Liraglutide a review of its use in the management of type 2 diabetes mellitus,how to relieve leg pain at night youtube,diabetes hindi free download,type 1 diabetes and insulin resistance symptoms - PDF Books


14.Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, et al Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. 29.Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide: A review of its therapeutic use as a once daily GLP-1 analog for the management of type 2 diabetes mellitus.
Despite the proliferation of newer novel treatment options, majority of people with T2DM do not achieve the glycemic goals and are at risk for serious diabetic complications. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Insulinotropin: glucagon-like peptide (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells.
Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1 (7-37). Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system.
Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy.
Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.
Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 study.
Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Liraglutide versus insulin glargine in combination with metformin and sulfonylurea therapy in type 2 diabetes: A randomized controlled trial (LEAD-5 met+SU). A study of two glucagonlike peptide-1 receptor agonists for the treatment of type 2 diabetes: liraglutide once daily compared with exenatide twice daily in a randomised, 26-week, open-label trial (LEAD-6). Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men.
The potential beneficial role of glucagon-like peptide-1 in endothelial dysfunction and heart failure associated with insulin resistance.
Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure.
Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Redictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules.
Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy. Effectivenes and tolerability of once daily GLP analogue-1 liraglutide in patients with type 2 diabetes in a real life clinical practice setting. Recent advances in diabetes research have revealed the important role of incretin hormones in maintaining glucose control. Fasting but not fed motility inhibited via nitric oxide independently of insulin and somatostatin. Studies have shown that incretin pathways play a role in the progression of T2DM.[1],[2] The significant reduction in the incretin effect seen in patients with T2DM has been attributed to several factors, including impaired secretion of glucagon-like peptide-1 (GLP-1), accelerated metabolism of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and defective responsiveness to both the hormones.
With the development of radioimmunoassay, this communication between the intestine and the endocrine pancreas was confirmed, when it was demonstrated that glucose ingestion is associated with a much greater increase in plasma insulin levels when compared to the insulin release after intravenous glucose administration. Thus, incretins are hormones secreted from the gastrointestinal tract into circulation in response to nutrient ingestion and enhance glucose-stimulated insulin secretion.GLP-1 contributes to the maintenance of circulating glucose levels also through its actions in the gastrointestinal tract, by inhibiting gastric emptying [7] and small bowel motility in a fed, but not fasting state. It is a potent stimulator of insulin release in pancreas [11],[12],[13],[14] and has the ability to render pancreatic β-cells glucose-competent[15] and has been used in the therapy of T2DM. In addition to its physiological effects on β-cells, GLP-1 has cytokine activity, although it is not classified as such due its small size. GLP-1 enhances cell differentiation, plays a role in tissue regeneration, and mediates cytoprotection.[9],[10] GLP-1 directly regulates signaling pathways coupled to cell proliferation and apoptosis. The first consists of the development of GLP-1 analogs, also called incretin mimetics that bind to the GLP-1 receptors with the same affinity as GLP-1 but resist the degradation by DPP-4.
The latter agents prolong the effects of native GLP-1 and increase their serum levels approximately two-fold. Unlike GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in human suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption, binding to albumin and stability toward the DPP-4 enzyme both resulting in a prolonged plasma half-life.
The analog is produced as the polypeptide precursor by r-DNA technology with Saccharomyces cerevisiae strain YES2085 as the production strain.
Liraglutide is a GLP-1 analog in which lysine at position 34 has been replaced with arginine, and palmitic acid has been attached via glutamoyl spacer to lysine at position 26. The apparent reduced potency of liraglutide underlines that only the free fraction of liraglutide is responsible for its pharmacological effect in vitro as well as in vivo.
Furthermore, liraglutide in a pharmaceutical solution forms a micell-like heptamer which may contribute to the slow absorption from the subcutis. Liraglutide is a potent, selective and efficacious agonist on the human as well as mouse, rat, rabbit, pig and Cynomolgus monkey GLP-1 receptor. Liraglutide has been shown to exert a number of actions in vitro that are known to be specific GLP-1 effects. Liraglutide has also been shown stimulate insulin secretion from isolated β-cell islets in a glucose-dependent manner in vitro.
Liraglutide-attenuated β-cell apoptosis in vitro under adverse conditions with high concentrations of free fatty acids and proinflammatory cytokines. The implementation of liraglutide therapy throughout the continuum of care is shown in [Figure 2]. A total of 4,456 subjects were included, recruited at more than 600 sites across 40 countries, of which 2,739 patients were treated with liraglutide.
LEAD trial was designed to investigate the efficacy and safety of patients treated with liraglutide across the continuum of care of T2DM versus placebo. In the LEAD trials, liraglutide was also compared to some commonly used antidiabetic therapies.
In addition to the registration studies (LEAD-1 to LEAD-5), [27],[28],[29],[30],[31] a head-to-head trial against exenatide (LEAD-6) [32] was also completed. The LEAD program established that liraglutide, used as monotherapy or in combination with one or two OADs, provides substantial reductions in HbA1c. In the liraglutide group there was less nausea and hypoglycemia caused by low blood sugar was less frequent, than with exenatide. Liraglutide was also shown to be effective at reducing postprandial glucose (PPG); consistent reductions were observed in peak PPG (across all three meals) in the LEAD-1-5 studies). However, exenatide is given twice daily, before morning and evening meals, thus PPG was reduced more with exenatide versus liraglutide during these peak times. An improvement of 62-71% in HOMA-B were reported from baseline values of 40-47% with all liraglutide treatment groups in combination with metformin. For instance, when liraglutide was added to metformin, HOMA-B increased to the same extent as with glimepiride (68%) and significantly greater than that with placebo which demonstrated no change from baseline. In liraglutide monotherapy weight loss occurred mostly in the initial 16 weeks; however, it was subsequently continued throughout the 52 weeks of the study. Weight loss with liraglutide has a tendency to be dose dependent both in monotherapy and in combination regimens. LEAD 2 trial subgroup of 160 patients with T2DM demonstrated that the greater part of weight loss reported was fat tissue and it was mostly due to visceral adipose tissue loss as demonstrated by dual energy X-ray absorptiometry and computed tomography.
In particular, continuous infusion of liraglutide is associated with an improvement in left ventricular function in patients with acute myocardial infarction and severe systolic dysfunction [38] and in patients with congestive heart failure. It ranged from 3 to 12%, in monotherapy or combination therapy trials and was mild to moderate, with no major episodes. Nausea, which occurred in 5 to 40% of liraglutide-treated patients, subsided within the first 4 weeks of use. Rat thyroid contains more C-cells and also expresses more GLP receptor, hence they are more prone, primates have less and human have even lesser hence risk is minimal. Furthermore, data from a long-term study did not reveal any notable difference in mean calcitonin levels between liraglutide and control groups over 2 years of follow-up.
A causal relationship between liraglutide and pancreatitis can neither be established nor excluded. In addition there was more than 50% reduction in average daily dose of insulin and close to one third of the patients were completely weaned off insulin.
Although the trial data suggest a broad application, experience of liraglutide in clinical practice is limited. Given a potential effect, if as yet unsubstantiated, on β-cell preservation, it seems possible that earlier use will extend the endogenous insulin function of patients, and perhaps slow progression of the disease.
Liraglutide, the first human once a day GLP-1 analog, improves glycemia with minimal risk of hypoglycemia and enhances β-cell function.
Liraglutide has the potential to provide long term control of hyperglycemia and improve the cardiometabolic profile of T2DM patients. The authors have indicated that there are no other conflicts of interest regarding the content of this article.



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