National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
Received 30 October 2001; in revised form 26 March 2002; accepted 5 May 2002
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The link between alcohol and carbohydrate consumption is supported by a number of studies. Human dietary studies show an inverse relationship between the consumption of carbohydrate and the intake of alcohol (Bresard and Chalbert, 1963; Eddy et al., 1971
; Yung et al., 1983
; Herbeth et al., 1988
; Colditz et al., 1991
). Animal studies show that the sum of the calories from food and alcohol remains constant when the diet is experimentally varied. At the neurochemical level, the same neuromodulator systems that influence glucoregulatory processes also influence alcohol intake (Grupp et al., 1997a
). Agents (e.g. naltrexone, isoproterenol, furosemide, 8 OH-DPAT, insulin zinc protamine, glibenclamide and angiotensin II) that have been shown in animals to modulate alcohol intake also modulate blood glucose (Grupp and Harding, 1996
); the reduction in alcohol intake induced by some of these agents has been related to their effect on glucose availability (Grupp et al., 1997a
,b
, 1998
).
If a common mechanism regulates carbohydrate and alcohol consumption, then subjects with abnormal alcohol consumption (i.e. alcoholics) might be expected to exhibit abnormalities in carbohydrate regulation (Roach and Williams, 1966). Although studies have rarely explored dietary measures in alcoholics, blood glucose has been frequently studied, and abnormalities have been found. Alcoholics have been shown to have an increased baseline glucose production rate (Bunout et al., 1989
), insulin resistance (Iturriaga et al., 1986
), abnormal glucose tolerance (Hed et al., 1968
; Sereny et al., 1975
; Adner and Nygren, 1990
; Piccardo et al., 1994
; Greenhouse and Lardinois, 1996
), and decreased utilization of glucose (Yki-Jarvinen and Nikkila, 1985
).
There are several possible causes for the abnormal glucose regulation seen in previous studies of alcoholics. First, the changes may represent an inherited abnormality in glucose regulation that may be associated with a predisposition to develop alcoholism. Second, the abnormal glucose regulation may result from a permanent, damage effect on the body from long-term alcohol consumption. Third, since these studies have been conducted with recently detoxified alcoholics, the findings of abnormal glucose regulation may be due to the transient, toxic effects of alcohol on cellular processes affecting glucose homeostasis [e.g. to the pancreas (Geokas, 1984) and liver (Preedy et al., 1997
)]. Studies involving long-term, rather than recently detoxified, alcoholics could be expected to avoid the potential confounding effect caused by alcohol.
If there is a common mechanism regulating alcohol and carbohydrate consumption, we speculate that alcoholics have an abnormality in this mechanism manifested by increased carbohydrate consumption at times when they are not drinking. In order to explore this possibility by accurately quantifying carbohydrate consumption, we employed 2-deoxy-d-glucose (2-DG) in an established laboratory paradigm that stimulates dietary intake (Thompson and Campbell, 1977; Welle et al., 1980
; Breier, 1989
; George et al., 1994
). Two-DG is a non-metabolizable analogue of glucose that inhibits glucose-6-phosphate dehydrogenase, blocks the breakdown of glucose and the production of ATP, and causes intracellular glucoprivation (Brown, 1962
). 2-DG activates the hypothalamus (the area of the brain responsible for macronutrient selection), inducing hunger and causing an increased consumption of carbohydrate. The magnitude of the effect of 2-DG can be quantified with metabolic measures, such as the compensatory rise in peripheral circulating glucose. This increase in blood glucose occurs via direct autonomic innervation of the liver (i.e. promoting glycogenolysis and an increase in the outflow of glucose) as well as via increased glucagon and adrenaline secretion (Matsunaga et al., 1989
).
We hypothesized in the present work that, at baseline and following an infusion of 2-DG, alcoholics would consume more carbohydrate than non-alcoholic controls. We also hypothesized that this 2-DG stimulus would stimulate the desire of the alcoholics to consume alcohol. To quantify the effective stimulus of the 2-DG infusion in each group, we monitored the compensatory metabolic response in the plasma concentrations of glucose, insulin and glucagon.
