to vehicle (P<0.0002), and plasma insulin was 2-3-fold higher during a normal 24-h feeding period (P<0.001). Judged by pair feeding, approximately 53% of the antihyperglycemic effect observed on 24-h glucose profiles was mediated by a reduction in food intake, which persisted throughout the study and averaged 16% (P<0.02). (3) Histological analyses revealed that beta-cell mass and proliferation were significantly lower in prediabetic animals still normoglycemic after 2 weeks treatment compared to vehicle-treated animals that had begun to develop diabetes. When the treatment period was 6 weeks, the liraglutide-treated animals were no longer completely normoglycemic and the beta-cell mass was significantly increased compared to overtly diabetic vehicle-treated animals, while beta-cell proliferation was unaffected. (4) In the experiments with 60% pancreatectomized rats, 8 days treatment with liraglutide resulted in a significantly lower glucose excursion in response to oral glucose compared to vehicle treatment. Again, part of the antihyperglycemic effect was due to reduced food intake. No effect of liraglutide on beta-cell mass was observed in these virtually normoglycemic animals. (5) In conclusion, treatment with liraglutide has marked antihyperglycemic effects in rodent models of beta-cell deficiencies, and the in vivo effect of liraglutide on beta-cell mass may in part depend on the metabolic state of the animals.
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PMID:GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. 1296 42

Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-(3)H-glucose infusion and (2)H(2)O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first- and second-phase insulin response during a hyperglycemic clamp (plasma glucose approximately 16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 micro g/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P = 0.01) and glucagon (P = 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P = 0.04) as a result of a reduced glycogenolysis (P = 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P = 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P = 0.01). Thus, 1 week's treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This study further emphasizes GLP-1 and its derivatives as a promising novel concept for treatment of type 2 diabetes.
Diabetes 2004 May
PMID:One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. 1511 85

The "incretin effect" describes the enhanced insulin response from orally ingested glucose compared with intravenous glucose leading to identical postprandial plasma glucose excursions. It makes up to 60% of the postprandial insulin secretion but is diminished in type 2 diabetes. Gastrointestinal hormones promoting the incretin effect are called incretins. Glucagon-like peptide- 1 (GLP-1) is an important incretin. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1 or incretin mimetics that act like GLP-1. Furthermore, GLP-1 inhibits glucagon secretion and rarely causes hypoglycemia. It may represent an attractive therapeutic method for type 2 diabetes because of its multiple effects, including a slowing of gastric emptying and the simulation of satiety by acting as a transmitter in the CNS. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasable for routine therapy. Long-acting GLP-1 analogs (e.g., Liraglutide [Novo Nordisk, Copenhagen, Denmark]) and exenadin-4 (Exenatide [Eli Lilly, Indianapolis, IN]) that are resistant to degradation, called "incretin mimetics," are being investigated in clinical trials. Dipeptidyl peptidase IV inhibitors (e.g., Vildagliptin [Novartis, Basel, Switzerland]) that inhibit the enzyme responsible for incretin degradation are also under study.
Diabetes Technol Ther 2005 Aug
PMID:Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. 1612 42

Orally ingested glucose leads to a much higher insulin response than intravenous glucose leading to identical postprandial plasma glucose excursions. This phenomenon, termed ''incretin effect'' comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. The gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) promote the incretin effect. Type 2 diabetes is characterized by an incretin defect: while GIP does not stimulate insulin secretion, GLP-1 action is still preserved under supraphysiological concentrations. GLP-1 stimulates insulin secretion only under hyperglycaemic conditions, therefore it does not cause hypoglycaemia. Furthermore, GLP-1 inhibits glucagon secretion and delays gastric emptying. In vitro and animal data demonstrated that GLP-1 increases beta cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1. In contrast to GIP, GLP-1 may represent an attractive therapeutic method for type 2 diabetes due to its multiple effects also including the simulation of satiety in the central nervous system by acting as transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. Liraglutide) and exendin-4 (Exenatide, Byetta) that are resistant to degradation, called ''incretin mimetics'' are approved (Exenatide, Byetta) or in clinical trials. DPP-4-inhibitors (e.g. Vildagliptin), Sitagliptin and Saxagliptin) that inhibit the enzyme DPP-4 responsible for incretin degradation are also under study.
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PMID:Therapies for the treatment of type 2 diabetes mellitus based on incretin action. 1668 37

Metabolic effects of the glucagon-like peptide-1 analog liraglutide and the dipeptidyl peptidase-IV inhibitor vildagliptin were compared in rats made obese by supplementary candy feeding. Female Sprague-Dawley rats were randomized to 12-week diets of chow or chow plus candy. The latter were randomized for 12 further weeks to continue their diet while receiving 0.2 mg/kg liraglutide twice daily subcutaneously, 10 mg/kg vildagliptin twice daily orally, or vehicle or to revert to chow-only diet. Energy expenditure was measured, and oral glucose tolerance tests (OGTTs) were performed. Body composition was determined by dual-energy X-ray absorptiometry scanning, and pancreatic beta-cell mass was determined by histology. Candy feeding increased weight, fat mass, and feeding-associated energy expenditure. Liraglutide or reversal to chow diet fully reversed weight and fat gains. Liraglutide was associated with decreased calorie intake and shifted food preference (increased chow/decreased candy consumption). Despite weight loss, liraglutide-treated rats did not decrease energy expenditure compared with candy-fed controls. Vildagliptin affected neither weight, food intake, nor energy expenditure. OGTTs, histology, and blood analyses indirectly suggested that both drugs increased insulin sensitivity. Liraglutide and vildagliptin inhibited obesity-associated increases in beta-cell mass. This was associated with weight and fat mass normalization with liraglutide, but not vildagliptin, where the ratio of beta-cell to body mass was low.
Diabetes 2007 Jan
PMID:Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. 1719 59

