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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 4  |  Issue : 2  |  Page : 35-41

Effects of adenosine and caffeine on blood glucose levels in rats


1 Department of Physiology, School of Medicine and Pharmacy, University of Rwanda College of Medicine and Health Sciences, Huye, Republic of Rwanda, East Africa
2 Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Kwara
3 Department of Physiology, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria
4 Department of Physiology, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria

Date of Web Publication16-Aug-2018

Correspondence Address:
Dr. Abdullateef Isiaka Alagbonsi
Department of Physiology, School of Medicine and Pharmacy, University of Rwanda College of Medicine and Health Sciences, Huye, Republic of Rwanda
East Africa
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_2_16

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  Abstract 


Background: Reports from previous studies on the effects of adenosine and caffeine on blood glucose are controversial and inconclusive. The present study sought to investigate the effect of acute adenosine infusion and caffeine injection on blood glucose level in rats. Materials and Methods: Thirty-four male albino rats (300–400 g) were randomly divided in a blinded-fashion into six groups, namely, Group I (n = 6) received normal saline (0.1–0.2 ml), Group II (n = 6) received adenosine (347.8 μg/kg/min), Group III (n = 5) received caffeine (6 mg/kg), followed by adenosine (347.8 μg/kg/min), Group IV (n = 5) were diabetic rats that received adenosine (347.8 μg/kg/min), Group V (n = 6) received caffeine (6 mg/kg), and Group VI (n = 6) received nifedipine (300μg/kg), followed by caffeine (6 mg/kg). Administrations were done through the femoral vein, while blood samples were taken from the carotid artery for glucose measurement. Results: Adenosine caused a reduction in blood glucose level in normal and diabetic rats, though the reduction was more noticeable in diabetic rats. Pretreatment of rats with caffeine completely abolished the adenosine-induced reduction in blood glucose and produced an exaggerated increase in blood glucose comparable to the level seen in rats that received caffeine alone. Pretreatment of rats with nifedipine reduced the caffeine-induced hyperglycemia by two-third. Conclusion: This study suggests that adenosine receptors could be of therapeutic target in the treatment of Type 1 diabetes due to its blood glucose-lowering potential in both diabetic and normal rats. It also suggests that intracellular calcium mobilization is more implicated in caffeine-induced hyperglycemia than adenosine receptor antagonism, even though other unidentified mechanism(s) remain to be explored.

Keywords: Adenosine, blood glucose, caffeine, diabetes, nifedipine


How to cite this article:
Alagbonsi AI, Salman TM, Salahdeen HM, Alada AA. Effects of adenosine and caffeine on blood glucose levels in rats. Niger J Exp Clin Biosci 2016;4:35-41

How to cite this URL:
Alagbonsi AI, Salman TM, Salahdeen HM, Alada AA. Effects of adenosine and caffeine on blood glucose levels in rats. Niger J Exp Clin Biosci [serial online] 2016 [cited 2018 Nov 12];4:35-41. Available from: http://www.njecbonline.org/text.asp?2016/4/2/35/239099




  Introduction Top


Adenosine, a purine nucleoside, is produced by most tissues that utilize adenosine triphosphate as an energy source. It is an endogenous ligand for the four pharmacologically well-defined G-protein-coupled receptors widely distributed in mammalian tissues.[1] Adenosine receptors are divided into four major classes; designated A1, A2a, A2b, and A3, all of which have been isolated, cloned, and expressed.[2] These receptor subtypes differ in their influence on cell metabolism and their tissue distribution.[1]

Adenosine has multiple well-established cardioprotective effects, but its role in glucose metabolism remains controversial. For instance, in adipocytes and erythrocytes, adenosine has been consistently shown to enhance glucose metabolism.[3] In cardiac muscle, several lines of evidence support a role for adenosine receptor activation in increasing glucose uptake in response to insulin [4] or without insulin in dog, cat,[5] and rats.[6] In contrast to the studies mentioned above, Challis et al. have provided evidence for an opposing action of adenosine on insulin stimulation of glucose transport in isolated rodent muscle.[7]

Only a few inconsistent studies have examined the direct effect of adenosine on blood glucose. Adenosine injected intraperitoneally at a bolus dose of 0.05–0.2 mg/kg produced hyperglycemia in rodents.[8] The increase in blood glucose concentration was proposed to be due to increased gluconeogenesis and glycogenolysis.[8],[9] Conversely, adenosine has been shown to inhibit gluconeogenesis in isolated hepatocytes.[10] Recently, endogenous adenosine, through A1 adenosine receptor, tonically suppresses plasma concentrations of insulin, glucose, and lactate; exogenous adenosine lowers insulin levels and raises glucose and lactate concentrations; A1 adenosine receptor activation attenuates the hyperglycemia and hyperlactatemia elicited by exogenous adenosine; A2A receptors promote the hypoinsulinemia, hyperglycemia, and hyperlactatemia triggered by exogenous adenosine; and endogenous adenosine, through A1 and A2A receptors, contributes to hypoxia-induced hyperglycemia in fetal sheep.[11]

