Department of Biological Sciences, Chapman University, Orange, California, USA
* Author to whom correspondence should be addressed at: Department of Biological Sciences, Chapman University, One University Drive, Orange, CA 92866, USA. Tel.: +714 997 6995; Fax: +714 532 6048; E-mail: sumida{at}chapman.edu
(Received 8 March 2004; first review notified 4 May 2004; in revised form 15 May 2004; accepted 31 May 2004)
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ABSTRACT |
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INTRODUCTION |
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Freinkel et al. (1963) were among the first to report a decline in blood glucose levels after acute ethanol (hereafter and perhaps inappropriately, also referred to as alcohol) consumption. Studies by Krebs and coworkers (Krebs, 1968
; Krebs et al., 1969
) determined that alcohol could reduce the gluconeogenic capacity from lactate in perfused livers from fasted rats. The inhibitory effect of ethanol on glucose production capacity as observed by many investigators (Krebs, 1968
; Arky and Freinkel, 1969
; Krebs et al., 1969
) support a possible mechanism for the prevalence of alcohol-induced hypoglycaemia. Albeit not a consistent observation, reports in fasted humans (Freinkel et al., 1963
; Searle et al., 1974
; Wolfe et al., 1976
; Wilson et al., 1981
) and fasted rats (Souza and Masur, 1981
, 1982
, 1984
) have demonstrated a significant decline in blood glucose concentration after an acute ethanol load.
While acute ethanol ingestion may lead to hypoglycaemia in the glycogen-depleted state, the impact of chronic alcohol consumption remains to be elucidated. This is of considerable import given that some alcoholics tend to significantly reduce their food intake (Salaspuro, 1993; Addolorato et al., 1998
), or if they do consume food, their diet is low in carbohydrates (Addolorato et al., 1998
). Under these circumstances of fasting or inadequate nutritional intake, renal and hepatic glycogen stores would be compromised. For the alcoholic, this may result in greater susceptibility for alcohol-induced hypoglycaemia upon their next consumption of ethanol (Emanuele et al., 1998
). Further, in humans, chronic alcohol consumption has been observed to decrease first-pass ethanol metabolism that is exacerbated with fasting (DiPadova et al., 1987
). This would elevate the availability of alcohol and could augment its attenuating effect upon glucose production capacity. Moreover, reports in humans (Maly and Sasse, 1991
) and in rats (Maly and Sasse, 1985
) suggest that there are sex differences in the location of hepatic alcohol dehydrogenase, sex differences in fatty acid accumulation within the liver resulting from chronic alcohol consumption in rats (Shevchuk et al., 1991
), and sex differences in the alcohol elimination rate in humans (Van Thiel et al., 1988
; Lieber, 2000
). Thus, the effect of chronic alcohol consumption upon glucose production capacity between males and females is unknown.
The purpose of the current investigation was to assess whole-body glucose production and glucose carbon recycling after a 48-h fast in male and female rats in the presence and absence of an acute ethanol injection. Specifically, with use of standard tracer techniques to measure in vivo rates of glucose appearance and apparent glucose carbon recycling, we sought to determine if chronic alcohol consumption resulted in: (1) any sex difference in glucose production capacity in the absence of acute ethanol and (2) any sex difference in glucose production capacity in the presence of acute ethanol. Based upon previous studies (Souza and Masur, 1981, 1982
, 1984
), we hypothesized that an acute alcohol injection would lower the gluconeogenic capacity of all animals. In addition, we anticipated a much larger reduction in glucose production from female rats chronically fed ethanol compared to male rats. Finally, we expected the ethanol fed female rats to demonstrate greater susceptibility to alcohol-induced hypo-glycaemia in the presence of an acute ethanol load.
