Verapamil Prevents Decline of IGF-I in Subjects With Type 1 Diabetes and Promotes β-Cell IGF-I Signaling.
In: Diabetes, Jg. 72 (2023-10-01), Heft 10, S. 1460-1469
academicJournal
Zugriff:
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. Article Highlights: 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. [ABSTRACT FROM AUTHOR]
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Verapamil Prevents Decline of IGF-I in Subjects With Type 1 Diabetes and Promotes β-Cell IGF-I Signaling.
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Autor/in / Beteiligte Person: | Xu, Guanlan ; Chen, Junqin ; Lu, Brian ; Sethupathy, Praveen ; Qian, Wei-Jun ; Shalev, Anath |
Zeitschrift: | Diabetes, Jg. 72 (2023-10-01), Heft 10, S. 1460-1469 |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 0012-1797 (print) |
DOI: | 10.2337/db23-0256 |
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