Caffeine, 1, 3, 7-trimethylxanthine, is a member of methylxanthine group, which also includes theophylline, paraxanthine, and theobromine. It is one of the most widely consumed behaviorally active substances in the world.[12] It is commonly found in many food substances including coffee, chocolate, and tea.[13] It is also found in kola nut which is a common masticatory in Nigeria.[14]

In studies conducted several years ago, blood glucose levels were reported to be higher,[15] lower,[16] or unchanged [17] after coffee or caffeine administration. Recently, caffeine has been shown to improve glucose tolerance in diabetic but not normal rats.[18] In addition, epidemiological studies have shown that high intake of coffee reduces the risk of development of insulin resistance and Type 2 diabetes.[19] In small-scale clinical trial, coffee consumption has also been shown to lower fasting glucose concentrations, an indicator of improved insulin resistance.[20] Surprisingly, chronic decaffeinated coffee consumption in rodents improved both whole-body insulin action and glucose disposal, but these effects disappear when caffeine was added to the mixture.[21] Similarly, administration of 4.45 mg/kg alkaloid caffeine, caffeinated coffee, decaffeinated coffee, or placebo of equivalent volume to human showed that caffeine elevated blood glucose approximately 160% compared with caffeinated coffee and approximately 320% compared with decaffeinated coffee. Decaffeinated coffee resulted in the lowest rise in blood glucose of all the groups (including placebo), suggesting that a component of coffee other than caffeine is responsible for its role in preventing Type 2 diabetes.[22] This may be due to lactone as it has been shown to counteract the effect of caffeine through adenosine receptors.[23]

Majority of previous studies have investigated the effect of adenosine on glucose metabolism using glucose loading and/or insulin clamping, while majority that investigated caffeine action on glucose homeostasis administered it chronically. Moreover, the effect of caffeine and adenosine on blood glucose remain inconclusive. The present study sought to investigate the effect of acute adenosine infusion and caffeine injection on blood glucose level in rats.


  Materials and Methods Top


Animals

Thirty-four male albino rats (300–400 g) were housed at room temperature with free access to food and water ad libitum and were maintained on a 12-h light/dark cycle, with the lights on from 7:00 am. Principles of laboratory animal care (NIH publication No. 85-23, revised 1985) were followed. All experiments have been examined and approved by our institutional ethics committee.

Experimental protocol

Each animal was fasted for 16–18 h before the start of each experiment with access to water only.[24],[25] This was to ensure that the blood glucose measured was only the fasting one and not a result of recently absorbed food. Anesthesia was induced by an intraperitoneal injection of 0.6 ml/100g body weight of 25% urethane. The animal was laid supine and firmly secured on the dissecting board. A carotid artery and a femoral vein were exposed, an incision was made and a size one cannula already flushed with 100 IU/ml heparinized saline was inserted into each of these blood vessels.

The trachea was then intubated to allow free air flow. At the end of the surgical procedure, sodium heparin, 300 IU per/kg body weight was administered intravenously to prevent blood clotting. A 30-min stabilization period was then observed after the surgical procedure. Drugs were injected through the femoral vein, while samples were collected from the carotid artery for blood glucose measurements. The rats were divided into 6 groups as shown below:

Group I (control, n = 6): A bolus injection of normal saline (0.1–0.2 ml) was given intravenously through the femoral vein after measuring the basal blood glucose.

Group II (adenosine, n = 6): After measuring the basal blood glucose, adenosine (Alfa Aeser, Avocado, US) dissolved in normal saline was infused at a dose of 347.8 μg/kg/min [26] through the femoral vein for 1 h using an injection apparatus (Palmer, England).

Group III (caffeine and adenosine, n = 5): Caffeine (Alfa Aeser, Avocado, US) dissolved in normal saline was first given to the rats intravenously (6 mg/kg)[24],[25] through the femoral vein after measuring the basal blood glucose. Thirty minutes after caffeine injection, another basal glucose measurement was obtained from the carotid artery. Then, adenosine (347.8 μg/kg/min) dissolved in normal saline was infused through the femoral vein for 1 h.