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MATERIALS AND METHODS |
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All experiments were performed at the same time of day. On the day of the experiment, animals were anesthetized (Ketamine, Rompun, Acepromazine) and catheters (filled with saline) were inserted into the carotid artery (advanced to the aortic arch) and jugular vein (advanced to the right atrium). Once the catheters were secured, the animal was kept warm under a lamp. When blood samples were not collected, the blood pressure was monitored in-line via the carotid artery catheter with use of a blood pressure transducer (Grass-Astro Med, PT-300). For most of the experiments, no additional anaesthesia was needed during the experimental period. In a few instances (a total of three animals), when blood pressures started to elevate, animals were given an additional dose of anaesthesia (Ketamine). For a small minority of animals (n = 1, 2 per group) we collected an initial blood sample to determine the initial pH and blood gas pressures (Radiometer, ABL 5). For all animals, a primed-constant infusion of dual labelled glucose, U-14C at 0.15 µCi/min and 6-3H at 0.45 µCi/min, was initiated via the venous catheter at 75 min, after a priming dose equivalent to 60 times the minute infusion rate was given. Starting at 15 min, sequential arterial blood samples (150 µl) were collected every 15 min via the carotid catheter. At time 0, a small abdominal incision was made and either water (4 g/kg) or an equivalent volume (4 g/kg) of an ethanol solution (40% w/v) was injected directly into the stomach. The ethanol dose has previously been observed to elicit alcohol-induced hypoglycaemia in rats (Souza and Masur, 1982
, 1984
). About half the animals (n = 7) from each group (MC, ME, FC, or FE) were injected with water and the other half (n = 8) were injected with ethanol. For the animals given the ethanol injection, a small blood sample (
50 µl) was collected in heparinized tubes 15 min after the injection and every 15 min thereafter. The sample was centrifuged and the plasma used for the determination of alcohol content (Sigma Kit, Catalogue No. 3325). Prior to the end of the experiment, an additional blood sample was collected from the same small set of animals from each group (n = 1, 2) for the determination of the ending pH and blood gas pressures (PO2 and PCO2). To minimize the amount of blood collected from each animal, we chose to use a representative subset of animals to examine pre- and post- blood pH and blood gas pressures. At 60 min, all animals were killed and the entire liver and right kidney was rapidly removed and freeze-clamped with aluminium tongs pre-cooled in liquid nitrogen. These samples were stored at 85°C for subsequent analyses.
For all animals, the sequential arterial blood samples (150 µl) collected throughout the experiment were deproteinized in ice-cold perchloric acid (8% w/v), centrifuged, and the supernatant neutralized with 3.5 N KOH. A portion of the supernatant was used for the analysis of glucose (Raabo and Terkildsen, 1960
). For the remaining portion, ion-exchange chromatography was used for the separation of radioactive glucose (Donovan and Sumida, 1990
) and the subsequent determination of glucose specific activity (GSA). Duplicate aliquots of the glucose eluant derived from the ion-exchange procedure were evaporated to dryness (Organomation, N-Evap dry bath with aluminium beads) and reconstituted in distilled water. The measurement of 14C and 3H activities was determined via liquid scintillation counting. Samples of the liver and kidney were pulverized under liquid nitrogen and solubilized in KOH (Good et al., 1933
) for the determination of glycogen content (Dubois et al., 1956
).
Glucose rates of appearance (Ra) and disappearance (Rd) were calculated using non-steady-state equations (Steele, 1959), as follows.
