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

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.