A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Finan, Brian; Yang, Bin; Ottaway, Nickki; Smiley, David L.; Ma, Tao; Clemmensen, Christoffer; Chabenne, Joe; Zhang, Lianshan; Habegger, Kirk M.; Fischer, Katrin; Campbell, Jonathan E.; Sandoval, Darleen A.; Seeley, Randy J.; Bleicher, Konrad H.; Uhles, Sabine; Riboulet, William; Funk, Jürgen; Hertel, Cornelia; Belli, Sara; Seböková, E; Conde-Knape, Karin; Konkar, Anish; Drucker, Daniel J.; Gelfanov, Vasily; Pfluger, Paul T.; Müller, Timo; Pérez-Tilve, Diego; DiMarchi, Richard D.; Tschöp, Matthias H.

doi:10.1038/nm.3761

Cited by 525 publications

(466 citation statements)

References 35 publications

Supporting

Mentioning

446

Contrasting

Unclassified

Order By: Relevance

“…Interestingly enough, the last two actions buffer against the diabetogenic effect of inherent glucagon activity of the peptide. Thus these preclinical studies in rodents suggest that this unimolecular, polypharmaceutical strategy has the potential to reversing obesity and related metabolic disorders 1 . Further studies should confirm whether this innovative pharmacological approach, which proved superior to any existing dual coagonists and best-in-class monoagonists in rodents, might be effective and safe to treat obesity and type 2 diabetes (T2DM) in humans and thus ultimately offer a valuable pharmacological alternative to bariatic surgery 2,3 .…”

Section: Wordsmentioning

confidence: 95%

“…Finan and colleagues reported the discovery of a new agonist acting simultaneously at three key metabolically-related peptide hormone receptors : glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors 1 . This rationally designed monomeric peptide that exerts a balanced agonism proved remarkable activity to reduce body weight, improve glucose control and reverse hepatic steatosis in various relevant models (either diet-induced or genetically determined) of obesity and diabetes in rodents.…”

Section: Wordsmentioning

confidence: 99%

“…Of note, GIP action to potentiate the incretin effect, as present in the new triagonist, could also contribute buffer against the diabetogenic effect of inherent glucagon activity 5 . Finan and colleagues are confident that the glucagon activity can be selectively fine-tuned with minimal structural or chemical change 1 . If it is the case, the ability to choose among several options that differ in their inherent molecular pharmacology would certainly increase the likelihood of ultimate success in humans.…”

Section: Wordsmentioning

confidence: 99%

See 2 more Smart Citations

A new paradigm for treating obesity and diabetes mellitus

Scheen

Paquot

2015

Nat Rev Endocrinol

View full text Add to dashboard Cite

Standfirst :An innovative unimolecular, polypharmaceutical strategy using a well-balanced monomeric peptide triagonist targeting three metabolically-related hormone receptors (glucagon-like peptide-1, glucose-dependent insulinotropic poplypeptide and glucagon) appears the most effective pharmacological approach to reversing obesity and metabolic comorbidities in rodents and could open new perspective to tackle the dual obesity-diabetes burden in humans.

show abstract

Section: Wordsmentioning

confidence: 95%

Section: Wordsmentioning

confidence: 99%

Section: Wordsmentioning

confidence: 99%

See 1 more Smart Citation

A new paradigm for treating obesity and diabetes mellitus

Scheen

Paquot

2015

Nat Rev Endocrinol

View full text Add to dashboard Cite

show abstract

“…The GLP-1 receptor agonist liraglutide elicits far less weight loss than bariatric surgery (Table 1), and it has been hypothesised that no single gut hormone is dominant in mediating the effects of bariatric surgery. Therefore, compounds have been investigated in rodents that mimic two [78] or even three gut hormone receptors, such as a 'triagonist' of the GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors [79].…”

Section: Mimicry Of Bariatric Surgerymentioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

View full text Add to dashboard Cite

Abstract:Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.3

show abstract

“…The synthesis of hybrid peptides allows the affinity of the drugs toward different receptors to be optimised. Triple agonists may target GLP-1, GIP and glucagon receptors [12]. From a theoretical standpoint, combination of these peptide actions sounds intriguing.…”

Section: Dual/triple Peptide Agonists or Antagonistsmentioning

confidence: 99%

Incretin-based therapies: where will we be 50 years from now?

Meier

Nauck

2015

Diabetologia

View full text Add to dashboard Cite

The development of incretin-based therapies (glucagon-like peptide 1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has changed the landscape of type 2 diabetes management over the past decade. Current developments include longer-acting GLP-1 receptor agonists, fixed-ratio combinations of GLP-1 analogues and basal insulin, as well as implantable osmotic minipumps for long-term delivery of GLP-1 receptor agonists. In longer terms, oral or inhaled GLP-1 analogues may become a reality. In addition, oral enhancers of GLP-1 secretion (e.g. via G-protein-coupled receptors, nuclear farnesoid-receptor X and the G-proteincoupled bile acid-activated receptor [TGR5]) are currently being explored in experimental studies. Combination of GLP-1 with other gut hormones (e.g. peptide YY, glucagon, gastrin, glucose-dependent insulinotropic polypeptide [GIP], secretin, cholecystokinin, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide) may enhance the glucose-and weight-lowering effect of GLP-1 alone, and dual or triple hormone receptor agonists may even exploit the properties of different peptides with just one molecule. There is also an increasing interest in employing incretin-based therapies in other areas, such as type 1 diabetes, impaired glucose metabolism, obesity, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), psoriasis or even neurodegeneration. Thus, incretin-based therapies may continue to broaden the therapeutic spectrum for type 2 diabetes and for various other indications in the coming years. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965Diabetologia ( -2015.Keywords GIP . GLP-1 . Gut hormones . Type 2 diabetes Where are we today and where have we come from?The development of incretin-based therapies is a splendid and unique example of the successful development of novel glucose-lowering medications based on basic research findings from academic researchers. Physiological experiments in human volunteers revealed different increments in insulin secretion after oral and intravenous glucose administration, which were subsequently attributed to the actions of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [1]. These peptide hormones were later synthesised and prepared for intravenous infusion in patients with type 2 diabetes. On this basis, the glucose-lowering activity of GLP-1 was first discovered by academic researchers. Later on, dipeptidyl peptidase-4 (DPP-4) inhibition was identified as an effective way of raising endogenous GLP-1 levels [2]. These clinical research findings have prompted the development of GLP-1 receptor

show abstract

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Cited by 525 publications

References 35 publications

A new paradigm for treating obesity and diabetes mellitus

A new paradigm for treating obesity and diabetes mellitus

Horizons in the Pharmacotherapy of Obesity

Incretin-based therapies: where will we be 50 years from now?

Contact Info

Product

Resources

About