title: Impaired glucose tolerance in the absence of adenosine A1 receptor signaling.
abstract: OBJECTIVE
  The role of adenosine (ADO) in the regulation of glucose homeostasis is not clear. In the current study, we used A1-ADO receptor (A1AR)-deficient mice to investigate the role of ADO/A1AR signaling for glucose homeostasis.
  
  
  METHODS
  After weaning, A1AR(-/-) and wild-type mice received either a standard diet (12 kcal% fat) or high-fat diet (HFD; 45 kcal% fat). Body weight, fasting plasma glucose, plasma insulin, and intraperitoneal glucose tolerance tests were performed in 8-week-old mice and again after 12-20 weeks of subsequent observation. Body composition was quantified by magnetic resonance imaging and epididymal fat-pad weights. Glucose metabolism was investigated by hyperinsulinemic-euglycemic clamp studies. To describe pathophysiological mechanisms, adipokines and Akt phosphorylation were measured.
  
  
  RESULTS
  A1AR(-/-) mice were significantly heavier than wild-type mice because of an increased fat mass. Fasting plasma glucose and insulin were significantly higher in A1AR(-/-) mice after weaning and remained higher in adulthood. An intraperitoneal glucose challenge disclosed a significantly slower glucose clearance in A1AR(-/-) mice. An HFD enhanced this phenotype in A1AR(-/-) mice and unmasked a dysfunctional insulin secretory mechanism. Insulin sensitivity was significantly impaired in A1AR(-/-) mice on the standard diet shortly after weaning. Clamp studies detected a significant decrease of net glucose uptake in A1AR(-/-) mice and a reduced glucose uptake in muscle and white adipose tissue. Effects were not triggered by leptin deficiency but involved a decreased Akt phosphorylation.
  
  
  CONCLUSIONS
  ADO/A1AR signaling contributes importantly to insulin-controlled glucose homeostasis and insulin sensitivity in C57BL/6 mice and is involved in the metabolic regulation of adipose tissue.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. rofaulhaber@web.de
authors.forename: Robert
authors.initials: R
authors.lastname: Faulhaber-Walter
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.forename: Jiandi
authors.initials: J
authors.lastname: Zhang
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Yuning
authors.initials: Y
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Josephine P
authors.initials: JP
authors.lastname: Briggs
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Jurgen B
authors.initials: JB
authors.lastname: Schnermann
mesh_terms: D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004435:Eating; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D043682:Receptor, Adenosine A1