The metabolic abnormality of Hereditary Hemochromatosis: mechanisms and consequences of hepcidin deficiency on glucose homeostasis and insulin signaling

Hereditary hemochromatosis (HH) is the most common hereditary disease of metabolism in Caucasians. All forms of HH are characterized by the lack of a hormone, named hepcidin, which normally prevents excessive entry of iron in the bloodstream and in certain organs, such as the liver, pancreas and heart: lack of hepcidin leads to progressive accumulation of iron in the body and serious diseases, such as cirrhosis, diabetes, and cardiomyopathy. All clinical problems in HH, including diabetes, have been attributed to the toxic effect of iron. In fact, the management is presently based on the diagnosis of the extent of iron overload and organ damage and, as sole cure, on the removal of iron excess by phlebotomy. However, we have recently discovered that hepcidin has a role in the adaptation to a variety of nutritional and metabolic stress. Our working hypothesis is that if hepcidin is involved in other important physiologic activities, lack of hepcidin per se may represent an additional problem for patients. Understanding the nature and causes of these problems, we may better manage the disease and help patients to prevent or cure its manifestations. We wish to examine the regulation of hepcidin by nutrients and hormones and clarify whether lack of hepcidin in HH may compromise patients' capability to confront metabolic and nutritional stress or predispose them to metabolic abnormalities and diseases. We plan to study the regulation of hepcidin using different experimental systems that reproduce common nutritional and hormonal disorders in humans using cellular and animal models of HH and a modern molecular biology approach. We expect to understand hepcidin regulation by nutritional/metabolic signals and the metabolic consequences of hepcidin deficiency in HH. This will help devising additional strategies and tools to better manage patients and prevent or cure the metabolic disturbances in HH.