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Published in final edited form as: Psychoneuroendocrinology. 2013 Sep 13;38(12):10.1016/j.psyneuen.2013.09.005. doi: 10.1016/j.psyneuen.2013.09.005

Fasting-Induced Increase in Plasma Ghrelin is Blunted by Intravenous Alcohol Administration: a Within-Subject Placebo-Controlled Study

Lorenzo Leggio 1,2,3,*, Melanie L Schwandt 4, Emily N Oot 1, Alexandra A Dias 1, Vijay A Ramchandani 5
PMCID: PMC3844072  NIHMSID: NIHMS525180  PMID: 24090583

Summary

Ghrelin is a 28-amino acid peptide produced mainly by mucosal neuroendocrine cells lining the fundus of the stomach. Preclinical and clinical studies suggest that ghrelin plays a role in alcoholism. Furthermore, human laboratory studies indicate that acute oral administration of alcohol results in reduced circulating ghrelin. As ghrelin is primarily produced in the stomach, one question never previously explored is whether alcohol administered intravenously (IV) results in similar decrease in ghrelin levels. Thus, this study analyzed the potential effects of IV alcohol administration on plasma ghrelin levels in healthy nonsmoking social drinkers (n = 44) who received either a 180-minute IV infusion of 6% v / v alcohol or 0.9% normal saline in two separate counterbalanced sessions. At each session, participants arrived having fasted for ~7 hours and received a light breakfast 60 minutes before the infusion. The percent change (%Δ) in ghrelin levels was 4.5-fold less in the alcohol condition than the saline condition. In fact, there was only a modest change in ghrelin levels from baseline in the IV alcohol condition (9.6%Δghrelin) while in the IV saline condition there was a robust change (43.4%Δghrelin). There was a trend toward significance in %Δghrelin in the alcohol condition compared to the placebo condition (F[1,33] = 3.3, p = 0.07). While the exact mechanisms by which alcohol influences ghrelin levels are unclear, alcohol may act directly in the stomach by inhibiting ghrelin secretion and/or release, and may also attenuate ghrelin levels systemically. Although IV alcohol did not reduce circulating ghrelin levels, as seen in previous studies with oral alcohol administration, the present findings suggest that, despite bypassing the stomach, alcohol still attenuated circulating ghrelin levels, i.e. the fasting-induced increase in circulating ghrelin was blunted by IV alcohol administration. These findings lead us to hypothesize that alcohol might affect ghrelin signaling not only via a local effect on the stomach mucosa, but also via a systemic effect.

Keywords: Alcohol, Ghrelin, Insulin, GLP-1, PYY, Intravenous Alcohol Administration

INTRODUCTION

Ghrelin is a 28-amino acid peptide produced mainly by mucosal neuro-endocrine P/D1 cells lining the fundus of the human stomach, and acts as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a) (Inui et al., 2004; Kojima et al., 1999). Ghrelin activates hypothalamic orexigenic neurons and inhibits anorectic neurons to induce hunger (Toshinai et al., 2003). Accordingly, ghrelin stimulates feeding in animals (Tschop et al., 2000) and humans (Druce et al., 2005). Additionally, GHS-R1a’s are also highly co-expressed with dopamine receptors in other brain regions [e.g., midbrain, raphe nuclei and ventral tegmental area) (Katayama et al., 2000; Zigman et al., 2006)], suggesting that ghrelin modulates reward processing.

Consistent with the literature on the role of ghrelin in food reward (Dickson et al., 2011; Schellekens et al., 2012) and with the known overlap in pathways regulating food and alcohol intake (Leggio et al., 2011; Tomasi and Volkow, 2013), a growing body of preclinical and clinical literature [reviewed in:(Leggio, 2010)] suggests that ghrelin is involved in alcohol reward and plays an important role in alcohol-related seeking behaviors, e.g. locomotor activity, dopamine release, conditioned place preference, and free-choice drinking in rodents (Jerlhag et al., 2009; Jerlhag et al., 2011; Landgren et al., 2012), as well as alcohol craving and consumption in humans (Addolorato et al., 2006; Koopmann et al., 2012; Leggio et al., 2012).

