Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes.
Blood Glucose
/ metabolism
Diabetes Mellitus, Type 2
/ drug therapy
Gastric Inhibitory Polypeptide
/ administration & dosage
Glucagon-Like Peptide 1
/ administration & dosage
Glucose Tolerance Test
Humans
Incretins
/ administration & dosage
Insulin Secretion
/ drug effects
Insulin-Secreting Cells
/ drug effects
Models, Theoretical
Beta cell
Incretin effect
Insulin secretion
Mathematical modeling
Type 2 diabetes
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
16
03
2020
revised:
08
06
2020
accepted:
28
10
2020
pubmed:
3
11
2020
medline:
28
1
2021
entrez:
2
11
2020
Statut:
ppublish
Résumé
The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.
Sections du résumé
BACKGROUND AND AIMS
The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects.
METHODS
We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data.
RESULTS
a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion.
CONCLUSION
We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.
Identifiants
pubmed: 33137379
pii: S0026-0495(20)30279-1
doi: 10.1016/j.metabol.2020.154415
pii:
doi:
Substances chimiques
Blood Glucose
0
Incretins
0
Gastric Inhibitory Polypeptide
59392-49-3
Glucagon-Like Peptide 1
89750-14-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
154415Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Ele Ferrannini: membership of scientific advisory board (Boehringer Ingelheim/Eli Lilly); ad hoc consulting (AstraZeneca); occasional speaking engagement (AstraZeneca, Novo Nordisk, Sanofi, Tanabe-Mitsubishi, Eli Lilly&Co, Boehringer Ingelheim; Merck Sharp&Dohme; research grant support (Boehringer Ingelheim, AstraZeneca). Andrea Natali: research grant support (Boehringer Ingelheim). The other authors have no conflict of interest to declare.