Development Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Obesity management for the treatment of type 2 diabetes: emerging evidence and therapeutic approaches.

Excess adiposity can contribute to metabolic complications, such as type 2 diabetes mellitus (T2DM), which poses a significant global health burden. Traditionally viewed as a chronic and irreversible condition, T2DM management has evolved and new approaches emphasizing reversal and remission are emerging. Bariatric surgery demonstrates significant improvements in body weight and glucose homeostasis. However, its complexity limits widespread implementation as a population-wide intervention. The identification of glucagon-like peptide 1 (GLP-1) and the development of GLP-1 receptor agonists (GLP-1RAs) have improved T2DM management and offer promising outcomes in terms of weight loss. Innovative treatment approaches combining GLP-1RA with other gut and pancreatic-derived hormone receptor agonists, such as glucose-dependant insulinotropic peptide (GIP) and glucagon (GCG) receptor agonists, or coadministered with amylin analogues, are demonstrating enhanced efficacy in both weight loss and glycemic control. This review aims to explore the benefits of bariatric surgery and emerging pharmacological therapies such as GLP-1RAs, and dual and triple agonists in managing obesity and T2DM while highlighting the caveats and evolving landscape of treatment options.

Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice

Abstract Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3.

Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance.

Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.

Mechanism of Action of DPP-4 Inhibitors—New Insights

Mechanism of Action of DPP-4 Inhibitors—New Insights

Role and development of GLP-1 receptor agonists in the management of diabetes

Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine L cells of the intestine in response to food. Exogenous GLP-1 administration at pharmacological doses results in many effects that are beneficial for treating type 2 diabetes, these include: (1) an increase in insulin secretion from beta cells; (2) a suppression of glucagon secretion from alpha cells in the presence of hyperglycemia but not hypoglycemia; (3) a delay in gastric emptying and gut motility which in turns delays absorption of ingested nutrients and dampens post-prandial glucose excursion; and (4) an increase in the duration of postprandial satiety therefore suppressing appetite and decreasing food intake which eventually leads to weight loss. However, GLP-1 is subject to rapid enzymatic degradation, and therefore, not suitable for long-term treatment. A synthetic enzyme-resistant GLP-1 receptor agonist that reproduces the biological effects of GLP-1 is in use and more are under development. This review aims at providing a summary of the properties of GLP-1 and the development of GLP-1-based therapies for treatment of diabetes.

Role and development of GLP-1 receptor agonists in the management of diabetes

Role and development of GLP-1 receptor agonists in the management of diabetes Chee W Chia, Josephine M EganNational Institutes of Health, National Institute on Aging, Intramural Research Program, Baltimore, Maryland, USAAbstract: Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine L cells of the intestine in response to food. Exogenous GLP-1 administration at pharmacological doses results in many effects that are beneficial for treating type 2 diabetes, these include: (1) an increase in insulin secretion from β cells; (2) a suppression of glucagon secretion from α cells in the presence of hyperglycemia but not hypoglycemia; (3) a delay in gastric emptying and gut motility which in turns delays absorption of ingested nutrients and dampens post-prandial glucose excursion; and (4) an increase in the duration of postprandial satiety therefore suppressing appetite and decreasing food intake which eventually leads to weight loss. However, GLP-1 is subject to rapid enzymatic degradation, and therefore, not suitable for long-term treatment. A synthetic enzyme-resistant GLP-1 receptor agonist that reproduces the biological effects of GLP-1 is in use and more are under development. This review aims at providing a summary of the properties of GLP-1 and the development of GLP-1-based therapies for treatment of diabetes.Keywords: incretin, GLP-1, GLP-1R agonist, diabetes

What mediates the benefits associated with dipeptidyl peptidase-IV inhibition?

Inhibitors of the enzyme dipeptidyl peptidase-IV (DPP-IV) are a new class of agents for the treatment of type 2 diabetes [1]. DPP-IV is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1), reducing its active half-life to only 1–2 min. GLP-1 is an incretin hormone that is released from the gut when food is ingested to augment glucose-stimulated insulin secretion [2]. It exhibits multiple actions that are beneficial for the treatment of type 2 diabetes, including glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, delaying gastric emptying, and induction of satiety. In addition, it has the potential to increase beta cell mass by stimulating the differentiation of precursor cells into beta cells and by inhibiting beta cell apoptosis [2]. The beneficial effects of GLP-1 were shown as early as 1992 and have been supported by numerous studies, one of which investigated the effects of a continuous 6-week subcutaneous infusion [3, 4]. GLP-1 therefore offers a novel approach to the treatment of type 2 diabetes, but its positive effects are counterbalanced by the need for continuous infusion. This limitation may be overcome by the development of GLP-1 receptor agonists (GLP-1 mimetics) with either low affinity or no affinity for DPP-IV. The discovery that DPP-IV can cleave GLP-1 in plasma [5], whether exogenously administered or endogenously secreted [6, 7], has opened the way for an alternative strategy for the treatment of type 2 diabetes— the development of inhibitors of DPP-IV [8]. Although the rationale for the use of DPP-IV inhibitors is based upon their prolonging the actions of GLP-1, they also have other beneficial effects. DPP-IV inhibition blocks the inactivation of the other major incretin hormone, gastric inhibitory peptide (GIP). DPP-IV inhibitors therefore enhance concentrations of the active forms of both incretin hormones precisely when they are most needed (i.e. following meal ingestion), resulting in improved postprandial glucose control. Since the actions of both GLP-1 and GIP are glucose dependent, DPP-IV inhibition has the additional advantage that it carries a minimal risk of hypoglycaemia. Treatment with GLP-1 also lowers fasting glucose levels. Further support for this approach to therapy comes from the observations that glucose tolerance is improved in animals in which the enzyme has been genetically deleted [9] and in animals treated with DPP-IV inhibitors [10]. Clinical studies of type 2 diabetes show improved metabolic control, increased insulin secretion, reduced glucagon secretion, and favourable tolerability and safety during a treatment period of up to 1 year [11–13]. For example, the addition of a DPPIV inhibitor to metformin resulted in a reduction in HbA1c of 1.1% relative to metformin plus placebo by the end of 1 year [13] (Fig. 1). DPP-IV is a widespread enzyme with the potential to cleave a large number of bioactive peptides other than GLP1 and GIP [14]. The requisite for cleavage is that an alanine or a proline must be present as the second amino acid from the N-terminal end, in which case the two N-terminal amino acids are cleaved from the rest of the peptide. When this cleavage results in a loss of activity, as with GLP-1 and GIP, DPP-IVacts as an inactivation enzyme. However, it is possible that the effects of DPP-IV inhibition in diabetes are mediated by the inhibition of bioactive peptides other than GLP-1. One puzzling finding might support this: in patients with type 2 diabetes, concentrations of active GLP-1 after meal ingestion are doubled by DPP-IV inhibition (compared with placebo), and glucose control improves [13]. In contrast, when similar increases in GLP-1 levels are proB. Ahren (*) Department of Medicine, Lund University, Lund, Sweden e-mail: Bo.Ahren@med.lu.se Tel.: +46-46-2220758 Fax: +46-46-2220757