Given the link between ghrelin and alcohol-related behaviors, an important question that has been investigated is how alcohol affects blood ghrelin levels. Studies with alcohol-dependent patients indicate that blood ghrelin levels are lower in actively drinking alcoholic patients (Addolorato et al., 2006; Badaoui et al., 2008; de Timary et al., 2012; Koopmann et al., 2012; Leggio et al., 2012) and higher in those who are abstinent (de Timary et al., 2012; Kim et al., 2005; Kim et al., 2013; Koopmann et al., 2012; Kraus et al., 2005; Leggio et al., 2012; Wurst et al., 2007). Findings with alcohol-dependent patients, however, are not without inconsistencies, probably due to several differences across studies [e.g., differences in metabolic conditions and control groups; see also:(Leggio, 2010)]. One of the potential issues to consider is that in most of these studies with alcoholic patients, the “actively drinking” or “abstinent” status of the patients was primarily based on self-reported data. A few placebo-controlled human laboratory studies have provided more accurate information, at least on the effects of an acute oral administration of alcohol on blood ghrelin levels. Specifically, Calissendorff and colleagues (Calissendorff et al., 2005) conducted a within-subject controlled study in eight healthy individuals who consumed alcohol (0.55 g/kg) during one session and water in another counterbalanced session. Compared to baseline, blood total ghrelin levels significantly decreased after consuming alcohol, while no changes were observed after drinking water. The same group replicated these results in two subsequent studies (Calissendorff et al., 2006; Calissendorff et al., 2012), one of which demonstrated that both total and active ghrelin levels continued to significantly decline after alcohol ingestion (Calissendorff et al., 2006). In another within-subject, counterbalanced controlled study by Zimmermann and colleagues (Zimmermann et al., 2007), nine healthy men consumed 0.6 g/kg alcohol mixed with grapefruit juice on one day and a matched volume of grapefruit juice on another day. Ghrelin levels rapidly and significantly declined after drinking the alcoholic beverage, reaching 66% below baseline after 75 minutes and remained at this level for the duration of observational period (120 minutes). Furthermore, ghrelin levels were lower after consuming the alcoholic drink compared to the non-alcoholic juice. In summary, human laboratory studies conducted with rigorous experimental designs and under well-controlled conditions have consistently shown that oral administration of alcohol results in reduced circulating ghrelin. These studies have all examined changes in ghrelin levels after an oral alcohol administration (Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007). Given that ghrelin is primarily produced in the stomach (Inui et al., 2004), an additional question never explored is whether bypassing the gastrointestinal tract by using alcohol administered intravenously (IV) has the same inhibitory effect on ghrelin levels. Therefore, the goal of this study was to analyze the potential effects of IV alcohol administration on plasma ghrelin levels. In addition to ghrelin, we also assessed other related appetitive peptides, namely insulin, glucagon-like peptide 1 (GLP-1), and Peptide YY (PYY) in order to explore if IV alcohol may also affect these other hormones.

METHODS

Study Population

Participants were healthy nonsmoking social drinkers recruited for a laboratory study, approved by the Institutional Review Board at the National Institutes of Health (NIH), investigating age×gender interactions on the effects of IV alcohol administration. Details of the main study were reported in: (Vatsalya et al., 2012). In brief, potential participants were evaluated by a screening consisting of medical history, physical exam, electrocardiogram and laboratory tests. Participants were stratified by gender and age (young [21–25 years] and older [55–65 years]). Younger females included in the study had normal menstrual cycles (based on self-reports of regular frequency of menses and low variation in cycle length in the past year) and a negative urine pregnancy test prior to each study session. Older females included were in the postmenopausal phase for at least 1 year prior to participation. Participants were excluded from this study if they had a present or prior clinically significant medical disease; current history of axis-I psychiatric illness; current or prior history of any alcohol or substance abuse or dependence; positive urine drug screen; self-reported abstinence from alcohol; pregnancy or intention to become pregnant; menstrual cycle irregularities; use of oral contraceptive pills in female subjects; or use of prescription or over-the-counter medications known to interact with alcohol pharmacokinetics within 2 weeks of the study. The sample of the main study consisted of 48 participants (Vatsalya et al., 2012).

Procedures

Each participant performed two sessions, i.e. IV alcohol or saline solution, on two different days and in a counterbalanced order. During each session, participants arrived at the NIH Clinical Center (Bethesda, MD) having fasted since midnight (~7 hours) and received a light breakfast (~300 kcal) 60 minutes before the infusion in order to standardize the effects of food on alcohol metabolism during the study (Ramchandani et al., 2001; Vatsalya et al., 2012). No additional food was provided after breakfast, or after the start until the infusion was over. A breathalyzer test (Alcotest 7410 plus; Draeger Safety Diagnostics Inc., Irving, TX) was performed to ensure zero breath alcohol concentration, a urine pregnancy test was performed on the female subjects to ensure that they were not pregnant, and an indwelling IV catheter was inserted. At each session, participants received a 180-minute infusion of either 6% v / v alcohol or 0.9% normal saline. During the alcohol session, the infusion-rate profile was determined by a physiologically based pharmacokinetic model for alcohol (Ramchandani et al., 1999) in order to bring participants to a target breath alcohol concentration of 50 mg% at 15 minutes and then maintain (or clamp) it for an additional 165 minutes [for additional details, see:( Vatsalya et al., 2012)].

