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 Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Olof Eriksson ◽  
Torsten Haack ◽  
Youssef Hijazi ◽  
Lenore Teichert ◽  
Veronique Tavernier ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Receptor Occupancy ◽  
Strong Interactions ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Positron Emission ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68Ga]Ga-DO3A-Tuna-2 and [68Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (− 3.30 ± 1.14 mmol/L) and body weight (− 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.

Dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist SAR425899 improves beta‐cell function in type 2 diabetes

2019 ◽  
Vol 22 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Roberto Visentin ◽  
Michele Schiavon ◽  
Britta Göbel ◽  
Michela Riz ◽  
Claudio Cobelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Receptor Agonist ◽  
Cell Function ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

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.

scholarly journals Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2474-2482 ◽  
Author(s):  
Elena Sebokova ◽  
Andreas D. Christ ◽  
Haiyan Wang ◽  
Sabine Sewing ◽  
Jesse Z. Dong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Affinity Constant ◽  
Camp Production ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [125I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 ± 0.2 nm) to the natural ligand (affinity constant 1.5 ± 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC50 Taspo 0.06 nm and EC50 hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.

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