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.
Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. kenjoji@bidmc.harvard.edu
Keiichi
K
Enjyoji
Ko
K
Kotani
Chandrashekar
C
Thukral
Benjamin
B
Blumel
Xiaofeng
X
Sun
Yan
Y
Wu
Masato
M
Imai
David
D
Friedman
Eva
E
Csizmadia
Wissam
W
Bleibel
Barbara B
BB
Kahn
Simon C
SC
Robson
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