Hormone Assays

Plasma samples were collected right before the start of the IV infusion (time point 0) and at the end of the IV infusion (time point +180 minutes). Samples were frozen at −80 °C immediately after collection and then thawed and centrifuged at 3000 ×g for five minutes prior to assay set up. Assays were performed using the Milliplex Map Kit Human Metabolic Hormone Magnetic Bead Panel (Millipore Corporation, Billerica, MA). Plates were run using the MAGPIX instrument (Luminex Corporation, Austin, TX) and data were extracted with Luminex xPONENT software. Preliminary data check, analysis and cleaning was then conducted using Milliplex Analyst Software (Millipore Corporation, Billerica, MA).

Statistical Analysis

The data from the hormone assays were examined for outliers, and values more than 3 standard deviations from the mean were excluded from analyses. Data were analyzed using a repeated measured design in SAS PROC MIXED, with experimental session (alcohol vs. saline) as the within-subject factor. Each model included age group, gender, and sequence of alcohol/saline presentation as covariates. In addition, race, body mass index, and number of heavy drinking days were initially included in each model. If any of these were not significant or at least showed a trend, then they were removed.

RESULTS

Out of 48 participants enrolled in the main study (Vatsalya et al., 2012), samples from four participants were not available. Therefore, all analyses for this study were conducted in a final sample of 44 nonsmoking social drinkers, whose characteristics are reported in Table 1.

Table 1.

Characteristics of the study participants (n = 44).

Total Sample
(n=44)		 Younger Females
(n=11)		 Younger Males
(n=11)		 Older Females
(n=11)		 Older Males
(n=11)
Age [years] 41.2 ± 18.5 23.1 ± 1.0 23.0 ± 1.1 59.0 ± 3.9 59.6 ± 1.9
Height [cm] 170.4 ± 10.2 165.4 ± 7.2 176.8 ± 9.9 162.3 ± 6.9 177.1 ± 6.8
Weight [kg] 73.4 ± 15.6 61.4 ± 11.5 77.6 ± 11.1 66.9 ± 9.4 87.9 ± 15.8
Body Mass Index [kg/m2] 25.1 ± 4.0 22.3 ± 3.2 24.8 ± 2.3 25.3 ± 2.4 28.1 ± 5.3
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The main goal of this study was to analyze the effects of the IV conditions (alcohol vs. saline) on the changes in plasma ghrelin levels, expressed as percentage of change (%Δ) compared to baseline. The percentage of change in ghrelin levels was 4.5-fold less in the alcohol condition than in the saline condition. Specifically, there was only a modest change in ghrelin levels from baseline in the IV alcohol condition (9.6%Δghrelin), while there was a robust change in the saline condition (43.4%Δghrelin). There was a trend toward significance in the difference in %Δghrelin between the two IV conditions (F[1,33] = 3.3, p = 0.07) (Figure 1) with a small effect size, i.e. Cohen’s dz = 0.4. No significant effects of gender or age on %Δghrelin were found, nor were there any significant interactions between IV conditions and either gender or age.

Figure 1.

Figure 1

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There was a trend toward significance (#F[1,33] = 3.3, p = 0.07) for an effect of the intravenous drug condition (alcohol vs. saline) on the percent change from baseline of plasma active ghrelin levels.

Additionally, changes in insulin, GLP-1 and PYY from baseline and possible effects of the IV conditions on these changes were analyzed. There were robust changes in plasma insulin levels from baseline, both in the alcohol (−58.5%Δinsulin) and saline (−70.4%Δinsulin) conditions, with no significant difference between the two IV conditions. There was a significant age effect on the %Δinsulin levels, such that the change in insulin levels from baseline was significantly more pronounced in the younger individuals compared to the older ones (p = 0.007); however, no IV condition×age interaction was found. Changes in plasma GLP-1 levels in the alcohol (24.8%ΔGLP-1) and saline (−3.7%ΔGLP-1) conditions were not significantly different between the two groups. Similarly, changes in plasma PYY levels in the alcohol (24.8%ΔPYY) and saline (−3.7%ΔPYY) conditions were not significantly different between the two groups. There was a significant gender effect on the %ΔPYY levels such that the change in PYY levels from baseline was significantly more pronounced in males as compared to females (p = 0.02).

