The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy.
DACRA
GPCR
obesity
preclinical
type 2 diabetes
Journal
Biomedicines
ISSN: 2227-9059
Titre abrégé: Biomedicines
Pays: Switzerland
ID NLM: 101691304
Informations de publication
Date de publication:
22 Sep 2022
22 Sep 2022
Historique:
received:
17
08
2022
revised:
13
09
2022
accepted:
17
09
2022
entrez:
27
10
2022
pubmed:
28
10
2022
medline:
28
10
2022
Statut:
epublish
Résumé
Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague-Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.
Sections du résumé
BACKGROUND
BACKGROUND
Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles.
METHODS
METHODS
To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague-Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats.
RESULTS
RESULTS
KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control.
CONCLUSION
CONCLUSIONS
different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.
Identifiants
pubmed: 36289629
pii: biomedicines10102365
doi: 10.3390/biomedicines10102365
pmc: PMC9599033
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : The Danish Research Foundation
ID : NA
Déclaration de conflit d'intérêts
M.A.K. and K.H. own stock in Nordic Bioscience. M.A.K. and K.H. hold patent in KBP-042, KBP-088, KBP-088A and KBP-066A. N.S. holds patent in KBP-066A. All authors are employed by Nordic Bioscience A/S.
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