![]() |
SUBJECTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Drinking history was determined for each subject, using a structured research questionnaire (Eckardt et al., 1978). Psychiatric diagnoses were derived using the Structured Clinical Interview DSM-III-R (Mazure and Gershon, 1979
), which was administered by a social worker with extensive training in diagnostic interviewing. All alcoholics fulfilled DSM-III-R criteria (American Psychiatric Association, 1987
) for past alcohol dependence. Nine alcoholics met DSM-III-R criteria for past drug abuse or dependence. Some healthy volunteers drank alcohol socially, but none fulfilled DSM-III-R criteria for alcoholism, depression or any Axis I diagnosis. Healthy volunteers had a negative family history in first-degree relatives for significant alcohol abuse or dependence in parents or siblings.
Procedure
Following an overnight fast in the hospital, patients remained at bed rest and were given an i.v. line in the forearm. This line was kept open with a slow infusion of saline for a stabilization period of 1 h. At approximately 09:30, each subject received a continuous i.v. infusion for 30 min of either 25 mg/kg of 2-DG in 100 ml of normal saline or a placebo of 100 ml of normal saline. The two infusions were administered according to a random-ordered double-blind design, separated by 7 days and
48 h. The intent in utilizing this dose of 2-DG was to induce dietary changes with few other physiological effects (George et al., 1994
).
Biochemical variables
To obtain blood for biochemical analysis, samples were drawn through the i.v. line at baseline and at 60, 90, 120 and 150 min after the beginning of the infusion. Blood for glucose was collected in tubes containing potassium oxalate/sodium fluoride, and were sent immediately to the Clinical Pathology Department of the National Institutes of Health Clinical Center for photometric assay with hexokinase. Blood for glucagon was collected in tubes containing Trazilol and EDTA. Blood for insulin was collected in a separate serum separation tube. These samples were immediately placed on wet ice, centrifuged, aliquoted, and stored at 80°C prior to analysis. Covance Laboratory in Vienna (VA, USA) performed the analyses. Insulin was assayed using a TOSOH (San Francisco, CA, USA) enzyme-linked immunosorbent assay and had a 4.6% inter-assay variation. Glucagon was assayed using radioimmunoassay and had a 5.5% inter-assay variation.
Physiological variables
Blood pressure (BP) and pulse rate were measured from the non-dominant arm using a Dinamap automated BP cuff (Critikon Co., Tampa, FL, USA). Vitals signs were determined at baseline, and 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 120, 135, 150, 165, 180 and 240 min after the beginning of the infusion. The subjects temperature and ECG were also monitored to safeguard against any abnormalities during the study.
Test meal
Following the 150-min blood draw, subjects ate ad libitum from a specially prepared and carefully quantified lunch tray provided by the National Institutes of Health Nutrition Departments Metabolic Kitchen. By measuring the food and beverage consumed from this quantified lunch tray, the Nutrition Department staff calculated the total amount of carbohydrate, fat, protein, and kilocalories consumed by each subject.
Urge to Drink Alcohol Questionnaire
The Urge to Drink Alcohol Questionnaire was adapted, with permission, from the Questionnaire of Smoking Urges (Tiffany and Drobes, 1991), to reflect alcohol use. The questionnaire consists of 32 items, assessing four categories: desire to drink; intention to drink; anticipation of positive outcome; and anticipation of relief from withdrawal or negative state. Each of these categories consists of eight items from the scale. This self-report instrument was obtained at baseline and at 150, 180 and 240 min following the infusion. Subjects completed the scales based on how they felt at the height of the infusion at 150 min, and at 180 and 240 min, based on how they felt since the previous time they had completed the instrument.
Statistical analysis
The statistical package used for all analyses was Statistica by Statsoft (Tulsa, OK, USA). Tests utilized included analysis of variance, multiple analysis of variance, and correlations. A significance level of P = 0.01 was selected, because of the number of tests performed. Results are expressed as means ± SD.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
Test meal
Two-DG increased the consumption of carbohydrates and total calories in both alcoholics and healthy volunteers [F(1,36) = 10.08, P = 0.003 and F(1,36) = 7.19, P = 0.01, respectively]. There was no significant drug effect on the consumption of fat or protein, and there were no group effects on any of these dietary variables.
