Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Abstract

The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.

Vincamine as a GPR40 agonist improves glucose homeostasis in type 2 diabetic mice

“…Ablation of IRS2 in whole pancreas caused β-cell mass decrease with reduced β-cell proliferation in the mouse model (Cantley et al 2007). Agents able to upregulate IRS2 may promote β-cell function under physiological stress during T2DM progression (Kuznetsova et al 2016). Currently, our result has clearly demonstrated that vincamine as an upregulator of IRS2 expression in vivo and in vitro efficiently improved β-cell function, which further supported the key role of IRS2 in β-cells.…”

“…As IRS2/PI3K/Akt signaling has been indicated to be involved in the vincamine-mediated β-cell protection and a published report has indicated that IRS2 is mediated by cAMP or Ca 2+ -regulated transcription factors in β-cells (Kuznetsova et al 2016), we next investigated whether regulation of vincamine involved these two second messengers in INS-832/13 cells.…”

Insulin action at a molecular level – 100 years of progress

“…IRS2 expression through these mechanisms maintains PDX1 action, which is essential for β-cell growth, function, and survival ( Figure 5 ) [ 98 ]. Compounds that augment IRS2 expression may be useful for treatment of β-cell failure during insulin resistance and the progression of T2DM [ 99 ].

Figure 5 The integrative role of IR/IGF1R→IRS2 signaling in pancreatic β-cell function.

…”

IL-4 and IL-13 Receptor Signaling From 4PS to Insulin Receptor Substrate 2: There and Back Again, a Historical View

“…This can be useful in designing treatment strategies for certain cancers as mentioned above but also for inflammatory diseases and diabetes in which IL-4 and insulin play an important role. Several strategies to increase expression of IRS2 with pharmacologic agents are being explored to enhance pancreatic β-cell and endothelial cell survival in the context of Type II diabetes ( 18 , 95 ). However, our current understanding of the relative roles of IRS1 and IRS2 in mediating and modulating allergic diseases is quite limited.…”

“…What about IRS1? Targeting strategies are just beginning to be explored and developed in the context of epithelial cancers and Type II diabetes ( 18 , 80 , 95 ). What about allergic disease?…”