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Effects of ethanol on carbohydrate metabolism: I. Influence on oral glucose tolerance test
Effects of Ethanol on Carbohydrate Metabolism I. Influence on Oral Glucose Tolerance Test Sont
P. Singh and
Dhonooprosod
To study the effect of ethanol on glucose tolerance test, a series of experiments were performed on Sprague-Dawley male mts weighing 250 g. After 18-hr fast, each mt was given, at random, the following test substances (one test substance at a time) intmgastrically in a volume of 0.5 ml/100 g body weight: saline; glucose 0.75 g/kg (3 kcal); ethanol 0.4 g/kg (3 kcal); and ethanol with glucose. Wine or ethanol alone produced no significant changes in blood glucose or plasma insulin
:
G. Pate1
concentmtions. Addition of ethanol to glucose load resulted in glucose intolerance as well as a lower and sluggish insulin response when compared to these with glucose load alone. The results suggest that ethanol per se has no effect on blood glucose or plasma insulin. However, when given together with glucose load, ethanol produces glucose intolemnce as well as inhibition of glucose mediated insulin response.
C
DATA have been reported on the effects of ethanol on ONFLICTING glucose tolerance. For instance, Dornhorst and Ouyang’ showed that a single dose of ethanol given together with glucose load impaired glucose tolerance in the normal subjects. Shanley et al.z did not confirm these results but observed that relatively large amounts of ethanol ingested over several days induced “alcohol diabetes.” In contrast, other investigators have reported an improvement in glucose tolerance and enhanced glucose mediated insulin response in normal humans after pretreatment with ethanol.3s4 Due to these diverse observations, the present study was undertaken to learn more about the alterations in carbohydrate metabolism after oral administration of ethanol. MATERIALS
AND
METHODS
Thirty-two male rats of the Sprague-Dawley strain, weighing 250 g were housed individually in conditions of controlled temperature, humidity, light cycle, and were fed Purina chow and water ad lib. After 18-hr fast, each rat was given, at random, the following test substances (one test substance at a time) intragastrically in a volume of 0.5 ml/l00 g body weight: (I) saline; (2) glucose 0.75 g/kg body weight; (3) ethanol 0.4 g/kg body weight (10% v/v); (4) glucose + ethanol. Glucose and ethanol loads were isocaloric as each provided 3 kcal/kg body weight. Each test solution was given in a volume of 0.5 ml/100 g body ;,eight by intragastric intubation at 4-6 day intervals. No anaesthesia was used during the experiments. Blood samples were obtained from the tail directly into heparinized microtubes before (baseline), 30, 60, and I20 min after the administration of each solution. Whole blood was used for glucose and ethanol estimations. For plasma insulin determination.
the microtubes
From the Veterans Administration Medical
were kept at 4°C
Hospital.
for I hr and then centrifuged
Downey. IN. and the Department
for 3 min
of Medicine. Chicago
School. Downey. IN.
Received for publication July 3, 1975. Supported by US VA research funds. Presented in part at the 59th Annual Meeting of Federation oJAmerican Societies for Experimental Biology, Atlantic City. N. J., April 15. 1975. Reprint requests should be addressed to Dr. Sant P. Singh. Associate Chief of StaNfor Research. Veterans Administration Hospitanf, Downey, 111.60064. o 1976 by Grune & Stratton, Inc.
Mefobofirm, Vol. 25, No. 2 (February),
1976
239
240
SINGH
Table 1. Blood Ethanol Dose/Kg Treatment
Blood
Body Weight (9)
Ethanol (32)
Rats
Ethanol
30 min
0.4
Ethanol + Glucose (32) (
Levels in Normal
18 f
0.4 -I- 0.75
AND PATE1
Mg/l
DO ml (Mean
60 min
1.4
23 + 2.0
*
SEM) 120 min
16 zt 1.6
6 % 0.08
18 f
5 f
1.4
0.05
) Number of animals.