Urge to Drink Questionnaire
There were no differences between alcoholics and healthy volunteers at baseline for any of the subscales on the Urge to Drink Alcohol Questionnaire. Similarly, there were no drug, time, or group effects noted during the study.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The primary objective of this study was to explore carbohydrate consumption in alcoholics. Our interest in this area was generated by both clinical observations and reports in the Alcoholics Anonymous literature that sober alcoholics frequently consume excessive sweets. The fact that we did not find any difference in carbohydrate consumption between alcoholics and non-alcoholics at baseline or following 2-DG suggests that previous accounts about sweet consumption and alcoholics may be more applicable to the peri-withdrawal period of time and do not persist into long-term abstinence. The length of time spent in alcohol recovery may also have an important effect on the alcoholics desire to drink alcohol, as measured by the Urge to Drink Questionnaire. Measures of actual alcohol consumption were not feasible.
The significance of the atypical glucose regulation (i.e. blunted blood glucose response) noted following 2-DG is not known. Although it is possible that such atypical glucose regulation precedes the onset of alcoholism, it is also possible that alcohol exposure causes this abnormality. A similar abnormality, that of a blunted glucose increase following insulin-induced hypoglycaemia, has been noted by Eisenhofer (1984) in a group of long-term abstinent alcoholics. All the subjects in this group displayed nervous system damage that was attributable to the effects of alcohol exposure. In one subject, who had no hormonal response at all, Eisenhofer (1984) attributed the defect in glucose regulation to alcohols damaging effect on central glucoreceptors. Such damage to central glucoreceptors (i.e. in the hypothalamus) could be one mechanism for the depressed blood glucose response we noted following 2-DG administration. Specific neurons in the hypothalamus (i.e. vasoactive intestinal peptide neurons in the hypothalamic suprachiasmatic nucleus) that are sensitive to damage from alcohol (Madeira et al., 1997) also mediate the glucose elevation induced by 2-DG (Chun et al., 1998
). Permanent alcohol damage to other areas of the body, such as the adrenal medulla, might possibly contribute to the blunted response of the alcoholics. However, if a catecholamine defect was involved, then alcoholics might be expected to have an increased insulin response and increased cardiovascular markers of sympathetic activity (i.e. blood pressure and heart rate), but this did not occur. Other alcohol-associated changes may also contribute to the atypical blood glucose response to 2-DG noted in our study. However, there is little evidence that the peculiar metabolic characteristics and nutritional deficiencies which have been previously reported in alcoholics actually persist after 6 months of abstinence from alcohol (Gloria et al., 1997
; Addolorato et al., 1998
, 1999
).
In summary, we did not find any evidence for increased carbohydrate consumption, at least in short-term experiments, in long-term abstinent alcoholics. However, we did find that long-term abstinent alcoholics have a blunted hyperglycaemic response after an infusion of 2-DG. The origin of the atypical response is unknown. This finding does, however, add another dimension to the theory that the regulation mechanisms of alcohol and glucose are related and are altered in alcoholics. In the future, 2-DG could be given to alcohol-naïve subjects who are at different degrees of risk of developing alcoholism. Such a study could determine if our findings are indicative of carbohydrate regulatory abnormalities associated with a trait that predisposes an individual to become alcoholic, or if they are merely indicative of long-lasting alcohol-induced damage.
![]() |
ACKNOWLEDGEMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
FOOTNOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Addolorato, G., Capristo, E., Caputo, F., Greco, A. V., Ceccanti, M., Stefanini, G. F. and Gasbarrini, G. (1999) Nutritional status and body fluid distribution in chronic alcoholics compared with controls. Alcoholism: Clinical and Experimental Research 23, 12321237.[ISI][Medline]
Adner, N. and Nygren, A. (1990) Insulin sensitivity in alcoholics in a withdrawal state. Journal of Internal Medicine 228, 5964.[Medline]
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. American Psychiatric Association, Washington, DC.
Anonymous (1975) Living Sober, pp. 2224. Alcoholics Anonymous, New York.
Breier, A. (1989) Experimental approaches to human stress research: assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients. Biological Psychiatry 26, 438462.[ISI][Medline]
Bresard, M. and Chalbert, A. (1963) Note sur la relation entre la consummation dalcool et celle du sucre. Bulletin Institut National dHygiene (Paris) 18, 639649.