DISCUSSION

In this study, consistent with the physiologically expected increase in ghrelin during fasting conditions (Inui et al., 2004), we observed a robust increase in plasma ghrelin levels from baseline (zero minutes) to the end of the 180-minute IV saline infusion. By contrast, there was only a minor change in plasma ghrelin levels from baseline to the end of the IV alcohol infusion. The difference in the change in plasma ghrelin levels across the two IV conditions was 4.5-fold and approached significance, suggesting that IV alcohol administration blunted fasting-induced plasma ghrelin increase. There are no conclusive data explaining the mechanisms by which alcohol reduces circulating ghrelin levels. Nonetheless, several possible explanations may be hypothesized. Alcohol may act locally and directly in the stomach by inhibiting ghrelin secretion and/or release, and may also act systemically to inhibit ghrelin levels, as detailed next.

The present findings suggest that, despite bypassing the stomach, alcohol still attenuated circulating ghrelin levels. However, IV alcohol administration only blunted fasting-induced ghrelin increase, while the previous studies with oral alcohol administration reported a significant reduction in circulating ghrelin (Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007). It is possible that bypassing the stomach via the IV route of administration results in a weaker effect of alcohol on circulating ghrelin levels. Therefore, consistent with other research (Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007), our data suggest that the local and direct effects of alcohol on the gastric mucosa play a major role on the ability of alcohol to acutely reduce circulating ghrelin. This local effect (and the lack thereof, in our study) is consistent with the evidence that gastric ghrelin-secreting cells are a closed-type endocrine cell but lie within close proximity to the gastric lumen (Date et al., 2000; Kojima et al., 1999; Lu et al., 2012). The local effects of alcohol in reducing circulating ghrelin levels might be due to the ability of alcohol to acutely induce an inflammatory response in ghrelin-producing cells within oxyntic glands, and an increase in intragastric acidity. Furthermore, molecular studies also support a chemosensory role for ghrelin cells due to their gastric location and their potential for direct sensing of luminal contents (Lu et al., 2012). An additional possible explanation for why alcohol administered IV has a weaker effect on circulating ghrelin than alcohol administered orally is that alcohol administered IV bypasses the hepatic first-pass metabolism. It has been suggested that hepatic cells are involved in regulating the transition of ghrelin from portal to central venous compartments across the liver, thus affecting systemic ghrelin levels (Goodyear et al., 2010). It is conceivable that alcohol may influence the effects of the liver on systemic ghrelin levels, and these effects may be weaker when alcohol is administered IV rather than orally. In summary the lack of all these local (gastric and portal) effects may explain why, IV alcohol resulted in a weaker effect on circulating ghrelin levels in our study, compared to previous studies with oral alcohol administration (Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007).

Our data also indicate that, despite bypassing the stomach and the portal system, alcohol still affects circulating ghrelin. A possible explanation for this systemic effect of alcohol on ghrelin levels may be the ability of alcohol to inhibit ghrelin secretion and/or release via vagal system activation. In fact, vagus nerve activation results in inhibited ghrelin secretion (Heath et al., 2004; Lee et al., 2002; Murakami et al., 2002). By contrast, both fasting condition (a time when vagal activity is at a nadir) and truncal vagotomy increase ghrelin secretion (Lee et al., 2002; Williams et al., 2003). Alcohol activates the vagus nerve (Nadareishvili et al., 2004; Penna et al., 1985; Varga et al., 1994), hence alcohol-induced vagal activation may inhibit ghrelin secretion. Notably, while in most of the previous studies alcohol was administered orally as a single dose and then systemic ghrelin levels were measured over time, here we measured systemic ghrelin levels before and after an IV alcohol ‘clamp’ during which the alcohol level was constantly maintained at a target value. A possible overall conclusion is that while an acute oral dose of alcohol may result in a sharp reduction in circulating ghrelin primarily via a local (gastric and portal) and direct effect, constant breath alcohol levels may act systemically on vagal activity, thus exerting a tonic inhibitory force on ghrelin secretion. In summary, alcohol administered IV, by bypassing the stomach and the portal system, might result only in a vagal activation responsible for blunting fasting-induced ghrelin increase, but without sufficient strength to decrease ghrelin levels. However, in order to fully test these mechanisms, future studies will need to include both oral and IV alcohol conditions (and matched placebos) tested in a within-subject counterbalanced manner.

