Metabolic stress levels influence the ability of the myelin transcription factors to regulate b-cell identity and survival

Abstract

A hallmark of type 2 diabetes (T2D) is endocrine islet b-cell failure, which can occur via cell dysfunction, loss-of-identity, and/or death. How each is induced remains largely unknown. Here, we use mouse b-cells that are deficient for Myelin transcription factors (Myt TFs, including Myt1, 2, and 3) to address this question. We have reported that inactivating all three Myt genes in pancreatic progenitor cells (MytPanc^D) causes b-cell failure and late onset diabetes in mice. Their lower expression in human b-cells is correlated with b-cell dysfunction and SNPs in MYT2 and MYT3 are associated in higher risk of T2D. We now show that these Myt TF-deficient postnatal b-cells also de-differentiate by reactivating several progenitor markers. Intriguingly, mosaic Myt TF inactivation in only a portion of islet b-cells does not results in overt diabetes, but this creates a condition where Myt TF-deficient b-cells stay alive while activating several markers of Ppy-expressing islet cells. By transplanting MytPanc^D islets into the anterior eye chambers of immune-compromised mice, we directly show that glycemic and obesity-related conditions influence cell fate, with euglycemia inducing several Ppy+ cell markers while hyperglycemia and insulin resistance inducing additional cell death. These findings suggest that the observed b-cell defects in T2D depend on not only their inherent genetic/epigenetic defects, but also the metabolic load.

Highlights:

· Myt TF-deficient b-cells dedifferentiate under euglycemia and hyperglycemia.

· Myt TF-deficient b-cells activate markers of Ppy-expressing cells at euglycemia.

· Myt TF-deficient b-cells die at hyperglycemia.

· Myt TF-deficient b-cells gain several Ppy-cell features under obesity-induction.