Group IV (adenosine in diabetic rats, n = 5): After measuring the basal blood glucose, adenosine (347.8 μg/kg/min) dissolved in normal saline was then infused through the femoral vein of alloxan-induced diabetic rats for 1 h.

Group V (caffeine, n = 6): After measuring the basal blood glucose, a bolus injection of caffeine (6 mg/kg) dissolved in normal saline was given intravenously through the femoral vein.

Group VI (nifedipine and caffeine, n = 6): Each animal was first given 300 μg/kg of nifedipine (Mepha, Switzerland) through the femoral vein after measuring the basal blood glucose. Thirty minutes after nifedipine injection, another basal glucose measurement was obtained from the carotid artery. Then, caffeine (6 mg/kg) dissolved in normal saline was injected through the femoral vein.

In all the groups, blood samples were obtained from the carotid artery at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min postinjection.

Induction of diabetes mellitus

Diabetes was induced in the rats by intraperitoneal injection of 100 mg/kg alloxan monohydrate (Sigma Chemical Co., St. Louis, MO, USA) dissolved in physiological saline. The presence of diabetes was verified by blood glucose concentrations >200 mg/dl in blood obtained from the cut tip of the tail. Animals were rendered diabetic within 10 days of induction.

Measurement of blood glucose

Measurement of glucose from each blood sample was done with OneTouch Ultra glucometer, which uses the glucose oxidase method [27] as its principle. Results of glucose measurement using glucometers have been shown to correlate excellently with the result obtained from standard laboratory methods.[28] Apart from this, glucometers are easy to use and can measure blood glucose in very small blood samples.

Statistical analysis

Data were analyzed with ANOVA and Student's t-test, and subjected to post hoc Tukey for multiple comparison where required using GraphPad Prism Version 5.0.3.0 (San Diego CA, USA) and were presented as mean ± standard error of the mean. P ≤ 0.05 were considered statistically significant.


  Results Top


Effect of normal saline on blood glucose levels

All the blood glucose levels observed after injection of normal saline were not statistically different from the basal level (P > 0.05). This indicated that normal saline had no effect on blood glucose level of rats [Figure 1] and [Figure 2].
Figure 1: Effects of adenosine on blood glucose level in caffeine-pretreted and untreated rats. Value are expressed as mean ± standard error of the mean (n = 6). (*P < 0.05, **P < 0.01, ***P < 0.01 vs. control value of same duration)

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Figure 2: Effect of caffeine on blood glucose level in nifedipine-pretreated and untreated rats. Values are expressed as mean ± standard error of the mean (n = 6). (*P < 0.05, **P < 0.01, ***P < 0.01 vs. control value of same duration)

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Effect of adenosine on blood glucose level in normal rats

Adenosine caused a significant reduction in blood glucose level. The decrease in blood glucose level became apparent some 15 min into infusion of adenosine and continued throughout the infusion period [Figure 1] and [Table 1].
Table 1: Effects of adenosine on blood glucose level (mg/dl) in nondiabetic and diabetic rats

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Effects of adenosine on blood glucose level of caffeine-pretreated rats

Initial blockade of the adenosine receptors with caffeine abolished the effect of adenosine on blood glucose level and caused highly significant increase in blood glucose (P < 0.001) in a pattern similar to that seen in rats that received caffeine only [Figure 1] and [Figure 2]. The increase in blood glucose level attained its peak at 30 min when it increased by 102% (from 104 ± 1.0 mg/dl to 210 ± 1.2 mg/dl) [Figure 1].

Effects of adenosine on blood glucose of diabetic rats

The blood glucose levels in diabetic rats are significantly higher than normal rats. While the reductions in blood glucose level caused by adenosine in normal rats are only significant at 30 min (P < 0.05), 45 min (P < 0.01), and 60 min (P < 0.01), the reductions in blood glucose by adenosine in diabetic rats were significant throughout the observation periods (P < 0.01) [Table 1]. In addition, the extent of reduction in blood glucose by adenosine in diabetic rats is more than the reduction observed in normal rats. For instance, the reduction in blood glucose caused by adenosine at 15 min in normal rats was only 5 mg/dl but was as much as 26 mg/dl in diabetic rats [Figure 3].
Figure 3: Reduction in blood glucose levels of normal and diatetic rats treated with adenosine. *P < 0.05, **P < 0.01, ***P < 0.01 versus normal rats value of same duration

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Effect of caffeine on blood glucose level

Blood glucose level significantly increased throughout the postinjection observation periods (P < 0.01, P < 0.001), reaching its highest level of 193 ± 13.5 mg/dl at 20 min postinjection and remained sustainably high throughout the remaining postinjection period [Figure 2].

