The Babitt laboratory focuses on understanding the molecular underpinnings of iron homeostasis in health and disease. We previously discovered that the bone morphogenetic protein (BMP)-SMAD signaling pathway plays a crucial role in regulating systemic iron homeostasis by coordinating the regulation of the iron hormone hepcidin in the liver. Indeed, we previously determined that HJV (encoding hemojuvelin), the gene most commonly mutated in the severe juvenile onset form of the iron overload disorder hereditary hemochromatosis, is a BMP co-receptor, and that hemojuvelin-mediated BMP signals control hepcidin transcription in the liver. We also showed that BMP signaling pathway activators and inhibitors modulate hepcidin expression and systemic iron balance in vivo. More recently, we discovered that BMP6 and BMP2 are the main BMP ligands involved in hepcidin regulation and iron homeostasis, and that Bmp6 global or endothelial knockout (KO) mice and endothelial Bmp2 KO mice develop a similar iron overload phenotype as Hjv KO mice. Additionally, we demonstrated that the SMAD signaling pathway is not only critical for hepcidin regulation to control body iron balance, but also plays an independent protective role against tissue injury and fibrosis caused by iron excess.

Diabetes mellitus is a common complication of hemochromatosis and other iron overload disorders. Even in apparently healthy populations, increased dietary iron, especially heme iron, and high body iron stores, as measured by serum ferritin, are associated with an increased risk of type 2 diabetes mellitus and other insulin resistance states. A causative role for iron in the development of diabetes mellitus is supported by the fact that body iron reduction by phlebotomy or iron chelators improves glycemic control in these patients. Although the mechanisms by which iron contributes to the pathogenesis of diabetes and diabetic complications are not fully understood, oxidative stress induced by iron excess is thought to play a role. Evidence also suggests that the BMP signaling pathway itself plays a role in glucose homeostasis. For example, BMP9 has been proposed to play a role as a hepatic insulin sensitizing substance. Additionally, BMP ligands and the BMP receptors are expressed in pancreatic islet cells, and mice heterozygous for mutations in the BMP type I receptor ALK3 develop abnormal glucose metabolism with impaired insulin secretion.

A new focus in the laboratory is to use our novel genetic mouse models of impaired BMP signaling and hemochromatosis to explore the role of BMP-SMAD signaling and iron in islet cell physiology, pathology, and glucose metabolism.