Brown, J. (1962) Effects of 2-deoxyglucose on carbohydrate metabolism: review of the literature and studies in the rat. Metabolism 11, 10981112.[ISI]
Bunout, D., Petermann, M., Bravo, M., Kelly, M., Hirsch, S., Ugarte, G. and Iturriaga, H. (1989) Glucose turnover rate and peripheral insulin sensitivity in alcoholic patients without liver damage. Annals of Nutrition and Metabolism 33, 3138.[ISI][Medline]
Chun, S. J., Niijima, A., Nagai, N. and Nagai, K. (1998) Effect of bilateral lesions of the suprachiasmatic nucleus on hyperglycemia caused by 2-deoxy-d-glucose and vasoactive intestinal peptide in rats. Brain Research 809, 165174.[ISI][Medline]
Colditz, G. A., Giovannucci, E., Rimm, E. B., Stampfer, M. J., Rosner, B., Speizer, F. E., Gordis, E. and Willett, W. C. (1991) Alcohol intake in relation to diet and obesity in women and men. American Journal of Clinical Nutrition 54, 4955.[Abstract]
Eckardt, M. J., Parker, E. S., Noble, E. P., Feldman, D. J. and Gottschalk, L. A. (1978) Relationship between neuropsychological performance and alcohol consumption in alcoholics. Biological Psychiatry 13, 551564.[ISI][Medline]
Eddy, T. P., Wheeler, E. F. and Stock, A. L. (1971) Nutritional and environmental studies on an ocean-going oil tanker. 4. The diet of seamen. British Journal of Industrial Medicine 28, 342352.[ISI][Medline]
Eisenhofer, G., Johnson, R. H. and Lambie, D. G. (1984) Growth hormone, vasopressin, cortisol, and catecholamine responses to insulin hypoglycemia in alcoholics. Alcoholism: Clinical and Experimental Research 8, 3336.[ISI][Medline]
Forsander, O. A. (1994) Hypothesis: factors involved in the mechanisms regulating food intake affect alcohol consumption. Alcohol and Alcoholism 29, 503512.[Abstract]
Geokas, M. C. (1984) Ethanol and the pancreas. Medical Clinics of North America 68, 5775.[ISI][Medline]
George, D. T., Lindquist, T., Alim, T., Flood, M., Eckardt, M. J. and Linnoila, M. (1994) Abstinent alcoholics exhibit an exaggerated stress response to 2-deoxy-d-glucose (2DG) challenge. Alcoholism: Clinical and Experimental Research 18, 685691.[ISI][Medline]
Gloria, L., Cravo, M., Camilo, M. E., Resende, M., Cardoso, J. N., Oliveira, A. G., Leitao, C. N. and Mira, F. C. (1997) Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption. American Journal of Gastroenterology 92, 485489.[ISI][Medline]
Greenhouse, L. and Lardinois, C. K. (1996) Alcohol-associated diabetes mellitus. A review of the impact of alcohol consumption on carbohydrate metabolism. Archives of Family Medicine 5, 229233.[Abstract]
Grupp, L. A. and Harding, S. (1996) Neurotensin attenuates the reduction in alcohol drinking produced by angiotensin II. Psychopharmacology 125, 5764.[ISI][Medline]
Grupp, L. A., Hsu, G., Ng, N. and Harding, S. (1997a) Glucose and the insulin-releasing drug tolbutamide attenuate the effects of morphine and angiotensin on alcohol consumption. Alcohol 14, 7179.[ISI][Medline]
Grupp, L. A., Lau, V. and Harding, S. (1997b) The reduction in alcohol intake by the 5-HT1A agonist 8-OH DPAT and its attenuation by the alpha 2 adrenergic antagonist idazoxan correlates with blood glucose levels. Psychopharmacology 133, 172178.[ISI][Medline]
Grupp, L. A., Lau, V. and Harding, S. (1998) The reduction in alcohol intake in rats by isoproterenol is attenuated by indomethacin but not enalapril: relationship to blood glucose levels. Psychopharmacology 138, 167175.[ISI][Medline]
Hed, R., Nygren, A. and Sunblad, L. (1968) Insulin response in chronic alcoholism. Lancet i, 145.
