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Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

¹ Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
² Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Corresponding author: Keiichi Enjyoji, kenjoji{at}bidmc.harvard.edu

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 ectoenzyme 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, interferon-, and tumor necrosis factor- levels are observed in Cd39/Entpd1-null mice in keeping with a proinflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-Jun NH₂-terminal kinase/stress-activated protein kinase in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of insulin receptor substrate-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.

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