Elsevier

Biochemical Pharmacology

Volume 74, Issue 11, 3 December 2007, Pages 1628-1635
Biochemical Pharmacology

A1 receptor deficiency causes increased insulin and glucagon secretion in mice

https://doi.org/10.1016/j.bcp.2007.08.006Get rights and content

Abstract

Adenosine influences metabolism and the adenosine receptor antagonist caffeine decreases the risk of type 2 diabetes. In this study the metabolic role of one adenosine receptor subtype, the adenosine A1R, was evaluated in mice lacking this receptor [A1R (−/−)]. The HbA1c levels and body weight were not significantly different between wild type [A1R (+/+)] and A1R (−/−) mice (3–4 months) fed normal lab chow. At rest, plasma levels of glucose, insulin and glucagon were similar in both genotypes. Following glucose injection, glucose tolerance was not appreciably altered in A1R (−/−) mice. Glucose injection induced sustained increases in plasma insulin and glucagon levels in A1R (−/−) mice, whereas A1R (+/+) control mice reacted with the expected transient increase in insulin and decrease in glucagon levels. Pancreas perfusion experiments showed that A1R (−/−) mice had a slightly higher basal insulin secretion than A1R (+/+) mice. The first phase insulin secretion (initiated with 16.7 mM glucose) was of the same magnitude in both genotypes, but the second phase was significantly enhanced in the A1R (−/−) pancreata compared with A1R (+/+). Insulin- and contraction-mediated glucose uptake in skeletal muscle were not significantly different between in A1R (−/−) and A1R (+/+) mice. All adenosine receptors were expressed at mRNA level in skeletal muscle in A1R (+/+) mice and the mRNA A2AR, A2BR and A3R levels were similar in A1R (−/−) and A1R (+/+) mice. In conclusion, the A1R minimally affects muscle glucose uptake, but is important in regulating pancreatic islet function.

Introduction

Adenosine is the endogenous ligand for four pharmacologically well defined G protein-coupled adenosine receptors, the A1, A2A, A2B and A3 receptors [1]. Caffeine can block all the adenosine receptors, although the affinity of caffeine is much higher for the A1, A2A and A2B receptors than for the A3 receptor [2]. Several, but not all, epidemiological studies have concluded that coffee consumption decreases the risk of developing non-insulin-dependent diabetes (type 2 diabetes) [3], [4]. Coffee contains several thousand active components including chlorogenic acid and magnesium [2]. Nevertheless it is tempting to speculate that the inverse association between coffee and type 2 diabetes may be due to the effects of caffeine, and hence that adenosine acting on one or more of the caffeine sensitive receptors is important in the regulation of glucose homeostasis. It is not certain which receptor is involved and how it transmits its signal although the results of previous studies using pharmacological approaches have suggested that the A1R is the adenosine receptor most involved in metabolism [5], [6], [7], [8].

Adenosine and adenosine agonists have also been shown to decrease insulin secretion [9], [10], [11] and increase glucagon secretion [12], [13], [14] in pancreas. Regarding skeletal muscle, some studies suggest that adenosine has positive effects on glucose uptake [15], [16], [17], [18], whereas others indicate negative effects [19], [20], [21], [22]. It is still unclear which adenosine receptor underlies these changes.

In the present study, we used A1 knock out [A1R (−/−)] mice to examine the role of A1 receptors in glucose homeostasis. The results indicate that the A1R is not critical for regulating muscle glucose uptake, but strongly influences pancreatic islet function.

Section snippets

Materials

Midazolam was from Hoffmann-La Roche (Nutley, NJ). Fentanyl was from Janssen Pharmaceuticals (Neuss, Germany). Trasylol was from Bayer (Leverkusen, Germany). 2-Deoxy-d-[1,2-3H]glucose (2-DG) and carboxy-[14C]inulin were from Amersham Bioscience (Buckinghamshire, UK). Human insulin (Actrapid) was from Novo Nordisk (Bagsvaerd, Denmark). 2-Chloro-N6-cyclopentyladenosine (CCPA) and tribromoethanol were from Sigma (St. Louis, MO). Scintillation liquid Ultima Gold was from Packard (Meriden, CT).

Body weight and HbA1c levels

Body weight and HbA1c values were not significantly different between A1R (+/+) and A1R (−/−) mice (Table 1). The HbA1c data thus do not indicate an abnormal blood glucose status over a longer period of time in the A1R (−/−) mice. The A1R (−/−) mice fed normal lab chow had a normal body weight despite the fact that a major antilipolytic factor (the A1R) has been eliminated [5], [35], [36]. The weight of the abdominal adipose tissue was also not significantly different between genotypes (data

Discussion

The major findings of the present study are: (1) an essentially normal glucose homeostasis and (2) altered pancreatic hormone responses to a glucose challenge in A1R (−/−) mice fed normal lab chow. That glucose levels were normal despite elevated plasma insulin responses to the glucose challenge in the A1R (−/−) mice suggested the presence of peripheral insulin resistance. Since skeletal muscle is quantitatively the most important organ for glucose disposal during hyperinsulinemia [39], glucose

Acknowledgements

We thank Astrid Nordin and Britt-Marie Nilsson for skilled technical assistance. We thank Dr. Eva Björkstrand for help with the HbA1c determinations, Dr Shi-Jin Zhang for help with dissecting out muscles and Dr Elisabetta Daré for help with the real time RT-PCR. The studies were supported by grants from the Swedish Research Council, Novo Nordisk Foundation, the Swedish Diabetes Foundation, Albert Påhlsson Foundation, Crafoord Foundation and by Biovitrum.

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    These authors contributed equally.

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