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Verapamil prevents decline of IGF-1 in subjects with T1D and promotes beta-cell IGF-1 signaling

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posted on 2023-07-26, 20:06 authored by Guanlan Xu, Junqin Chen, Brian Lu, Praveen Sethupathy, Wei-Jun Qian, Anath Shalev

Verapamil promotes functional beta-cell mass and improves glucose homeostasis in diabetic mice and humans with type 1 diabetes (T1D). Now, our global proteomics analysis of serum from T1D subjects at baseline and after 1 year of receiving verapamil or placebo revealed insulin-like growth factor 1 (IGF-1) as a protein with significantly changed abundance over time. IGF-1, which promotes beta-cell survival and insulin secretion, decreased during disease progression and this decline was blunted by verapamil. In addition, we found that verapamil reduces beta-cell expression of IGF-binding protein 3 (IGFBP3), whereas IGFBP3 was increased in human islets exposed to T1D-associated cytokines and diabetic NOD mouse islets. IGFBP3 binds IGF-1 and blocks its downstream signaling, which has been associated with increased beta-cell apoptosis and impaired glucose homeostasis. Consistent with the downregulation of IGFBP3, we have now discovered that verapamil increases beta-cell IGF-1 signaling and phosphorylation/activation of the IGF-1 receptor (IGF1R). Moreover, we found that thioredoxin interacting protein (TXNIP), a pro-apoptotic factor downregulated by verapamil, promotes IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R. Thus, our results reveal IGF-1 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.

Funding

This work was supported by R01DK078752 granted to A.S., R01DK122160 granted to W.J.Q., and UAB Diabetes Research Center Pilot & Feasibility Award (NIH P30 DK079626) granted to G.X. Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH Grant # 2UC4DK098085.

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