INTRODUCTION: GLP-1 receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, exenatide, was approved in the mid-2000s, other agents with longer durations of action (that do not require twice-daily dosing) are now being developed. Indeed, liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, and more recently, a once-weekly formulation of exenatide was approved in 2011. This review considers the mechanism of action of GLP-1 receptor agonists and considers the various agents in this class. AREAS COVERED: The importance of GLP-1 itself in glycemic control and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the five GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide and taspoglutide) since 2005 is provided and their mechanisms of action, efficacy in terms of glycemic control and weight loss, and tolerability are reviewed. EXPERT OPINION: GLP-1 receptor agonists result in clinically meaningful weight loss in addition to their beneficial effects on glucose homeostasis. These agents provide substantial clinical benefits for patients compared with sulfonylureas or DPP-4 inhibitors and will, therefore, become one of the major therapeutic choices for patients with T2DM.
"Additionally, endogenous expression of Glp-1 in murine models of streptozotocin (STZ)induced diabetes has been shown to prevent hyperglycemia and to improve β-cell survival   . Clinical trials targeting the GLP-1 pathway by the administration of Lixisenatide have reported encouraging data in terms of novel therapeutic approaches for T2DM, however, if GLP-1 contributes to β-cell regeneration in humans remains to be clarified   . Years of research indicate that β-cells retain the capacity to undergo dynamic changes to compensate for both physiological (pregnancy) and pathological (e.g. "
[Show abstract][Hide abstract] ABSTRACT: Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells resulting in failure of metabolic control. Even though type 1 and 2 diabetes differ in their pathogenesis, restoring β-cell function is the overarching goal for improved therapy of both diseases. This could be achieved either by cell-replacement therapy or by triggering intrinsic regenerative mechanisms of the pancreas. For type 1 diabetes, a combination of β-cell replacement and immunosuppressive therapy could be a curative treatment, whereas for type 2 diabetes enhancing endogenous mechanisms of β-cell regeneration might optimize blood glucose control. This review will briefly summarize recent efforts to allow β-cell regeneration where the most promising approaches are currently (1) increasing β-cell self-replication or neogenesis from ductal progenitors and (2) conversion of α-cells into β-cells.
"Hence, administration of endogenous gut peptides or more metabolically-stable analogue represents a potential long-term therapeutic approach to obesity and diabetes. With the promising results seen with GLP1R agonists , the next generations of diabetes drugs will likely focus on the alternate delivery for injectables as illustrated by recent experience with GLP-1 analogues and insulin     and the combined activation of more than one receptor . Among these, oxyntomodulin is a promising weight-loss and "
[Show abstract][Hide abstract] ABSTRACT: Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) resulting in superior body weight lowering to selective GLP1R agonists. OXM reduces food intake and increases energy expenditure in humans. While activation of the GCGR increases glucose production posing a hyperglycemic risk, the simultaneous activation of the GLP1R counteracts this effect. Acute OXM infusion improves glucose tolerance in T2DM patients making dual agonists of the GCGR and GLP1R new promising treatments for diabetes and obesity with the potential for weight loss and glucose lowering superior to that of GLP1R agonists.
"In contrast, GIP does not increase insulin secretion in patients with T2DM. Therefore, GLP-1 receptor (GLP-1R) agonists have been developed as adjunctive therapy for T2DM (Garber 2012; Lovshin and Drucker 2009). GLP-1 is normally produced by the L cells of the intestines by alternative proteolytic processing of proglucagon (Figure 1). "
[Show abstract][Hide abstract] ABSTRACT: Glucagon-like peptide-1 is an incretin hormone from the gastrointestinal tract, which enhances insulin secretion, slows gastric emptying, and reduces food intake. GLP-1 receptor agonists are being developed for Type 2 diabetes mellitus. GLP-1 is rapidly degraded by serum dipeptidyl peptidase IV, so analogues with a prolonged serum half-life are used clinically. Exenatide was the first GLP-1 agonist approved and is a synthetic version of exendin-4 derived from the Gila monster. Liraglutide was approved for clinical use in 2010. GLP-1 receptor agonists have been shown to increase calcitonin secretion and stimulate C-cell hyperplasia and neoplasia in rats and mice of both sexes. Rat C-cells are more sensitive to the effects of GLP-1 agonists than mice. The effects of GLP-1 agonists on C-cell proliferation or neoplasia have not been documented in nonhuman primates or humans. The proliferative C-cell effects may be rodent-specific. GLP-1 receptors have been demonstrated on normal rodent C-cells, but are either not present or occur in low numbers on C-cells of nonhuman primates and humans. Hyperplasia and neoplasia of C-cells in rodents treated with GLP-1 agonists represent a unique example of an on-target species-specific effect that may not have relevance to humans.
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