Verapamil Prevents Decline of IGF-I in Subjects With Type 1 Diabetes and Promotes β-Cell IGF-I Signaling.
Humans
Mice
Animals
Diabetes Mellitus, Type 1
/ drug therapy
Insulin-Like Growth Factor I
/ metabolism
Receptor, IGF Type 1
/ metabolism
Verapamil
/ pharmacology
Insulin-Like Growth Factor Binding Protein 3
/ metabolism
Diabetes Mellitus, Experimental
/ metabolism
Mice, Inbred NOD
Thioredoxins
/ metabolism
Glucose
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
01 10 2023
01 10 2023
Historique:
received:
01
04
2023
accepted:
23
07
2023
pmc-release:
01
10
2024
medline:
22
9
2023
pubmed:
26
7
2023
entrez:
26
7
2023
Statut:
ppublish
Résumé
Verapamil promotes functional β-cell mass and improves glucose homeostasis in diabetic mice and humans with type 1 diabetes (T1D). Now, our global proteomics analysis of serum from subjects with T1D at baseline and after 1 year of receiving verapamil or placebo revealed IGF-I as a protein with significantly changed abundance over time. IGF-I, which promotes β-cell survival and insulin secretion, decreased during disease progression, and this decline was blunted by verapamil. In addition, we found that verapamil reduces β-cell expression of IGF-binding protein 3 (IGFBP3), whereas IGFBP3 was increased in human islets exposed to T1D-associated cytokines and in diabetic NOD mouse islets. IGFBP3 binds IGF-I and blocks its downstream signaling, which has been associated with increased β-cell apoptosis and impaired glucose homeostasis. Consistent with the downregulation of IGFBP3, we have now discovered that verapamil increases β-cell IGF-I signaling and phosphorylation/activation of the IGF-I receptor (IGF1R). Moreover, we found that thioredoxin-interacting protein (TXNIP), a proapoptotic factor downregulated by verapamil, promotes IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R. Thus, our results reveal IGF-I signaling as yet another previously unappreciated pathway affected by verapamil and TXNIP that may contribute to the beneficial verapamil effects in the context of T1D. Verapamil prevents the decline of IGF-I in subjects with type 1 diabetes (T1D). Verapamil decreases the expression of β-cell IGF-binding protein 3 (IGFBP3), whereas IGFBP3 is increased in human and mouse islets under T1D conditions. Verapamil promotes β-cell IGF-I signaling by increasing phosphorylation of IGF-I receptor and its downstream effector AKT. Thioredoxin-interacting protein (TXNIP) increases IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R in β-cells. Regulation of IGFBP3 and IGF-I signaling by verapamil and TXNIP may contribute to the beneficial verapamil effects in the context of T1D.
Identifiants
pubmed: 37494660
pii: 153437
doi: 10.2337/db23-0256
pmc: PMC10545554
doi:
Substances chimiques
Insulin-Like Growth Factor I
67763-96-6
Receptor, IGF Type 1
EC 2.7.10.1
Verapamil
CJ0O37KU29
Insulin-Like Growth Factor Binding Protein 3
0
Thioredoxins
52500-60-4
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1460-1469Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK078752
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK122160
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK098085
Pays : United States
Informations de copyright
© 2023 by the American Diabetes Association.
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