Impaired Glucose Tolerance in the Absence of Adenosine A1 Receptor Signaling
- Robert Faulhaber-Walter1⇓,
- William Jou1,
- Diane Mizel1,
- Lingli Li1,
- Jiandi Zhang1,
- Soo Mi Kim1,
- Yuning Huang1,
- Min Chen1,
- Josephine P. Briggs2,
- Oksana Gavrilova1 and
- Jurgen B. Schnermann1
- 1National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- 2National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland
- Corresponding author: Robert Faulhaber-Walter, .
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.
RESEARCH DESIGN AND 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.
- Received January 18, 2011.
- Accepted June 28, 2011.
- © 2011 by the American Diabetes Association.
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