An orally available hypoglycaemic peptide taken up by caveolae transcytosis displays improved hypoglycaemic effects and body weight control in db/db mice.
Animals
Blood Glucose
Body Weight
Caco-2 Cells
Caveolae
/ metabolism
Diabetes Mellitus, Experimental
/ drug therapy
Diabetes Mellitus, Type 2
/ drug therapy
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Humans
Hypoglycemic Agents
/ pharmacology
Insulin
/ metabolism
Mice
Mice, Inbred Strains
Peptides
/ pharmacology
Rats
Rats, Wistar
Transcytosis
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
12
12
2019
revised:
29
03
2020
accepted:
05
04
2020
pubmed:
16
4
2020
medline:
22
6
2021
entrez:
16
4
2020
Statut:
ppublish
Résumé
Type 2 diabetes is one of the most severe chronic diseases and is an increasingly important public health problem worldwide. Several agonists of the glucagon-like peptide-1 (GLP-1) receptor have been developed to treat Type 2 diabetes but most of them are administered by injection. This mode of administration seriously reduces patient compliance and increases the risk of infection. Here, we describe the actions of a novel, orally available, GLP-1 receptor agonist - oral hypoglycaemic peptide 2 (OHP2) - derived from exendin-4 by replacing amino acids. We have also investigated its pharmacokinetic profiles, therapeutic effects and absorption mechanism. Healthy Wistar rats were used for pharmacokinetic analyses. In diabetic db/db mice. OHP2 was given for 8 weeks to evaluate its effects on hyperglycaemia, dyslipidaemia, basal metabolism and tissue injury. Possible endocytosis and transcytosis mechanisms of OHP2 uptake were explored in Caco-2 cell monolayers. In rats, the absolute bioavailability of orally administered OHP2 was 20-fold greater than that of orally administered exendin-4. In db/db mice, OHP2 dose-dependently exhibits good potential in glucose-lowering and weight loss after oral administration. OHP2 also alleviated hyperlipidaemia, ameliorated energy metabolism and promoted tissue repair in diabetic mice. Furthermore, uptake of OHP2 by Caco-2 cells was dependent on caveolae-mediated transcytosis rather than endocytosis mediated by GLP-1 receptors. OHP2 is a potential, orally bioavailable, candidate drug for the treatment of Type 2 diabetes. Its transcytosis mechanism of uptake could help in the development of absorption enhancers of OHP2.
Sections du résumé
BACKGROUND AND PURPOSE
Type 2 diabetes is one of the most severe chronic diseases and is an increasingly important public health problem worldwide. Several agonists of the glucagon-like peptide-1 (GLP-1) receptor have been developed to treat Type 2 diabetes but most of them are administered by injection. This mode of administration seriously reduces patient compliance and increases the risk of infection. Here, we describe the actions of a novel, orally available, GLP-1 receptor agonist - oral hypoglycaemic peptide 2 (OHP2) - derived from exendin-4 by replacing amino acids. We have also investigated its pharmacokinetic profiles, therapeutic effects and absorption mechanism.
EXPERIMENTAL APPROACH
Healthy Wistar rats were used for pharmacokinetic analyses. In diabetic db/db mice. OHP2 was given for 8 weeks to evaluate its effects on hyperglycaemia, dyslipidaemia, basal metabolism and tissue injury. Possible endocytosis and transcytosis mechanisms of OHP2 uptake were explored in Caco-2 cell monolayers.
KEY RESULTS
In rats, the absolute bioavailability of orally administered OHP2 was 20-fold greater than that of orally administered exendin-4. In db/db mice, OHP2 dose-dependently exhibits good potential in glucose-lowering and weight loss after oral administration. OHP2 also alleviated hyperlipidaemia, ameliorated energy metabolism and promoted tissue repair in diabetic mice. Furthermore, uptake of OHP2 by Caco-2 cells was dependent on caveolae-mediated transcytosis rather than endocytosis mediated by GLP-1 receptors.
CONCLUSIONS AND IMPLICATIONS
OHP2 is a potential, orally bioavailable, candidate drug for the treatment of Type 2 diabetes. Its transcytosis mechanism of uptake could help in the development of absorption enhancers of OHP2.
Identifiants
pubmed: 32293707
doi: 10.1111/bph.15069
pmc: PMC7348098
doi:
Substances chimiques
Blood Glucose
0
Glucagon-Like Peptide-1 Receptor
0
Hypoglycemic Agents
0
Insulin
0
Peptides
0
Glucagon-Like Peptide 1
89750-14-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3473-3488Subventions
Organisme : "111 Project" from the Ministry of Education of China and the State Administration of Foreign Expert Affairs of China
ID : 111-2-07
Organisme : Postgraduate Research & Practice Innovation Program of Jiangsu Province
ID : KYCX19_0661
Organisme : Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
Organisme : 'Double First-Class' University project
ID : CPU2018GF08
Organisme : National Natural Science Foundation of China
ID : 81430082
Informations de copyright
© 2020 The British Pharmacological Society.
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