Herbeth, B., Didelot-Barthelemy, L., Lemoine, A. and Le Devehat, C. (1988) Dietary behavior of French men according to alcohol drinking pattern. Journal of Studies on Alcohol 49, 268272.[ISI][Medline]
Iturriaga, H., Kelly, M., Bunout, D., Pino, M. E., Pereda, T., Barrera, R., Petermann, M. and Ugarte, G. (1986) Glucose tolerance and the insulin response in recently drinking alcoholic patients: possible effects of withdrawal. Metabolism 35, 238243.[ISI][Medline]
Kampov-Polevoy, A. B., Garbutt, J. C. and Janowsky, D. S. (1999) Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol and Alcoholism 34, 386395.
Kampov-Polevoy, A. B., Tsoi, M. V., Zvartau, E. E., Neznanov, N. G. and Khalitov, E. (2001) Sweet liking and family history of alcoholism in hospitalized alcoholic and non-alcoholic patients. Alcohol and Alcoholism 36, 165170.
Madeira, M. D., Andrade, J. P., Lieberman, A. R., Sousa, N., Almeida, O. F. and Paula-Barbosa, M. M. (1997) Chronic alcohol consumption and withdrawal do not induce cell death in the suprachiasmatic nucleus, but lead to irreversible depression of peptide immunoreactivity and mRNA levels. Journal of Neuroscience 17, 13021319.
Matsunaga, H., Iguchi, A., Yatomi, A., Uemura, K., Miura, H., Gotoh, M., Mano, T. and Sakamoto, N. (1989) The relative importance of nervous system and hormones to the 2-deoxy-d-glucose-induced hyperglycemia in fed rats. Endocrinology 124, 12591264.[Abstract]
Mazure, C. and Gershon, E. S. (1979) Blindness and reliability in lifetime psychiatric diagnosis. Archives of General Psychiatry 36, 521525.[Abstract]
Piccardo, M. G., Pacini, G., Nardi, E., Rosa, M. S. and De Vito, R. (1994) Beta-cell response and insulin hepatic extraction in noncirrhotic alcoholic patients soon after withdrawal. Metabolism 43, 367371.[ISI][Medline]
Preedy, V. R., Peters, T. J. and Why, H. (1997) Metabolic consequences of alcohol dependency. Adverse Drug Reactions and Toxicological Reviews 16, 235256.[ISI][Medline]
Roach, M. K. and Williams, R. J. (1966) Impaired and inadequate glucose metabolism in the brain as an underlying cause of alcoholism an hypothesis. Proceedings of the National Academy of Sciences of the United States of America 56, 566571.[ISI][Medline]
Schuman, M., Gitlin, M. J. and Fairbanks, L. (1987) Sweets, chocolate, and atypical depressive traits. Journal of Nervous and Mental Disease 175, 491495.[ISI][Medline]
Sereny, G., Endrenyi, L. and Devenyi, P. (1975) Glucose intolerance in alcoholism. Journal of Studies on Alcohol 36, 359364.[ISI][Medline]
Thompson, D. A. and Campbell, R. G. (1977) Hunger in humans induced by 2-deoxy-d-glucose: glucoprivic control of taste preference and food intake. Science 198, 10651068.[ISI][Medline]
Tiffany, S. T. and Drobes, D. J. (1991) The development and initial validation of a questionnaire on smoking urges. British Journal of Addiction 86, 14671476.[ISI][Medline]
Welle, S. L., Thompson, D. A., Campbell, R. G. and Lilavivathana, U. (1980) Increased hunger and thirst during glucoprivation in humans. Physiology and Behavior 25, 397403.[ISI][Medline]
Yki-Jarvinen, H. and Nikkila, E. A. (1985) Ethanol decreases glucose utilization in healthy man. Journal of Clinical Endocrinology and Metabolism 61, 941945.[Abstract]
Yung, L., Gordis, E. and Holt, J. (1983) Dietary choices and likelihood of abstinence among alcoholic patients in an outpatient clinic. Drug and Alcohol Dependence 12, 355362.[ISI][Medline]