Test solutions were given intragostrically in a final volume of 0.5 ml/100
g body weight and blood sam-
ples were taken at various time intervals afterwards as shown above. There was no statistical difference in blood ethanol levels between the two groups at any time of the experiments.
in a Beckman Spinco Microfuge. subsequent insulin assay.
Plasma
was separated
and stored
in plastic
tubes at -2o’C
for
Blood glucose was determined on a Technicon Autoanalyzer by Hoffman’s ferricyanide micromethod.5 Plasma immunoreactive insulin (IRI) was estimated by the double antibody radioimmunoassay method of Morgan and Lazarow as modified by Blanks and Gerritsen.6 Rat insulin kindly supplied by Eli Lilly Company was used as standard. The presence of ethanol in the plasma did not affect the assay. Blood ethanol estimation was done by the enzymatic method.’ Insulin and glucose increments above their respective fasting value for the first 60 min were calculated. The insulinogenic index was determined by dividing insulin increment with glucose increment. The data were analyzed by Student t Test.
RESULTS
Table 1 shows that essentially similar blood ethanol levels were observed at 30, 60, and 120 min after oral administration of ethanol or given in combination with glucose. The rate of disappearance of ethanol from blood was nearly equal in both groups. None of the rats appeared intoxicated. Figure 1 illustrates blood glucose profile obtained after oral administration of saline (control), ethanol, glucose, and glucose + ethanol. Ethanol alone or saline produced a minimal change in blood glucose levels at 30 and 60 min compared to the fasting level (5.4 f 1.0 and 5.1 f 0.5 mg/lOO ml for ethanol and 10.8 f 0.5 and 11.8 + 0.7 mg/lOO ml for saline, mean f SEM, n = 32). Furthermore, blood glucose changes after ethanol treatment were not significantly
160
_ o-+--o -ETHANOL
SALINE GLUCOSE
. ..... ....
GLUCOSE
R ETHANOL
140
ae & E
120
w z? 0
100
3 ” 8 0
60
60
30 TIME
IN MINUTES
17.0
Fig. 1. Mean + SEM blood glucose pg/lOO ml after oral administration of saline, glucose, ethanol, or glucose with ethanol in 1g-hr fasted normal rats. Ethanol and glucose loads were isocaloricand were given in amounts as shown in Toble 1.
241
ETHANOL
_ SALINE o.---oGLUCOSE -ETHANOL -GLUCOSE
5 1
Fig. 2. Plasma immunomactive insulin levels (pU/ml f SEM) after oml administmtion of saline, gluethanol, or glucose with COS%, ethanol in 18-hr fasted normal mts. Ethanol and glucose loads were isocaloric and were given in amounts as shown in Table 1.
0
8 ETHANOL
6b
30 TIME
120
IN MINUTES
different from that of saline treatment. However, administration of ethanol simultaneously with glucose resulted in significantly higher blood glucose levels at all points of study compared to the corresponding blood glucose levels attained following glucose load alone. After 30 min the two curves were significantly different (p < 0.001) and the blood glucose curve following the glucose + ethanol load did not return to fasting level by 120 min. Mean values f SEM for plasma insulin concentration during the control experiment, OGTT and the two ethanol experiments are shown in Fig. 2. Basal insulin levels were not statistically different between groups. Ethanol administration alone did not influence insulin concentration compared to the control experiments. Isocaloric load of a glucose, however, resulted in a significantly higher (p < 0.001) plasma insulin response compared to the control group. Addition of ethanol to glucose load produced a similar response but of significantly lesser (p < 0.05) magnitude in the same animals. To see if observed difference in insulin and glucose response was interrelated, blood glucose and plasma insulin increments above the respective fasting values and the insulinogenic index were calculated (Table 2). The insulin-ogenic index was significantly less (p < 0.05) when the rats were given ethanol + glucose solution compared to glucose alone. Table 2. Effect of Ethanol on Insulinogenic Index in Normal Rats
Dose/Kg Body Weight Treatment
(9)
(15)
0.75
Glucose
Glucose+ Ethanol
(8)
0.75
Blood Glucose Increments mg/lDC ml/hr
Plasma IRI Increments IrU/ml/hr
lnsulinogenic Index rl IRI _ A Glucose
82 zk 4
25 f 2
0.32 f 0.04
22 f
0.19
+ 0.4
119*
10
< 0.01
P
( ) Number Results ing values of 0.5
NS
f
0.03
< 0.05
of animals.
