A Hepatocyte Growth Factor Receptor (Met)–Insulin Receptor hybrid governs hepatic glucose metabolism

Met is the transmembrane tyrosine kinase cell surface receptor for Hepatocyte Growth Factor (HGF) and is related to the insulin receptor (INSR) tyrosine kinase. Here we report that the HGF–Met axis controls metabolism by stimulating hepatic glucose uptake and suppressing hepatic glucose output. We show that Met is essential for an optimum hepatic insulin response; Met exerts this by virtue of directly engaging the insulin receptor (INSR) in a Met–INSR hybrid complex. We found that the HGF–Met system restores insulin responsiveness in a mouse model of insulin refractoriness. The results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential in the clinical setting of type 2 diabetes.