Liraglutide is a novel glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence identity to native GLP-1. An amino acid substitution and fatty acid side chain enable a more protracted pharmacokinetic profile of over 24 hours. These modifications make liraglutide suitable for once-daily dosing. Liraglutide use exploits the incretin effect to glucose-dependently stimulate insulin secretion. The LEAD (Liraglutide Effect and Action Diabetes) program evaluated the safety and efficacy of liraglutide and demonstrated an improved level of glycemic control relative to currently used oral antidiabetic drugs, including other GLP-1-based therapies. In these trials, liraglutide was shown to enable many patients to achieve hemoglobin A1c (HbA1c) targets and to improve several morbidities commonly associated with type 2 diabetes; liraglutide induced weight loss, reduced systolic blood pressure and improved beta-cell function. Liraglutide was well tolerated, although an increased incidence of mild nausea was observed. Since liraglutide mimics the glucose-sensitive action of native GLP-1, it does not induce hypoglycemia. Liraglutide offers an interesting alternative therapy to control blood glucose levels in patients with type 2 diabetes, who commonly present with hypertension and overweight. It is expected to be approved by the U.S. Food and Drug Administration and the European Medicines Agency in Europe for use in 2009.
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PMID:Liraglutide: a new treatment for type 2 diabetes. 1934 30

Standard therapies for type 2 diabetes often fail to maintain glycemic control over the long term, in part because they do not target the underlying cause. Current treatments may also be associated with weight gain, hypoglycemia, and other adverse effects, and can be difficult to use. Disease progression is accompanied by a progressive decline in beta-cell function, which begins early in the disease course, and an impaired incretin response. The recently developed glucagon-like peptide-1 (GLP-1) receptor agonists overcome some of the limitations of conventional treatments. This article summarizes the key results of the new GLP-1 receptor agonist (liraglutide) phase 3 Liraglutide Effect and Action in Diabetes (LEAD) studies. This series of 6 randomized controlled studies involved > 4400 patients with type 2 diabetes who were unable to maintain glycemic control with diet and exercise alone or with oral treatment, approximately 2700 of whom received liraglutide. The studies demonstrated the efficacy and safety of liraglutide both as monotherapy and as combination therapy with 1 or 2 oral agents. In addition to providing robust glycemic control in these studies, liraglutide reduced weight in most patients, improved beta-cell function, lowered blood pressure and triglycerides, and was well tolerated with minimal risk of hypoglycemia.
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PMID:Insights from the Liraglutide Clinical Development Program--the Liraglutide Effect and Action in Diabetes (LEAD) studies. 1949 36

Recently, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorization for liraglutide for the treatment of type 2 diabetes mellitus. Liraglutide is the first human glucagon-like peptide-1 (GLP-1) analog, based on the structure of native GLP-1, with pharmacokinetic properties suitable for once-daily dosing. In the phase III Liraglutide Effect and Action in Diabetes (LEAD) program, liraglutide has been shown to lower glycated hemoglobin to the same extent or more than other antidiabetic drugs including insulin. Liraglutide determines favorable changes in the global cardiovascular risk profile because its use is associated with weight loss, blood pressure reduction, as well as improvements of several cardiovascular risk biomarkers. Liraglutide is generally well tolerated, the most frequently reported adverse effect is transient nausea, and it does not seems to have significant interactions with medications commonly used for cardiovascular prevention. This article reviews, for the practicing cardiologist, the results of the LEAD program and explores liraglutide potentials for cardiovascular prevention in type 2 diabetes mellitus.
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PMID:[Drug therapy of type 2 diabetes and cardiovascular prevention: potentials for liraglutide]. 1976 Nov 1

Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based therapies have now been developed: DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide and exenatide are examples of GLP-1 receptor agonists that have been developed to mimic the insulinotropic characteristics of endogenous GLP-1. Both have demonstrated improved beta-cell function in patients with type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that both liraglutide and exenatide treatment can increase beta-cell mass, stimulate beta-cell proliferation, increase beta-cell neogenesis and inhibit beta-cell apoptosis. Clinical studies are needed to confirm these findings in humans. Replication of these data in humans could have important clinical implications for the treatment of type 2 diabetes.
Diabetes Obes Metab 2009 Dec
PMID:The effects of glucagon-like peptide-1 on the beta cell. 1987 57

Liraglutide is a new glucagon-like peptide-1 (GLP-1) receptor agonist and a true GLP-1 analogue. After successful phase 2 studies, liraglutide was assessed in a series of phase 3 trials [(Liraglutide Effect and Action in Diabetes (LEAD)] designed to demonstrate efficacy and safety across the continuum of type 2 diabetes antihyperglycaemic care, both as monotherapy and in combination with commonly used oral antidiabetic drugs (OADs). The LEAD programme also compared liraglutide with other OADs. As a monotherapy, liraglutide demonstrated significant improvements in glycaemic control in comparison with glimepiride. When combined with one or two OADs, reductions in haemoglobin A1c, fasting plasma glucose and postprandial glucose were generally greater with liraglutide than with comparators. Throughout the trials, liraglutide was associated with weight reduction; in most instances, the reduction from baseline was significantly greater than that seen with comparators. Improvements in assessments of beta-cell function were consistently shown with liraglutide treatment across all trials. Furthermore, reductions in systolic blood pressure were reported. Liraglutide was associated with a low risk of hypoglycaemia and was generally well tolerated. The majority of adverse effects were gastrointestinal, the most frequent of which was nausea.
Diabetes Obes Metab 2009 Dec
PMID:The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1-5 studies. 1987 59


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