Impaired glucose tolerance in the absence of adenosine A1 receptor signaling

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.Adenosine (ADO), a purine nucleoside, is a ubiquitous product of ATP breakdown, with a large variety of regulatory functions. ADO effects are mediated by four receptors (AR): A1, A2a, A2b, and A3, each showing an organ-specific expression pattern and different half-maximal effective concentration (EC50), thus facilitating differential effects (1). ARs mediate downstream effects mostly via G-protein–coupled receptors that are either stimulatory (A2a and A2b) or inhibitory (A1 and A3) to adenylate cyclase. The resulting increase or decrease of cAMP induces downstream signaling by triggering phosphorylation activation of key enzymes (2).A role of the metabolic byproduct of ATP utilization, adenosine, in the regulation of glucose uptake and utilization makes physiological sense. Nevertheless, previous studies of the effect of ADO on glucose transport have yielded conflicting results in that insulin sensitivity and/or glucose uptake were reported as either decreased (3–6) or increased (7–9). The availability of mice with adenosine receptor deletions offers a new way to assess the role of a chronic reduction in ADO signaling on glucose tolerance. Recently, we discovered a nephropathic phenotype in an A1AR-deficient Akita hybrid mouse model of type 1 diabetes, suggesting a relevant role for A1AR signaling in maintaining glucose homeostasis (10). Another recent study showed that mice with A1AR deletion have a higher fat content with aging (11). Because of the well-established relationship between excess body weight and insulin resistance, we considered it possible that the phenotype of A1AR-deficient mice may include the development of glucose intolerance and insulin resistance. In the current study, we have therefore used A1AR-deficient mice to examine the hypothesis that ADO signaling via A1AR contributes to glucose homeostasis. Our main findings support this notion in that A1AR-deficient mice show a defect in glucose tolerance that seems to be a result of insulin resistance.