Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia

Gilroy, Caslin A.; Capozzi, Megan E.; Varanko, Anastasia Kristine; Tong, Jenny; D’Alessio, David A.; Campbell, Jonathan E.; Chilkoti, Ashutosh

doi:10.1126/sciadv.aaz9890

Cited by 47 publications

(44 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gilroy et al. developed a unimolecular recombinant fusion protein encoding a long-acting GLP-1-FGF21 co-agonist using elastin-like polypeptide (ELP) linker technology to join the peptides, enabling continuous drug delivery via subcutaneous depots [ 39 ]. Remarkably, the EC 50 of GLP1-ELP-FGF21 (23.9 ± 5.7 pM) for GLP-1R was similar to that of GLP1-ELP alone (29.5 ± 5.0 pM).…”

Section: Fibroblast Growth Factors (Fgfs)mentioning

confidence: 99%

“…Remarkably, the EC 50 of GLP1-ELP-FGF21 (23.9 ± 5.7 pM) for GLP-1R was similar to that of GLP1-ELP alone (29.5 ± 5.0 pM). The GLP1-ELP-FGF21 fusion protein produced more effective reduction of glycemia and body weight relative to the administration of the single agonists or an equimolar mixture of GLP1-ELP and ELP-FGF21 without evidence of fasting-associated hypoglycemia [ 39 ]. Whether FGF co-agonists can be developed for metabolic disorder therapy without risks of osteoporosis or unwanted cell proliferation remains unclear.…”

Section: Fibroblast Growth Factors (Fgfs)mentioning

confidence: 99%

See 1 more Smart Citation

Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

Baggio

Drucker

2021

Molecular Metabolism

181

122

View full text Add to dashboard Cite

Background Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy. Scope of review In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity. Major conclusions Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.

show abstract

Section: Fibroblast Growth Factors (Fgfs)mentioning

confidence: 99%

Section: Fibroblast Growth Factors (Fgfs)mentioning

confidence: 99%

Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

Baggio

Drucker

2021

Molecular Metabolism

181

122

View full text Add to dashboard Cite

show abstract

“…Intriguingly, this novel metabolic regulator is increased in mice with hepatic FOXO1 ablation [ 10 ], suggestive of an integrated metabolic pathway whose significance in HGP regulation is yet unexplored. To note, in combination with another diabetes therapy, the glucose lowering efficacy of FGF21 is robustly potentiated [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice

Lee

Diaz

Deroose

et al. 2021

Molecular Metabolism

View full text Add to dashboard Cite

Objective Forkhead box protein O1 (FOXO1) plays a key role in regulating hepatic glucose production, but investigations of FOXO1 inhibition as a potential therapeutic approach have been hampered by a lack of selective chemical inhibitors. By profiling structurally diverse FOXO1 inhibitors, the current study validates FOXO1 as a viable target for the treatment of diabetes. Methods Using reporter gene assays, hepatocyte gene expression studies, and in vivo studies in mice, we profiled our leading tool compound 10 and a previously characterized FOXO1 inhibitor, AS1842856 (AS). Results We show that AS has significant FOXO1-independent effects, as demonstrated by testing in FOXO1-deficient cell lines and animals, while compound 10 is highly selective for FOXO1 both in vitro and in vivo and fails to elicit any effect in genetic models of FOXO1 ablation. Chronic administration of compound 10 improved insulin sensitivity and glucose control in db/db mice without causing weight gain. Furthermore, chronic compound 10 treatment combined with FGF21 led to synergistic glucose lowering in lean, streptozotocin-induced diabetic mice. Conclusions We show that the widely used AS compound has substantial off-target activities and that compound 10 is a superior tool molecule for the investigation of FOXO1 function. In addition, we provide preclinical evidence that selective FOXO1 inhibition has potential therapeutic benefits for diabetes as a monotherapy or in combination with FGF21.

show abstract

“…In summary, we generated FGF21 analogs with improved β-Klotho binding affinity and bioactivity and constructed a novel GLP-1/FGF21 dual agonist. As we were preparing this manuscript, we noticed that another group reported a similar GLP-1/FGF21 dual agonist fusion protein [36] , compared with the reported molecule GLP1-ELP-FGF21, our molecule GLP1-Fc-FGF21 exhibited potent and sustained glycemic control effects in diabetic mice models with a much lower dose. Additionally, it also performed superior body weight reduction, lipid profile improvement and anti-NASH effect in high-fat diet-induced ob/ob model.…”

Section: Discussionmentioning

confidence: 76%