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RESULTS |
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Water injection
Given that each group would be injected with ethanol, we chose to similarly inject all groups with water (our version of a sham operation). We also assumed that there would be no impact upon whole body glucose production between groups in the absence of ethanol (i.e. water injection). However, to substantiate this position, we injected water into the stomach for both male (MC, n = 7 and ME, n = 7) and female (FC, n = 7 and FE, n = 7) animals from each group. As anticipated, whole-body glucose production (Fig. 1) did not significantly vary between control-fed male rats (18.69 ± 1.26 µmol/kg/min) and female rats (19.47 ± 0.79 µmol/kg/min). Further, the glucose Ra did not significantly vary within the control groups throughout the experimental period. In support, the blood glucose concentration did not significantly vary between male and female rats fed the control diet and injected with water at any time point during the experimental period (Fig. 2). While the ME animals demonstrated a lower glucose Ra compared to controls, it was not statistically significant. In contrast, whole-body glucose production was significantly lower from the FE animals compared to the controls for most of the experimental period (Fig. 1). In addition, the glucose Ra was significantly lower for FE toward the end of the experimental time period compared to the initial level. Further, only the FE animals were observed to have a significantly lower blood glucose concentration compared to the control animals (MC and FC) beginning at 15 min and throughout the remaining experimental period. Apparent rates of glucose carbon recycling (Fig. 3) were similar in control groups and did not significantly vary during the experimental period (MC, 13.10 ± 0.80 µmol/kg/min and FC, 13.60 ± 0.77 µmol/kg/min). In contrast, the apparent rate of glucose carbon recycling (10.25 ± 0.72 µmol/kg/min) was significantly lower for the FE animals compared to controls. Consistent with the glucose Ra, glucose carbon recycling from FE animals was significantly lower at the last two points compared to their initial level.
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DISCUSSION |
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Taken together, the most significant observations in the current study were the lower glucose production capacity and the lower blood glucose concentration in female rats chronically fed the ethanol diet in the absence and presence of alcohol. While we did not observe a decline in whole-body glucose production and glucose carbon recycling at the initial time points from the FE animals given the water injection, we did observe such a decline for a majority of the time points. It is possible that we inadvertently evoked a significant catecholamine response and a corresponding elevation in blood glucose concentration in a few FE animals when administering the anaesthesia that did not decline within the hour prior to our sampling. In support, the glucose Ra and apparent glucose carbon recycling for the FE animals given the water injection was significantly lower towards the end of the experiment compared to the initial levels. We note that these final levels were similar to the FE group prior to the injection of ethanol (Figs 4 and 5). Alternatively, the inability to achieve statistical significance for these initial time points may simply be attributable to normal fluctuations. Of interest, these fluctuations were not observed for the FE animals injected with ethanol, as glucose production capacity was significantly lower prior to and throughout the experiment resulting in a significantly lower blood glucose concentration at all time points.
The mechanism by which ethanol induces a reduction in glucose production capacity in all groups could be attribut-able to the inhibitory effect of alcohol upon hepatic gluconeogenesis (Krebs, 1968; Arky and Freinkel, 1969
; Krebs et al., 1969
; Van Thiel et al., 1988
). In support, we observed significant decreases in glucose carbon recycling from all groups after the ethanol injection. Although our observed rates of glucose carbon recycling cannot be equated with absolute rates of gluconeogenesis, these rates constitute a relative index of Cori cycle activity. In this regard, our results provide additional in vivo evidence of the inhibitory effects of ethanol upon glucose production capacity. Further, we observed a greater reduction in glucose Ra and glucose carbon recycling from all chronically fed ethanol animals after the alcohol injection, suggesting exacerbated effects upon glucose production capacity.
In contrast to prior animal studies (Souza and Masur, 1981, 1982
, 1984
), the ethanol injection did not bring about alcohol-induced hypoglycaemia for any of the groups. While we have no explanation for the discrepancy, alcohol-induced hypoglycaemia is not a consistent observation. Abel (1996)
failed to observe any decline in blood glucose concentration in female rats 4 h after ethanol doses of 2 or 4 g/kg. Further, using various stable isotopes in humans, Siler et al. (1998)
observed a significant inhibition of gluconeogenesis in the absence of any change in blood glucose concentration 5 h after the alcohol consumption. Similarly, using tritiated glucose and examining the glucose kinetics over 5.5 h in men, Yki-Jarvinen et al. (1988)
reported a decline in glucose Ra attributable to ethanol infusion that was matched by a comparable decrease in glucose utilization, resulting in an absence of hypoglycaemia. Alternatively, our use of radioactive isotopes represents whole body glucose production. As such, it is possible that while ethanol inhibited hepatic glucose production, renal glucose production is augmented to help prevent a severe hypoglycaemic episode. Jones et al. (1971)
reported in anaesthetized dogs that the infusion of ethanol caused a significant increase in net renal glucose production and Chan et al. (1980)
reported elevations in renal gluconeogenic enzymes following an acute and chronic ingestion of ethanol in rats.
