HB-EGF Signaling Is Required for Glucose-Induced Pancreatic ß-Cell Proliferation in Rats.

The molecular mechanisms of ß-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced ß-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the ß-cell proliferative response to glucose, a ß-cell mitogen and key regulator of ß-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates ß-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks ß-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in ß-cells in response to glucose in a carbohydrate-response element-binding protein (ChREBP)-dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced ß-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in ß-cell compensation to increased metabolic demand.

Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated ß-Cell Proliferation.

Patients with both major forms of diabetes would benefit from therapies that increase ß-cell mass. Glucose, a natural mitogen, drives adaptive expansion of ß-cell mass by promoting ß-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPα) is required for glucose-stimulated ß-cell proliferation and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation. ChREBPα increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPα required the presence of ChREBPß. ChREBPα increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPα-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBPα-augmented ß-cell proliferation. Overexpression of Nrf2 was sufficient to drive human ß-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for ß-cell proliferation that may be exploited for therapeutic ß-cell regeneration.