(Mean during
ml/100
3
+
SEM)
first
g body
are given
as increments
60 min of the experiments. weight.
of Test
blood
glucose
solutions
and plasma
were
given
insulin
above
intragastrically
respective
in a final
fast-
volume
242
SINGH
AND PATEL
DISCUSSION
Ethanol has been reported both to improve3.’ and impair’.‘*’ glucose tolerance. The present study shows that a single moderate dose of ethanol per se has no influence on blood glucose and insulin levels. However, when it is given simultaneously with glucose load, an impairment in oral glucose tolerance occurs which is associated with a diminished insulin response. Studies to be reported later suggest similar effects of ethanol on blood glucose and insulin levels in diabetic rats. Several possible mechanisms can be responsible for the effects of ethanol on blood glucose and insulin levels. In vitro experiments with pancreas of rat, rabbit, and golden hamster have shown inhibition of insulin secretion in the presence of ethanol.rO,” Malaisse et al.12 interpreted their results as due to an interference of ethanol with the integrity of microtubular systems. During a single transhepatic circulation, liver normally retains 50% of the insulin presented. An enhancement of insulin degradation by liver because of ethanol might be responsible for the diminished plasma insulin response. However, except for the possibility that the amount of insulin reaching the liver itself affects the insulin uptake by liver,13 other factors which might influence retention of insulin by liver are not known. Another reason can be an increase in blood levels of catecholamines, fatty acids, and cortisol that result from alcohol ingestion. 14-16These responses can alter insulin secretion or insulin action or both. However, the influence of catecholamines or other hormones due either to stress or ethanol appear minimal as neither glucose nor insulin changes were significantly different from fasting values after administration of ethanol alone compared to control experiments. Lastly, ethanol might alter insulin secretion via one or more gut hormones that influence the islets of Langerhans. Further studies are necessary to elucidate such an effect. It has been postulated that when glucose and ethanol are available as alternate fuel, alcohol becomes preferential substrate for utilization compared to glucose.‘7*‘8 Although this suggestion might explain a high glucose level, it fails to account for the diminished glucose mediated insulin response. That the diabetogenic effect of ethanol is due to its caloric value is unlikely as our data show that isocaloric amounts of ethanol and glucose given separately to the same animals produced significantly different blood glucose and insulin responses. Lochner et al.lg and Kreisberg2’ reported that ethanol decreased peripheral glucose utilization in dog and man. Our data and in vitro studies of suggest that ethanol inhibits glucose mediated insulin Biven and Feldman” response. Perhaps the mechanism of ethanol induced glucose intolerance is multifactoral, including changes in insulin secretion and peripheral uptake of glucose. Nonetheless, the results of various above mentioned studies, including ours, are to be reconciled with other reports that ethanol potentiates glucose stimulated insulin secretion in normal humans3p4 and in patients with maturity onset diabetes mellitus.” However, in these experiments ethanol was preinfused for several hours to “prime” the pancreas before the administration of glucose. Finally, our data show no apparent effect of glucose on ethanol metabolism in normal rats. Ethanol disappearance rates were similar after oral administra-
ETHANOL
tion
243
of ethanol-glucose
mixture
or ethanol
given
alone.
Similar
have been made in dogs.*’ However, in man, it has been shown serum than
ethanol after
following
ethanol
alone.’
the
ingestion
The reasons
of ethanol-glucose for this discrepancy
observations that
mixture
levels are
of
lower
are unclear.