Conversely, blood glucose homeostasis could be attributable to alterations in peripheral glucose clearance. Normally, in vivo glucose production and glucose disposal are tightly regulated in order to maintain euglycaemia. Xu et al. (1996) observed that ethanol caused an acute insulin resistance in skeletal muscle thereby inhibiting whole body glucose utilization. However, the mechanism for sex differences in glucose production and regulation after chronic ethanol consumption and in the presence of an acute alcohol exposure remains unresolved. Although we failed to observe significant differences in the glucose clearance rate between groups, the ME animals demonstrated clearance rates that were significantly lower than their initial level (i.e. prior to the ethanol injection). Further, the RaRd (Fig. 7) provided an examination of the ability to match rates of glucose production and glucose utilization at a specific time point. Following the alcohol injection, the ME animals were able to match the marked declines in glucose Ra with comparable reductions in glucose clearance. In contrast, the FE animals failed to match the lower glucose production with decreased rates of glucose utilization. Given that the major site of glucose disposal is skeletal muscle, ME animals appear to maintain the ability to regulate glucose production with peripheral glucose utilization. However, because the FE animals demonstrate higher plasma alcohol levels, we cannot rule out the possibility that the amount of alcohol exposure is what caused the more dramatic decline in glucose production capacity and/or the failure to appropriately lower peripheral glucose clearance. We have preliminary evidence to support that chronic ethanol consumption elicits a distinct decline in gluconeogenic capacity from female compared to male rats in the absence of alcohol (Sumida et al., 2000
), albeit potential sex differences from alcohol consumption upon peripheral glucose utilization remains to be determined.
Despite an equivalent amount of alcohol injected, the tendency toward higher plasma alcohol contents exhibited by females fed the control diet compared to males is consistent with previous studies in rats (Rivier, 1993; Da-Silva et al., 1996
) and humans (Van Thiel et al., 1988
; Lieber, 2000
). Women have a lower amount of gastric alcohol dehydrogenase compared to men, which decreases first-pass ethanol metabolism (Lieber, 2000
). In addition, the distribution space for alcohol is smaller in women than in men (Van Thiel et al., 1988
). Further, our observation that FE animals had higher plasma alcohol contents is consistent with human studies which reported that the sex effect is exacerbated by alcoholism (Frezza et al., 1990
; Lieber, 2000
). In contrast to human studies, we did not observe a higher plasma alcohol content from ME animals compared to male controls. In alcoholic and nonalcoholic men, fasting has been observed to decrease first-pass ethanol metabolism and appears to be dose dependent (DiPadova et al., 1987
). As such, it is possible that our 48-h fast and elevated alcohol dose eliminated the normal differences observed between ME and MC animals. For alcoholic women, it has been reported that they lose the gastric protective barrier provided by first-pass ethanol metabolism (Lieber, 2000
). Assuming this also occurs in rodents, fasting would have little impact on the FE animals, which supports our observed plasma alcohol levels.
Collectively, the sex difference we report in animals underscores the deleterious effects of chronic alcohol con-sumption for females. Our female animals chronically fed the ethanol diet had lower resting blood glucose concentrations compared to all other groups. Further, after the ethanol injection FE animals had lower rates of glucose production attributable to lower rates of gluconeogenesis, higher plasma alcohol levels, and lower blood glucose concentrations. Accordingly, this may contribute to a greater vulnerability of alcoholic females to the toxic effects of ethanol. Specifically, the combination of low blood glucose concentration and high plasma alcohol content would enhance the pharmaco- logic effects of ethanol. Moreover, the higher plasma alcohol levels could generate elevated hepatotoxic products (e.g. acetaldehyde) resulting in greater susceptibility to medical complications.
