Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice.

BACKGROUND:Increased body iron stores have been implicated in the pathogenesis of diabetes mellitus. However, the molecular mechanisms involved are unclear. The liver plays a central role in homeostasis of iron and glucose in the body. Mice deficient in hepcidin (the central regulator of systemic iron homeostasis) (Hamp1^-/- mice) accumulate iron in the liver in vivo. The effects of such iron loading on hepatic insulin signaling and glucose metabolism are not known. METHODS:Hepatocytes isolated from Hamp1^-/- mice were studied for markers of insulin signaling (and its downstream effects), glucose production, expression of gluconeogenic and lipogenic enzymes, and markers of AMPK (AMP-activated protein kinase) activation and oxidative stress. These parameters were studied both in the absence and presence of insulin, and also with the use of an iron chelator. RESULTS:Akt in the insulin signaling pathway was found to be activated in the Hamp1^-/- hepatocytes to a greater extent than wild-type (WT) cells, both under basal conditions and in response to insulin. Incubation of the Hamp1^-/- hepatocytes with an iron chelator attenuated these effects. There was no evidence of oxidative stress or AMPK activation in the Hamp1^-/- hepatocytes. Glucose production by these cells was similar to that by WT cells. Gene expression of key gluconeogenic enzymes was decreased in these cells. In addition, they showed evidence of increased lipogenesis. CONCLUSIONS:Hepatocytes from Hamp1^-/- mice showed evidence of greater sensitivity to the effects of insulin than WT hepatocytes. This may explain the insulin-sensitive phenotype that has been reported in classical hemochromatosis.

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