ACKNOWLEDGMENT The authors are extremely indebted to Dr. Norbert Freinkel, Director, Center for Endocrinology, Metabolism, and Nutrition, Northwestern University, for his constructive suggestions and criticisms. We are also grateful to Dr. Beatrice M. Wyse of the Upjohn Company, Kalamazoo, Michigan for providing antiinsulin guinea pig serum, to Dr. Mary A. Root of the Lilly Research Laboratories, Indianapolis, Indiana for a generous supply of rat insulin, and to Mrs. Ruth M. Bonovich for typing the manuscript.
REFERENCES I. Dornhorst A, Ouyang A: Effect of alcohol on glucose tolerance. Lancet 2957, 1971 2. Shanley BC, Robertson EJ, Joubert SM, Morth-Goombes JD: Effects of alcohol on glucose tolerance. Lancet l:l232, 1972 3. Metz R, Berger S, Mako M: Potentiation of the plasma insulin response to glucose by prior administration of alcohol. Diabetes 18: 517, 1969 4. Freinkel N, Singer DL, Arky RA, Bleicher SJ, Anderson JB, Silbert CK: Alcohol hypoglycemia. 1. Carbohydrate metabolism of patients with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome with pure ethanol. J Clin Invest 42: I 112,1963 5. Hoffman WS: A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem 120:5 I, 1937 6. Blanks MC, Gerritsen GC: An ultra-micro immunoassay for insulin. Proc Sot Exp Biol Med 146:448, 1974 7. Bonnichsen RK, Theorell H: An enzymatic method for the determination of ethanol. Stand J Clin Lab Invest 3:58, 195 I 8. Friedenberg R, Metz R, Mako M, Surmaczynska B: Differential plasma insulin response to glucose and glucagon stimulation following ethanol priming. Diabetes 20:397, 1971 9. Phillips GB, Safrit HP: Alcohol diabetes; induction of glucose intolerance with alcohol.
12. Malaisse WJ, Malaisse-Lagae F, Walker WO, Lacy PE: The stimulussecretion coupling of glucose-induced insulin release. V. The participation of a microtubular-microfila-
JAMA 217:1513, 1971 10. Malaisse WJ, Malaisse-Lagae
20. Kreisberg RA, Siegal AM, Glucose-lactate interrelationship, ethanol. J Clin Invest 50:175, 1971
F, Lacy PE: Participation of a microtubular-microfilamentous system in insulin secretion. Diabetologia 6:638, 1970 I I. Bivens CH, Feldman JM: Effect of
ethanol and its metabolites on insulin secretion. Quart J Stud Alto 35:635, 1974
mentous
system.
Diabetes
20:257,
1971
JM, Dolkas CB, Reaven GM: Removal of insulin by perfused rat liver: effect of concentration. Metabolism 24: 153, 1975 13. Mondon
CE, Olefsky
14. Perman ES: The effect of ethyl alcohol on the secretion from the adrenal medulla in man. Acta Physio Stand 44~241, 1958 15. Isselbacher, KJ: Interrelationship of alcohol and lipid metabolism in the liver. Psychosom Med 28:424, 1966 16. Jenkins JS, Connolly J: Adrenocortical response to ethanol in man. Br Med J 2:804, 1968 17. Freinkel N, Cohen AK, Arky RA, Foster AE: Alcohol hypoglycemia: II. A postulated mechanism of action based on experiments with rat liver slices. J Clin Endocrinol 25:76, 1965 18. Benjafield cohol on glucose
JG, Rutter LF: Effect of altolerance. Lancet 2:1145, 1971
19. Lochner A, Wulff J, Madison LL: Ethanol-induced hypoglycemia. I. The acute effects of ethanol on hepatic glucose output and peripheral glucose utilization in fasted dogs. Metabolism l6:1, 1967 Owen WC: effect of
21. Clark WC, Hulpieu HR: Comparative effectiveness of fructose, dextrose, pyruvic acid and insulin in accelerating the disappearance of ethanol from dogs. Quart J Stud Alto 19: 47-53, 1958
P. Singh and
Dhonooprosod
To study the effect of ethanol on glucose tolerance test, a series of experiments were performed on Sprague-Dawley male mts weighing 250 g. After 18-hr fast, each mt was given, at random, the following test substances (one test substance at a time) intmgastrically in a volume of 0.5 ml/100 g body weight: saline; glucose 0.75 g/kg (3 kcal); ethanol 0.4 g/kg (3 kcal); and ethanol with glucose. Wine or ethanol alone produced no significant changes in blood glucose or plasma insulin
:
G. Pate1
concentmtions. Addition of ethanol to glucose load resulted in glucose intolerance as well as a lower and sluggish insulin response when compared to these with glucose load alone. The results suggest that ethanol per se has no effect on blood glucose or plasma insulin. However, when given together with glucose load, ethanol produces glucose intolemnce as well as inhibition of glucose mediated insulin response.
