Insulin resistance in liver cirrhosis is not associated with circulating Retinol Binding Protein 4

Background/Aims: Retinol Binding Protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and increased RBP4 expression by adipocytes has been proposed to mediate its pro-diabetogenic effects (Yang et al, Nature 2005; 436: 356). Moreover, elevated serum RBP4 indicated overt or impending insulin resistance in lean, obese and type 2 diabetic subjects (Graham et al, NEJM 2006; 354: 24). As insulin resistance is present in nearly all patients with liver cirrhosis and dysregulation(s) of adipocytokines have been shown in cirrhosis, we evaluated RBP4 in patients with chronic liver diseases (CLD).

Methods: Serum RBP4 was measured in 111 non-diabetic CLD patients and 99 age- and sex-matched healthy controls, alongside other adipocytokines and various clinical and laboratory parameters. Findings in patients were confirmed in an animal model of cirrhosis (bile duct ligation) by quantification of RBP4 gene expression in normal and cirrhotic rat liver.

Results: Serum RBP4 was significantly reduced in CLD patients compared with healthy controls (p<0.001), and closely correlated with the stage of liver cirrhosis (Child-Pugh or MELD). CLD patients without cirrhosis showed normal RBP4 concentrations, which correlated with serum glucose, insulin secretion (C-peptide) and inversely with insulin sensitivity (HOMA index). In patients with liver cirrhosis, however, RBP4 was not correlated with glucose metabolism or other adipokines like resistin or adiponectin, but closely linked to the hepatic biosynthetic capacity, fibrotic changes in liver histology or clinical complications such as portal hypertension. In an animal model of experimental cirrhosis, hepatic RBP4 gene expression decreased in cirrhotic liver.

Conclusion: RBP4 appears, unlike in obesity or type 2 diabetes, not to be a relevant systemic factor in the pathogenesis of insulin resistance in liver cirrhosis. Furthermore, RBP4 may not be a clinically useful marker indicating overt or impending insulin resistance, in the case of a concomitant liver dysfunction.