Article

Impaired glucose tolerance in the absence of adenosine A1 receptor signaling.

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Diabetes (impact factor: 8.29). 08/2011; 60(10):2578-87. DOI:10.2337/db11-0058 pp.2578-87
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

A1-ADO receptor
 
ADO/A1AR signaling contributes
 
Body composition
 
Body weight
 
decreased Akt phosphorylation
 
dysfunctional insulin secretory mechanism
 
epididymal fat-pad weights
 
fasting plasma glucose
 
glucose homeostasis
 
Glucose metabolism
 
hyperinsulinemic-euglycemic clamp studies
 
increased fat mass
 
insulin-controlled glucose homeostasis
 
magnetic resonance imaging
 
metabolic regulation
 
pathophysiological mechanisms
 
plasma insulin
 
reduced glucose uptake
 
slower glucose clearance
 
white adipose tissue