C
DATA have been reported on the effects of ethanol on ONFLICTING glucose tolerance. For instance, Dornhorst and Ouyang’ showed that a single dose of ethanol given together with glucose load impaired glucose tolerance in the normal subjects. Shanley et al.z did not confirm these results but observed that relatively large amounts of ethanol ingested over several days induced “alcohol diabetes.” In contrast, other investigators have reported an improvement in glucose tolerance and enhanced glucose mediated insulin response in normal humans after pretreatment with ethanol.3s4 Due to these diverse observations, the present study was undertaken to learn more about the alterations in carbohydrate metabolism after oral administration of ethanol. MATERIALS
AND
METHODS
Thirty-two male rats of the Sprague-Dawley strain, weighing 250 g were housed individually in conditions of controlled temperature, humidity, light cycle, and were fed Purina chow and water ad lib. After 18-hr fast, each rat was given, at random, the following test substances (one test substance at a time) intragastrically in a volume of 0.5 ml/l00 g body weight: (I) saline; (2) glucose 0.75 g/kg body weight; (3) ethanol 0.4 g/kg body weight (10% v/v); (4) glucose + ethanol. Glucose and ethanol loads were isocaloric as each provided 3 kcal/kg body weight. Each test solution was given in a volume of 0.5 ml/100 g body ;,eight by intragastric intubation at 4-6 day intervals. No anaesthesia was used during the experiments. Blood samples were obtained from the tail directly into heparinized microtubes before (baseline), 30, 60, and I20 min after the administration of each solution. Whole blood was used for glucose and ethanol estimations. For plasma insulin determination.
the microtubes
From the Veterans Administration Medical
were kept at 4°C
Hospital.
for I hr and then centrifuged
Downey. IN. and the Department
for 3 min
of Medicine. Chicago
School. Downey. IN.
Received for publication July 3, 1975. Supported by US VA research funds. Presented in part at the 59th Annual Meeting of Federation oJAmerican Societies for Experimental Biology, Atlantic City. N. J., April 15. 1975. Reprint requests should be addressed to Dr. Sant P. Singh. Associate Chief of StaNfor Research. Veterans Administration Hospitanf, Downey, 111.60064. o 1976 by Grune & Stratton, Inc.
Mefobofirm, Vol. 25, No. 2 (February),
1976
239
240
SINGH
Table 1. Blood Ethanol Dose/Kg Treatment
Blood
Body Weight (9)
Ethanol (32)
Rats
Ethanol
30 min
0.4
Ethanol + Glucose (32) (
Levels in Normal
18 f
0.4 -I- 0.75
AND PATE1
Mg/l
DO ml (Mean
60 min
1.4
23 + 2.0
*
SEM) 120 min
16 zt 1.6
6 % 0.08
18 f
5 f
1.4
0.05
) Number of animals.