The lower liver glycogen content in female compared to male rats following the 48-h fast was unexpected, but consistent with a prior report (Teutsch, 1984). Despite these differences, they appear to have no impact upon our observed glucose kinetics. In support, despite the difference in hepatic glycogen content there was no significant difference in glucose Ra and blood glucose concentration between MC and FC after the water or ethanol injection. There was also no significant difference in glycogen content between MC and ME or between FC and FE despite differences in glucose production for the FE animals. Further, the liver was clamped at the end of the experiment after both the water and alcohol injection. Because neither condition yielded a significant difference between a given group injected with water versus a given group injected with ethanol, the total glycogen content was pooled for each group. It was only upon pooling all values (water and ethanol injection) for each group (n = 15) that a significant difference was subsequently attained between groups.
We recognize that a potential limitation might be the use of anesthetized animals. However, the use of conscious animals requires the elimination of any acute stress (i.e. sympathetic activation), which would evoke a counter-regulatory response and the subsequent rise in blood glucose. Naïve control animals (i.e. unaccustomed to drinking alcohol) will not voluntarily drink ethanol. In addition, we wanted to ensure an equivalent dose of alcohol based upon body weight to be given through the gastric route. To accomplish this, the use of conscious animals would have required an intraperitoneal injection or gastric intubation and a corresponding counter-regulatory response. While intravenous infusion was an option, this would have avoided differences attributable to gastrointestinal ethanol oxidation and would have limited the potential for any immediate effects of alcohol upon the liver (a key glucose regulatory organ). The use of anaesthetized animals allowed us to inject the ethanol directly into the stomach. Further, the use of conscious animals requires chronic cannulation and the necessary recovery time where animals do not immediately eat after the surgery. Souza et al. (1981) reported an attenuated effect of ethanol in eliciting a decline in blood glucose concentration from chronically starved rats. As such, we attempted to maximize our ability to elicit alcohol-induced hypoglycaemia by exposing the animals to their first and only bout of fasting prior to the experiment. Further, the only general effect of ketamine/xylazine upon glucose homeostasis in rats we are aware of involves glucose intolerance when given a glucose load (Hindlycke and Jansson, 1992
) most likely attributable to insulin resistance. If the anaesthesia were to affect glucose homeostasis in the resting state (an absence of a glucose load), then the insulin resistance should have markedly elevated our blood glucose concentration for all animals. In contrast, we observed no elevation, but we cannot rule out the possibility of an alcohol/anaesthesia interaction. Even if there was an interaction, this would help to explain our inability to elicit hypoglycaemia suggesting that the effects of chronic alcohol consumption in the conscious (unanaesthetized) state might be more detrimental than what we report. Finally, due to the use of anaesthetized animals and the initial time required for the radioactive glucose to distribute into various pools, we only examined the glucose kinetics for 1 h after the ethanol injection. It is possible that more time is required for alcohol to elicit its effect upon blood glucose levels. However, given the prior studies in both rats (Abel, 1996
) and humans (Yki-Jarvinen et al., 1988
; Siler et al., 1998
) it seems unlikely that the glucose kinetics over an additional time period would have altered our conclusion.
In summary, the results indicate that, in female rats, chronic alcohol consumption lowers whole-body glucose production in the absence of alcohol exposure compared to controls. In all groups, following an acute ethanol injection, in vivo glucose production rates decline, attributable to a reduction in gluconeogenesis, but this did not result in significantly lower blood glucose concentrations. Further, after acute alcohol exposure, both ME and FE had lower whole-body glucose production rates compared to corresponding controls. In addition, FE (compared to ME) failed to match the decline in glucose production with a comparable decrease in glucose clearance. Finally, that FE continued to demonstrate reduced rates of glucose production and lower blood glucose levels in both the absence and presence of alcohol suggests a greater vulnerability to the pharmacologic effects of ethanol, enhanced susceptibility to alcohol-induced hypoglycaemia, or elevated risks for medical complications.
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ACKNOWLEDGEMENTS |
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