scholarly journals Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

Diabetes ◽  
2010 ◽  
Vol 59 (12) ◽  
pp. 3099-3107 ◽  
Author(s):  
K. W. Sloop ◽  
F. S. Willard ◽  
M. B. Brenner ◽  
J. Ficorilli ◽  
K. Valasek ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Small Molecule ◽  
Receptor Agonist ◽  
Human Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes

2007 ◽  
Vol 192 (2) ◽  
pp. 371-380 ◽  
Author(s):  
Thomas H Claus ◽  
Clark Q Pan ◽  
Joanne M Buxton ◽  
Ling Yang ◽  
Jennifer C Reynolds ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Receptor Agonist ◽  
Antagonist Activity ◽  
Glucagon Receptor ◽  
Glucagon Receptor Antagonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.

scholarly journals Exendin-4 Improves Reversal of Diabetes in NOD Mice Treated with Anti-CD3 Monoclonal Antibody by Enhancing Recovery of β-Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5136-5144 ◽  
Author(s):  
Nicole A. Sherry ◽  
Wei Chen ◽  
Jake A. Kushner ◽  
Mariela Glandt ◽  
Qizhi Tang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Insulin Secretion ◽  
Receptor Agonist ◽  
Glucose Transporter ◽  
Islet Cells ◽  
Nod Mice ◽  
Β Cells ◽  
Glucose Transporter 2 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of β-cells. Diabetic NOD mice treated with anti-CD3 mAb and exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or exendin-4 (0%) or insulin or IgG alone (0%) (P < 0.01). The effect of exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose level of less than 350 mg/dl at diagnosis (63 vs. 39%, P < 0.05). Exendin-4 did not affect β-cell area, replication, or apoptosis or reduce the frequency of diabetogenic or regulatory T cells or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in glucose transporter-2+/insulin− islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and exendin-4 increased insulin content and insulin release from β-cells. We conclude that treatment with glucagon-like peptide-1 receptor agonist enhances remission of T1DM in NOD mice treated with anti-CD3 mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new-onset T1DM.

scholarly journals Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist S6 Stimulates Insulin Secretion From Rat Islets

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohua Yang ◽  
Min Zhang ◽  
Zhihong Lu ◽  
Linping Zhi ◽  
Huan Xue ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Small Molecule ◽  
Imaging Techniques ◽  
Fluorescent Imaging ◽  
Imaging Plate ◽  
Dependent Manner ◽  
Kv Channels ◽  
Voltage Dependent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.

scholarly journals Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

2021 ◽  
Vol 22 (18) ◽  
pp. 9936
Author(s):  
Hwi Seung Kim ◽  
Chang Hee Jung
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Receptor Agonist ◽  
Body Weight Loss ◽  
Glucagon Secretion ◽  
Magic Bullet ◽  
Early Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

Dulaglutide, a glucagon-like peptide-1 receptor agonist: in the search for survival molecule

2020 ◽  
Vol 9 (2) ◽  
pp. 49-58
Author(s):  
A.S. Ametov ◽  
◽  
A.O. Nevolnikova ◽  
E.A. Tertychnaya ◽  
O.A. Mishra ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1
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