Test solutions were given intragostrically in a final volume of 0.5 ml/100
g body weight and blood sam-
ples were taken at various time intervals afterwards as shown above. There was no statistical difference in blood ethanol levels between the two groups at any time of the experiments.
in a Beckman Spinco Microfuge. subsequent insulin assay.
Plasma
was separated
and stored
in plastic
tubes at -2o’C
for
Blood glucose was determined on a Technicon Autoanalyzer by Hoffman’s ferricyanide micromethod.5 Plasma immunoreactive insulin (IRI) was estimated by the double antibody radioimmunoassay method of Morgan and Lazarow as modified by Blanks and Gerritsen.6 Rat insulin kindly supplied by Eli Lilly Company was used as standard. The presence of ethanol in the plasma did not affect the assay. Blood ethanol estimation was done by the enzymatic method.’ Insulin and glucose increments above their respective fasting value for the first 60 min were calculated. The insulinogenic index was determined by dividing insulin increment with glucose increment. The data were analyzed by Student t Test.
RESULTS
Table 1 shows that essentially similar blood ethanol levels were observed at 30, 60, and 120 min after oral administration of ethanol or given in combination with glucose. The rate of disappearance of ethanol from blood was nearly equal in both groups. None of the rats appeared intoxicated. Figure 1 illustrates blood glucose profile obtained after oral administration of saline (control), ethanol, glucose, and glucose + ethanol. Ethanol alone or saline produced a minimal change in blood glucose levels at 30 and 60 min compared to the fasting level (5.4 f 1.0 and 5.1 f 0.5 mg/lOO ml for ethanol and 10.8 f 0.5 and 11.8 + 0.7 mg/lOO ml for saline, mean f SEM, n = 32). Furthermore, blood glucose changes after ethanol treatment were not significantly
160
_ o-+--o -ETHANOL
SALINE GLUCOSE
. ..... ....
GLUCOSE
R ETHANOL
140
ae & E
120
w z? 0
100
3 ” 8 0
60
60
30 TIME
IN MINUTES
17.0
Fig. 1. Mean + SEM blood glucose pg/lOO ml after oral administration of saline, glucose, ethanol, or glucose with ethanol in 1g-hr fasted normal rats. Ethanol and glucose loads were isocaloricand were given in amounts as shown in Toble 1.
241
ETHANOL
_ SALINE o.---oGLUCOSE -ETHANOL -GLUCOSE
5 1
Fig. 2. Plasma immunomactive insulin levels (pU/ml f SEM) after oml administmtion of saline, gluethanol, or glucose with COS%, ethanol in 18-hr fasted normal mts. Ethanol and glucose loads were isocaloric and were given in amounts as shown in Table 1.
0
8 ETHANOL
6b
30 TIME
120
IN MINUTES
different from that of saline treatment. However, administration of ethanol simultaneously with glucose resulted in significantly higher blood glucose levels at all points of study compared to the corresponding blood glucose levels attained following glucose load alone. After 30 min the two curves were significantly different (p < 0.001) and the blood glucose curve following the glucose + ethanol load did not return to fasting level by 120 min. Mean values f SEM for plasma insulin concentration during the control experiment, OGTT and the two ethanol experiments are shown in Fig. 2. Basal insulin levels were not statistically different between groups. Ethanol administration alone did not influence insulin concentration compared to the control experiments. Isocaloric load of a glucose, however, resulted in a significantly higher (p < 0.001) plasma insulin response compared to the control group. Addition of ethanol to glucose load produced a similar response but of significantly lesser (p < 0.05) magnitude in the same animals. To see if observed difference in insulin and glucose response was interrelated, blood glucose and plasma insulin increments above the respective fasting values and the insulinogenic index were calculated (Table 2). The insulin-ogenic index was significantly less (p < 0.05) when the rats were given ethanol + glucose solution compared to glucose alone. Table 2. Effect of Ethanol on Insulinogenic Index in Normal Rats
Dose/Kg Body Weight Treatment
(9)
(15)
0.75
Glucose
Glucose+ Ethanol
(8)
0.75
Blood Glucose Increments mg/lDC ml/hr
Plasma IRI Increments IrU/ml/hr
lnsulinogenic Index rl IRI _ A Glucose
82 zk 4
25 f 2
0.32 f 0.04
22 f
0.19
+ 0.4
119*
10
< 0.01
P
( ) Number Results ing values of 0.5
NS
f
0.03
< 0.05
of animals.
