REprogramming Pancreatic Alpha-cells for Insulin production Restoration in diabetes

Diabetes affects some 500 million people worldwide (estimated 700 million by 2045), causing over one million deaths annually. The disease results from the loss / dysfunction of pancreatic islet insulin-producing β-cells, leading to chronic hyperglycemia and severe complications. Current treatments are symptomatic and fail to restore long-term glucose regulation, stressing the need for a transformative curative approach.Our proposal leverages α-cell reprogramming as a novel therapy for the restoration of insulin-production in situ, i.e. in the pancreas of diabetics. Islet α-cells remain abundant in diabetic patients and, along with δ- and γ-cells, they possess intrinsic plasticity, meaning that they can “learn” to produce insulin (Nature, 2010 & 2014; Diab Obes Metab, 2016; Nat Cell Biol, 2018; Nat Comm, 2021). Recently, we have shown that if all islet non-β-cells were converted into insulin producers, the islets containing only insulin-producing cells would be perfectly viable and functional, keeping optimal glucose homeostasis (Nat Metab, 2024). We have also reported that genetically reprogrammed human α-cells can secrete insulin and restore normal glucose levels when transplanted to diabetic mice (Nature, 2019). These findings establish islet non-β-cell reprogramming as a viable innovative strategy for diabetes cure.Here, we aim at developing a first-in-class, non-genetic therapy to induce in situ α-cell reprogramming using small molecules. From a targeted screening we identified six FDA-approved compounds that induce insulin expression above a reprogramming threshold in purified α-cells from 2 donors. We will now explore their mechanism of action re the functional conversion and conduct preclinical studies in healthy and diabetic mice to assess reprogramming efficiency in both endogenous and transplanted human cells. If successful, this approach could transform diabetes therapy, offering a safe and clinically viable alternative to current treatments.