Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes

Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals

“…In addition, expanding on a recent communication (19), we show that in human fetal intestine of 15-to 17-week gestational age, insulin-immunoreactive cells also colocalize with goblet/Paneth lineage markers but exclude active FOXO1, lending further support to the notion that FOXO1-inactive cells can be converted to -like cells. These findings address the question of which type of cell can be converted into insulin-immunoreactive β-like cells, extending previous observations (17,18,21).…”

“…TGFβ, WNT, FGF, Notch, BMP, and FOXO1, along with relevant receptors and signaling pathways, are involved in pancreatic and intestinal tissue patterning (40,41). FOXO1 and Notch signaling interact in determining intestinal stem cell differentiation into Paneth/goblet (42) and EEC lineages (19,21,43). Thus, we combined genetic FoxO1 knockout with pharmacological Notch inhibition (DBZ) to show that dual Notch/FOXO1 inhibition expands the Neurog3 + progenitor pool and its secretory lineage cell descendants.…”

“…5 mutant or lentivirus-encoded small hairpin RNA promotes generation of insulin-secreting cells in human iPSC-derived gut organoids (18). The potential therapeutic significance of this work was amplified by recent reports: one identifying -like cells in the human fetal intestine-and thus implying that conversion restores a fetal cell type (19); and the others showing that previously described small molecule FOXO1 inhibitors can yield insulin-producing cells in vivo and lower glycemia in diabetic mice (20,21). These findings prompted us to investigate whether other descendants of Neurog3 + progenitors, such as subsets of goblet and Paneth cells have the potential to be converted into insulin-secreting βlike cells.…”

“…To evaluate the translational value of this triple combination therapy in an autoimmune model of diabetes, we used Repsox and the gamma secretase inhibitor PF-03084014, currently in Phase II for the treatment of different forms of cancer (36), in combination with the chemical FOXO1 inhibitor, FBT10 (20,21). 5 days of oral administration with FBT10, PF, and Repsox only slightly decreased body weight (Fig 6B ), with a significant increase of plasma insulin and GLP1 levels (Fig 6C , D).…”

Diabetes treatment by conversion of gut epithelial cells to insulin‐producing cells

“…The newly arisen intestinal insulin‐producing cells have all the markings of pancreatic β‐cells, and can take over the function of pancreatic β‐cells after the latter have been destroyed by the toxin, streptozotocin, effectively “curing” diabetes in rodents 23 . Unlike iPS‐derived β‐like cells, enteroendocrine‐derived β‐like cells show glucose‐dose‐dependent insulin release as soon as they arise and do not require maturation 23 , 25 .…”