Effects of caffeine on blood glucose level of nifedipine-pretreated rats

Pretreatment of the rats with nifedipine drastically reduced (by two-third), though did not completely abolish the caffeine-induced hyperglycemia [Figure 2].


  Discussion Top


Reports of previous studies on the effect of adenosine on blood glucose have been contradictory. For instance, it has been shown to increase,[8] decrease,[10] or have no effect on blood glucose. In the present study, we have shown that adenosine, a natural nonselective adenosine receptor agonist, reduced blood glucose level in rats. To further substantiate this claim, we investigated the direct effect of adenosine receptors antagonism and also observed the effect of adenosine in rats whose adenosine receptors have been blocked. Administration of caffeine, a nonselective adenosine receptors blocker, caused an exaggerated increase in blood glucose. Similarly, administration of adenosine in caffeine pretreated rats showed an exaggerated increase in blood glucose that is comparable to that seen in rats that received caffeine alone. These observations convincingly showed that stimulation of adenosine receptors reduces blood glucose, while their antagonism/blockade increases blood glucose. The observed hyperglycemic effect of caffeine in this study in rats is similar to previous reports in dogs [24],[25] and humans.[29]

Is adenosine-induced reduction in blood glucose-dependent on endogenous insulin? Most of the previous studies have investigated the relationship between adenosine and insulin signaling on glucose uptake. Moreover, these studies have employed hyperinsulinemic-hyperglycemic clamp in investigating their relationship. In the present study, we investigated the role of insulin in the blood glucose lowering effect of adenosine by comparing the effect of adenosine in normal (with normal blood glucose and insulin level) and Type 1 diabetic rats (with very high blood glucose and insulin deficiency). We observed that acute adenosine infusion reduced blood glucose level in both normal and Type 1 diabetic rats. The reduction in blood glucose following adenosine infusion in this study is contrary to the previously reported hyperglycemia in previous studies that bolusly injected adenosine in rodents [9],[8] but similar to the blood-glucose-lowering effect of chronic 5'-N-ethylcarboxamidoadenosine (NECA, another nonselective adenosine receptor agonist) administration reported in streptozotocin-induced diabetic rats.[30]

Alloxan-induced Type 1 diabetes mellitus is characterized by little or no insulin and very high blood glucose due to its destruction of the pancreatic β-cell. One would expect the hyperglycemia in diabetic condition to stimulate increased glucose uptake and consequently glucose clearance, but the deficiency of insulin in Type 1 diabetic rats hinders the glucose clearance, especially by insulin-dependent tissues. Therefore, the substantial reduction in blood glucose following adenosine infusion in diabetic rats in this study suggests that the adenosine receptors in diabetic rats, though less expressed than in normal rats,[30] could be more sensitive to agonist stimulation than in normal rats. This observation suggests that adenosine could have acted directly or indirectly by improving insulin secretion to reduce blood glucose in diabetic rats. However, the latter appears more reasonable as a previous study has shown the potential of NECA (another nonselective adenosine receptor agonist) in enhancing pancreatic β-cell regeneration and accelerating restoration of normoglycemia in zebrafish and mice.[31]

However, it is also noteworthy that the reduction of blood glucose caused by adenosine in diabetic rats was more noticeable than in normal rats. The previous study has shown that NECA significantly reduced blood glucose but increased insulin in diabetic mice, while it has no effect on both in normal rats.[30] Similarly, adenosine receptors have been reported to be more active in adipocytes of obese Zucker rats than lean rats.[32] The enhanced activity in isolated adipocytes was reported not to be due to high receptor numbers or to excess adenosine in the medium surrounding the isolated cells, but rather to a high tonic activity of the receptors.[33] In fact, the mRNAs of adenosine receptors (except A1 type) are more expressed in normal mice than in diabetic mice.[30] Similarly, there are no differences in the expression of mRNAs for all the adenosine receptor types in normal rats, while A1 type mRNA expression is more than all others in diabetic mice.[30] Taking together, these evidence show that adenosine signaling; together with its consequent reduction of blood glucose, is more active in diabetic state than in normal state. Thus, the potential of adenosine to enhance pancreatic β-cell regeneration, increase insulin secretion, and reduce blood glucose in diabetic rats in a similar manner like NECA did in mice requires further investigation.

