Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Abstract

Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing β-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgfβ that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

“…The feasibility of converting gut cells into β-like cells has received further support by the recent discovery of bona fide insulin-producing cells in the human fetal gut (22), an observation that we have independently confirmed (23). In this regard, it is possible that FOXO1 inhibition arrests EEC maturation at a fetal stage of development, a speculation that is entirely consistent with the known effects of FOXO1 inhibition in the pancreatic islet, where it promotes reversion to a progenitor-like stage (24; 25).…”

Single-agent FOXO1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

“…The feasibility of converting gut cells into β-like cells has received further support by the recent discovery of bona fide insulin-producing cells in the human fetal gut [ 21 ], an observation that we have independently confirmed [ 22 ]. In this regard, it is possible that FOXO1 inhibition arrests EEC maturation at a fetal stage of development, a speculation that is entirely consistent with the known effects of FOXO1 inhibition in the pancreatic islet, where it promotes reversion to a progenitor-like stage [ 23 , 24 ].…”