Deletion of Cd39/Entpd1 results in hepatic insulin resistance

Abstract

Objective: Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type-2 purinergic (P2 )- receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ecto-enzyme that hydrolyzes extracellular nucleotides to regulate purinergic signaling.

Research Design and Methods: We have studied Cd39/Entpd1 null mice to determine whether any associated changes in extracellular nucleotide concentrations influence glucose homeostasis.

Results: Cd39/Entpd1 null mice have impaired glucose tolerance and decreased insulin sensitivity with significantly higher plasma insulin levels. Hyperinsulinemic euglycemic clamp studies indicate altered hepatic glucose metabolism. These effects are mimicked in vivo by injection into wild-type mice of either exogenous ATP or an ecto-ATPase inhibitor, ARL-67156 and by exposure of hepatocytes to extracellular nucleotides in vitro. Increased serum Interleukin-1β, Interleukin-6, IFN-γ and TNF-α levels are observed in Cd39/Entpd1 null mice in keeping with a pro-inflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-JNK/SAP in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of IRS-2 with impeded insulin signaling.

Conclusions: CD39/Entpd1 is a modulator of extracellular nucleotide signaling and also influences metabolism. Deletion of Cd39/Entpd1 both directly and indirectly impacts insulin regulation and hepatic glucose metabolism. Extracellular nucleotides serve as “metabolokines” indicating further links between inflammation and associated metabolic derangements.