Similar to the previous studies with oral alcohol administration [(Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007); see also (Cummings et al., 2007)], this study does not fully address the question of whether the effects of alcohol on plasma ghrelin were due to the caloric value of alcohol or to a specific effect of alcohol on ghrelin secretion, or a combination of both. It has been reported, however, that blood ghrelin response to food intake is independent of caloric value (Nedvidkova et al., 2003), leading us to hypothesize at least a partial specific effect of alcohol on ghrelin secretion and/or release. It is worth noting that the results of this study were somewhat specific for ghrelin, as no significant changes between the two IV conditions (alcohol vs. saline) were seen for the other feeding-related peptides tested in this study, e.g. insulin, GLP-1, and PYY. This supports the hypothesis that alcohol may exert a somewhat specific inhibitory effect on ghrelin levels (specific at least in respect to the other three peptides tested here). One may argue that, unlike ghrelin, none of the other three peptides are mainly produced by the stomach (i.e., insulin is mainly produced by the pancreatic beta cells, while GLP-1 and PYY are mainly produced by endocrine cells in the intestine) and that this difference could be responsible for the different effect observed. However, alcohol was administered IV, bypassing the stomach, therefore the fact that ghrelin was the only peptide examined that is mainly produced by the stomach might not be relevant. In support of this conclusion, previous human laboratory studies employing oral alcohol administration found that, unlike with ghrelin levels, there were no significant changes in circulating GLP-1 (Calissendorff et al., 2012), PYY (Calissendorff et al., 2006) or insulin (Zimmermann et al., 2007) levels between the oral alcohol and placebo conditions. Altogether, these findings suggest a possible direct pharmacological effect of alcohol on ghrelin secretion and/or release, at least as one of the possible mechanisms involved.

This study has both strengths and limitations. This was the first study that assessed the effects of IV alcohol administration on plasma ghrelin levels, using a well-validated IV alcohol clamp method that allowed us to test possible changes in ghrelin levels under constant alcohol exposure. Furthermore, the study was conducted under strict and well-controlled conditions, thus allowing us to control carefully for several possible confounding factors (e.g. recent alcohol and food intake; including only nonsmokers). Although the sample studied was not large, it was significantly larger than the samples enrolled in the previous human laboratory studies (Calissendorff et al., 2005, 2006; Calissendorff et al., 2012; Zimmermann et al., 2007), one of which only included males (Zimmermann et al., 2007). Here we explored possible age and gender effects, and provided preliminary evidence for the lack of age or gender influence on the effects of IV alcohol on circulating ghrelin. As for limitations, as mentioned before, the use of saline as the placebo condition does not fully address the question of whether the effects of alcohol on circulating ghrelin levels are due to the caloric value of alcohol or a specific effect of alcohol on ghrelin secretion or a combination of both. In this regard, future studies with a matched caloric placebo using the same route of administration (IV or oral) will be needed. Another limitation is the lack of additional blood samples during and after the IV clamp, as well as the assessment of active, but not total, ghrelin levels. Furthermore, given the post-hoc nature of this study, samples were not pretreated with protease inhibitor. While results were expressed as %Δ, on the other hand future prospective studies with plasma pretreated with protease inhibitor [for details, see: (Blatnik and Soderstrom, 2011)] are needed to validate our preliminary findings. Finally, human studies in the context of alcohol use have shown a possible role of other feeding peptides such as leptin, adiponectin and resistin in alcoholism (Hillemacher et al., 2007; Hillemacher et al., 2009). As such, possible interactions between ghrelin and these other appetite-regulating peptides might provide additional explanations of the present results. Leptin, adiponectin and resistin were not measured here, therefore future studies should explore whether there is an interaction between the ghrelin findings and alterations of these other peptides.

These results add to existing information on the interplay between alcohol and ghrelin in humans, and understanding how alcohol may affect ghrelin signaling is relevant given the suggested role of ghrelin as a novel pharmacological target to treat alcoholism (Dickson et al., 2011; Leggio, 2010). Also, understanding changes in ghrelin signaling in humans as a result of alcohol-related systemic effects vs. those in the gastric-portal system may also be intriguing, taking into account the recent preclinical evidence suggesting that ghrelin may modulate an increase in alcohol reward after gastric bypass surgical procedure [(Hajnal et al., 2012); but see: (Davis and Benoit, 2013; Davis et al., 2012; Hajnal et al., 2013)]. However, future studies are needed to shed light on the possible clinical significance of the present results.

In conclusion, this study provides the first preliminary evidence that the fasting-induced increase in circulating ghrelin is blunted by IV alcohol administration. These findings lead us to hypothesize that alcohol might affect ghrelin levels not only via a local effect on the stomach mucosa and in the portal system, but also via a systemic effect, perhaps mediated by vagal system activation.

Acknowledgements

The authors would like to thank Mr. Erick Singley, Laboratory of Clinical and Translational Studies, NIAAA for his technical support.

Research Support

This work was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA).

Footnotes

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Conflict of Interest

The authors report no biomedical financial interests or potential conflicts of interest.

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