A1 receptor deficiency causes increased insulin and glucagon secretion in mice
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.
References (50)
- et al.
Coffee consumption and risk of type 2 diabetes mellitus
Lancet
(2002) - et al.
Potentiation of arginine-induced glucagon secretion by adenosine
Life Sci
(1981) - et al.
Activation of adenosine A1 receptors by drugs to lower plasma glucose in streptozotocin-induced diabetic rats
Auton Neurosci
(2000) - et al.
Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat
Int J Biochem
(1988) - et al.
Effects of analogues of adenosine and methyl xanthines on insulin sensitivity in soleus muscle of the rat
FEBS Lett
(1984) - et al.
Effect of adenosine deaminase and an adenosine analogue on insulin sensitivity in soleus muscle of the rat
FEBS Lett
(1983) - et al.
Effects of CGS 9343B (a putative calmodulin antagonist) on isolated skeletal muscle. Dissociation of signaling pathways for insulin-mediated activation of glycogen synthase and hexose transport
J Biol Chem
(1995) - et al.
Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse
Diabetes Res Clin Pract
(1992) - et al.
Regulation by insulin of gluconeogenesis in isolated rat hepatocytes
Biochim Biophys Acta
(1976) - et al.
Evidence for an inhibitory A1 subtype adenosine receptor on pancreatic insulin-secreting cells
Eur J Pharmacol
(1987)
International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors
Pharmacol Rev
Actions of caffeine in the brain with special reference to factors that contribute to its widespread use
Pharmacol Rev
Coffee consumption and risk of type 2 diabetes: a systematic review
J Am Med Assoc
Facilatation by adenosine of the action of insulin on the accumulation of adenosine 3′,5′-monophosphate lipolysisand glucose oxidation in isolated fat cells
Eur J Biochem
Tissue-specific effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats
FASEB J
Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance
Diabetes Obes Metab
A1 adenosine receptor antagonism improves glucose tolerance in Zucker rats
Am J Physiol
Adenosine and the regulation of insulin secretion by isolated rat islets of Langerhans
Biochem J
Effects of adenosine, 2-deoxyadenosine and N6-phenylisopropyladenosine on rat islet function and metabolism
Biochem J
Effect of pertussis toxin on A1-receptor-mediated inhibition of insulin secretion
Br J Pharmacol
Effects of adenosine, adenosine triphosphate and structural analogues on glucagon secretion from the perfused pancreas of rat in vitro
Br J Pharmacol
Evidence for an A2-subtype adenosine receptor on pancreatic glucagon secreting cells
Br J Pharmacol
Adenosine receptors mediate synergistic stimulation of glucose uptake and transport by insulin and by contractions in rat skeletal muscle
J Clin Invest
Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contractions
Diabetes
Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise
Diabetes
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These authors contributed equally.