Deletion of cd39/entpd1 results in hepatic insulin resistance.
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.


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-1beta, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha 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 NH(2)-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.
Enjyoji
Keiichi
K
Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. kenjoji@bidmc.harvard.edu
Kotani
Ko
K
Thukral
Chandrashekar
C
Blumel
Benjamin
B
Sun
Xiaofeng
X
Wu
Yan
Y
Imai
Masato
M
Friedman
David
D
Csizmadia
Eva
E
Bleibel
Wissam
W
Kahn
Barbara B
BB
Robson
Simon C
SC
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D002001:Adipose Tissue, Brown / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology*; D001081:Apyrase / Q000235:genetics* / Q000276:immunology*; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004734:Energy Metabolism / Q000502:physiology; D015309:Glucose Clamp Technique; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006946:Hyperinsulinism / Q000276:immunology / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
D015703:Antigens, CD; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D001081:Apyrase; C067869:CD39 antigen