(Mean during
ml/100
3
+
SEM)
first
g body
are given
as increments
60 min of the experiments. weight.
of Test
blood
glucose
solutions
and plasma
were
given
insulin
above
intragastrically
respective
in a final
fast-
volume
242
SINGH
AND PATEL
DISCUSSION
Ethanol has been reported both to improve3.’ and impair’.‘*’ glucose tolerance. The present study shows that a single moderate dose of ethanol per se has no influence on blood glucose and insulin levels. However, when it is given simultaneously with glucose load, an impairment in oral glucose tolerance occurs which is associated with a diminished insulin response. Studies to be reported later suggest similar effects of ethanol on blood glucose and insulin levels in diabetic rats. Several possible mechanisms can be responsible for the effects of ethanol on blood glucose and insulin levels. In vitro experiments with pancreas of rat, rabbit, and golden hamster have shown inhibition of insulin secretion in the presence of ethanol.rO,” Malaisse et al.12 interpreted their results as due to an interference of ethanol with the integrity of microtubular systems. During a single transhepatic circulation, liver normally retains 50% of the insulin presented. An enhancement of insulin degradation by liver because of ethanol might be responsible for the diminished plasma insulin response. However, except for the possibility that the amount of insulin reaching the liver itself affects the insulin uptake by liver,13 other factors which might influence retention of insulin by liver are not known. Another reason can be an increase in blood levels of catecholamines, fatty acids, and cortisol that result from alcohol ingestion. 14-16These responses can alter insulin secretion or insulin action or both. However, the influence of catecholamines or other hormones due either to stress or ethanol appear minimal as neither glucose nor insulin changes were significantly different from fasting values after administration of ethanol alone compared to control experiments. Lastly, ethanol might alter insulin secretion via one or more gut hormones that influence the islets of Langerhans. Further studies are necessary to elucidate such an effect. It has been postulated that when glucose and ethanol are available as alternate fuel, alcohol becomes preferential substrate for utilization compared to glucose.‘7*‘8 Although this suggestion might explain a high glucose level, it fails to account for the diminished glucose mediated insulin response. That the diabetogenic effect of ethanol is due to its caloric value is unlikely as our data show that isocaloric amounts of ethanol and glucose given separately to the same animals produced significantly different blood glucose and insulin responses. Lochner et al.lg and Kreisberg2’ reported that ethanol decreased peripheral glucose utilization in dog and man. Our data and in vitro studies of suggest that ethanol inhibits glucose mediated insulin Biven and Feldman” response. Perhaps the mechanism of ethanol induced glucose intolerance is multifactoral, including changes in insulin secretion and peripheral uptake of glucose. Nonetheless, the results of various above mentioned studies, including ours, are to be reconciled with other reports that ethanol potentiates glucose stimulated insulin secretion in normal humans3p4 and in patients with maturity onset diabetes mellitus.” However, in these experiments ethanol was preinfused for several hours to “prime” the pancreas before the administration of glucose. Finally, our data show no apparent effect of glucose on ethanol metabolism in normal rats. Ethanol disappearance rates were similar after oral administra-
ETHANOL
tion
243
of ethanol-glucose
mixture
or ethanol
given
alone.
Similar
have been made in dogs.*’ However, in man, it has been shown serum than
ethanol after
following
ethanol
alone.’
the
ingestion
The reasons
of ethanol-glucose for this discrepancy
observations that
mixture
levels are
of
lower
are unclear.