Previous study has suggested that the ergogenic action of caffeine could be as a result of its potential to antagonize adenosine receptors,[12] stimulate adrenaline release and spare glucose,[34] and increase intracellular calcium mobilization.[35] Similarly, it is of interest to note that the extent to which caffeine increased blood glucose is extremely more than the extent to which adenosine reduced it. This is a pointer to the fact that additional mechanism(s) that might be independent of adenosine receptors antagonism are involved in caffeine-induced hyperglycemia. It is also a pointer to the fact that the contribution of adenosine receptors antagonism to its hyperglycemic effect is minimal and that other independent mechanism(s) contribute(s) substantially.

In human, caffeine ingestion had been shown to reduce insulin-mediated glucose disposal during hyperinsulinaemic clamps [36] and during an oral glucose tolerance tests.[37] Furthermore, caffeine has consistently been shown to stimulate adrenaline release in vivo in humans [38] by increasing adrenal medullary secretion in response to direct stimulation or by indirectly increasing central stimulation, causing increased sympathetic outflow.[29] It has also been shown to indirectly stimulate the release of catecholamines by the stimulation of the splanchno-adrenal system.[39] In rats, caffeine and theophylline are known to increase catecholamines secretion from perfused adrenal glands.[40]

Adrenaline is a well-known hyperglycemic agent.[41] Adrenaline increases blood glucose level through the process of hepatic glycogenolysis and gluconeogenesis.[42] Moreover, studies employing the euglycemic-hyperinsulinemic clamp have reported a 40%–50% decline in whole-body insulin-stimulated glucose disposal at plasma adrenaline concentration of 2–4 nM.[43] Due to the potency of adrenaline in the antagonism of insulin, it was speculated that the caffeine-induced increase in plasma adrenaline concentration may mediate its inhibitory effect on insulin action and consequently increased blood glucose observed in this study.

It is of interest to know if intracellular Ca 2+ has a role to play in caffeine-induced hyperglycemia. Caffeine-induced catecholamine release from the adrenal medulla has been shown to be secondary to intracellular Ca 2+ mobilization from some storage sites in this gland.[44] An intracellular Ca 2+ store in the adrenal medulla chromaffin cells that are sensitive to caffeine has been identified.[45] The importance of the caffeine-sensitive store is beginning to emerge in part because caffeine-induced release of Ca 2+ implicates the presence of Ca 2+-induced Ca 2+ release, a Ca 2+ release mechanism involving Ca 2+-dependent gating of the ryanodine receptor of the endoplasmic reticulum.[46] Splanchnic nerve endings make synaptic-like contacts with chromaffin cells.[47] Acetylcholine (ACh) released from splanchnic nerve endings consequently evokes catecholamine release from chromaffin cells by activation of cholinergic receptors. Thus, in vivo catecholamine release requires Ca 2+ influx through the voltage-dependent Ca 2+ channels at two different sites in the adrenal medulla: Splanchnic nerve endings and chromaffin cells. Both N and P/Q-type Ca 2+ channels control ACh release from preganglionic splanchnic nerve endings while L-type Ca 2+ channels do not. L-type Ca 2+ channels are involved in norepinephrine and epinephrine release from chromaffin cells.[48]

In the present study, treatment of rats with nifedipine before caffeine injection caused a two-third reduction in the blood glucose level when compared to rats that received only caffeine injection. The significant attenuation by two-third of caffeine-induced hyperglycemia with blockade of L-type calcium channels in this study shows that calcium plays an important role in caffeine's action on blood glucose. Moreover, because of the reported involvement of L-type Ca 2+ channels in catecholamine release from the adrenal medulla,[48] prior blockade of the channels with nifedipine was thought to reduce caffeine-induce catecholamine release. Reduced catecholamine release from the chromaffin cells of the adrenal medulla might thus account for the reduction on blood glucose level in nifedipine-pretreated rats following caffeine ingestion. This speculation in the present study using rat is consistent with a previous report from our laboratory which reported a complete abolition of caffeine's effect on blood glucose level in dogs pretreated with a combination of prazosin and propranolol (alpha and beta-adrenergic receptors blocking agents respectively).[25] The previous human study has also shown that β-adrenergic receptor blockade by propranolol abolished the caffeine-induced impairment of glucose tolerance.[49] While this study provided evidence for the significance of calcium in caffeine-induced hyperglycemia, lack of complete abolition of the caffeine-induced hyperglycemia also suggests that other calcium-independent mechanism(s) may be involved.


  Conclusion Top


This study suggests that adenosine receptors could be of therapeutic target in the treatment of Type 1 diabetes due to its blood glucose-lowering potential in both diabetic and normal rats. It also suggests that intracellular calcium mobilization is more implicated in caffeine-induced hyperglycemia than adenosine receptor antagonism, even though other unidentified mechanism(s) remain to be explored.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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