ACKNOWLEDGMENT The authors are extremely indebted to Dr. Norbert Freinkel, Director, Center for Endocrinology, Metabolism, and Nutrition, Northwestern University, for his constructive suggestions and criticisms. We are also grateful to Dr. Beatrice M. Wyse of the Upjohn Company, Kalamazoo, Michigan for providing antiinsulin guinea pig serum, to Dr. Mary A. Root of the Lilly Research Laboratories, Indianapolis, Indiana for a generous supply of rat insulin, and to Mrs. Ruth M. Bonovich for typing the manuscript.
REFERENCES I. Dornhorst A, Ouyang A: Effect of alcohol on glucose tolerance. Lancet 2957, 1971 2. Shanley BC, Robertson EJ, Joubert SM, Morth-Goombes JD: Effects of alcohol on glucose tolerance. Lancet l:l232, 1972 3. Metz R, Berger S, Mako M: Potentiation of the plasma insulin response to glucose by prior administration of alcohol. Diabetes 18: 517, 1969 4. Freinkel N, Singer DL, Arky RA, Bleicher SJ, Anderson JB, Silbert CK: Alcohol hypoglycemia. 1. Carbohydrate metabolism of patients with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome with pure ethanol. J Clin Invest 42: I 112,1963 5. Hoffman WS: A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem 120:5 I, 1937 6. Blanks MC, Gerritsen GC: An ultra-micro immunoassay for insulin. Proc Sot Exp Biol Med 146:448, 1974 7. Bonnichsen RK, Theorell H: An enzymatic method for the determination of ethanol. Stand J Clin Lab Invest 3:58, 195 I 8. Friedenberg R, Metz R, Mako M, Surmaczynska B: Differential plasma insulin response to glucose and glucagon stimulation following ethanol priming. Diabetes 20:397, 1971 9. Phillips GB, Safrit HP: Alcohol diabetes; induction of glucose intolerance with alcohol.
12. Malaisse WJ, Malaisse-Lagae F, Walker WO, Lacy PE: The stimulussecretion coupling of glucose-induced insulin release. V. The participation of a microtubular-microfila-
JAMA 217:1513, 1971 10. Malaisse WJ, Malaisse-Lagae
20. Kreisberg RA, Siegal AM, Glucose-lactate interrelationship, ethanol. J Clin Invest 50:175, 1971
F, Lacy PE: Participation of a microtubular-microfilamentous system in insulin secretion. Diabetologia 6:638, 1970 I I. Bivens CH, Feldman JM: Effect of
ethanol and its metabolites on insulin secretion. Quart J Stud Alto 35:635, 1974
mentous
system.
Diabetes
20:257,
1971
JM, Dolkas CB, Reaven GM: Removal of insulin by perfused rat liver: effect of concentration. Metabolism 24: 153, 1975 13. Mondon
CE, Olefsky
14. Perman ES: The effect of ethyl alcohol on the secretion from the adrenal medulla in man. Acta Physio Stand 44~241, 1958 15. Isselbacher, KJ: Interrelationship of alcohol and lipid metabolism in the liver. Psychosom Med 28:424, 1966 16. Jenkins JS, Connolly J: Adrenocortical response to ethanol in man. Br Med J 2:804, 1968 17. Freinkel N, Cohen AK, Arky RA, Foster AE: Alcohol hypoglycemia: II. A postulated mechanism of action based on experiments with rat liver slices. J Clin Endocrinol 25:76, 1965 18. Benjafield cohol on glucose
JG, Rutter LF: Effect of altolerance. Lancet 2:1145, 1971
19. Lochner A, Wulff J, Madison LL: Ethanol-induced hypoglycemia. I. The acute effects of ethanol on hepatic glucose output and peripheral glucose utilization in fasted dogs. Metabolism l6:1, 1967 Owen WC: effect of
21. Clark WC, Hulpieu HR: Comparative effectiveness of fructose, dextrose, pyruvic acid and insulin in accelerating the disappearance of ethanol from dogs. Quart J Stud Alto 19: 47-53, 1958