Effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with type ii (non-insulin-dependent) diabetes

Effects of Chronic Alcohol Intake on Carbohydrate and Lipid Metabolism in Subjects with Type II (Non-Insulin-Dependent) Diabetes GIANPAOLOBEN, M.D., Agordo, Italy, LUIGI GNUDI, M.D., ALBERTOMARAN,M.D., fadova, Italy, ALFONSOGIGANTE,M.D., Messina, Italy, ELENADUNER,B.S., ELISABETTA IORI, B.S., ANTONIO TIENGO, M.D., ANGELOAVOGARO,M.D., fadova, Italy

PURPOSE: To study the effects of chronic alcohol intake on carbohydrate and lipid metabolism ‘in subjects with non-insulin-dependent (type II) diabetes (NIDDM). To also evaluate the effect of alcohol withdrawal on metabolic control. PATIENTSANDMETHODS: Thestudygroupcon&ted of 46 alcohol-consuming patients with NIDDM (NIDDM-B group), 35 non-alcohol-consuming patients with NIDDM (NIDDM group), and 40 normal control subjects. All patients were admitted to the hospital. Carbohydrate and lipid metabolism was assessed in these individuals immediately on admission to the hospital and during the following days. RESULTS: In the NIDDM-B group, blood alcohol (ethyl alcohol) concentration was very low. However, chronic alcohol intake was associated with higher fasting and postprandial glucose concentrations and higher hemoglobin Al,. No significant differences were found in C-peptide levels. Moreover, higher concentrations of 3-hydroxybutyrate and free fatty acids were observed in the NIDDM-B group than in the NIDDM group. No differences were found in triglyceride concentrations, acid-base patterns, or electrolyte levels. The metabolic effects of alcohol completely waned after 3 days of complete withdrawal. CONCLUSION: Chronic alcohol intake causes deterioration in metabolic control of persons with NIDDM. The effects induced by alcohol are completely reversed after a few days of withdrawal. Strict metabolic assessment is necessary when alcohol is an important constituent of the diet.

ecent and past investigations have substantiated the diabetogenic effects of alcohol consumption in normal subjects. In 1971, Phillips and Safrit [l] observed impaired glucose tolerance in normal subjects after heavy ethanol intake. Nikkila and Taskinen [2] noted a direct, significant relationship between alcohol consumption and the onset of impaired glucose tolerance in a large group of subjects. Shanley et al [3] observed that patients admitted to the hospital for postalcoholic hypoglycemia showed impaired glucose tolerance. Similarly, Dornhorst and C&yang [4] detected impaired glucose tolerance in normal subjects drinking moderate amounts of alcohol. The onset of carbohydrate intolerance was also reported by Sereny and Endrenyi [5] in chronic alcoholics. They also observed that impaired glucose tolerance was reversible once alcohol consumption was suspended. Alcohol intake disrupts physiologic glucose metabolism by simultaneously inhibiting the insulin secretion of B cells [6,7] and by interfering with the biologic activity of insulin at receptor and at postreceptor sites [&lo], directly or indirectly via some metabolites [ll]. Few studies have been devoted to the importance of the effects of alcohol consumption on carbohydrate and lipid metabolism in patients with noninsulin-dependent diabetes (NIDDM). This is rather curious, since in this group of subjects, alcohol is known to be an important component of the diet. McDonald [12] reported that moderate alcohol consumption does not interfere with glucose metabolism in diabetic patients. These observations were previously reported by Walsh and O’Sullivan [13] in a small group of patients with NIDDM. Recently, Singh and colleagues [14] found that alcohol mixed with glucose did not affect glucose tolerance in subjects with NIDDM. However, there have been no exhaustive reports on the effects of customary alcohol consumption on glucose metabolism in subjects with NIDDM. Previous studies relied on a limited number of observations or on an artificially controlled study approach, such as alcohol added to a standard oral glucose

R

From the General Hospital of Agordo (GB), Agordo, Italy, the University of Messina (AG), Messina, Italy, and the University of Padova (LG, AM, ED, El, AT, AA), Padova, Italy. Requests for reprints should be addressed to Angelo Avogaro. M.D., Cattedra di Malattie del Ricambio, Via Giustiniani 2.35100 Padova. Italy. Manuscript submitted February 15, 1990, and accepted in revised form August 28. 1990.

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tolerance test. Furthermore, it seems curious that alcohol consumption could deeply affect intermediary metabolism of normal subjects but not of patients with NIDDM, who show both impaired insulin secretion and insulin action. Therefore, in this study, we illustrate the effects of chronic alcohol consumption on the glucose and lipid metabolism of a group of 46 elderly subjects with NIDDM admitted between 1987 and 1989 to a hospital in a northern Italian community. We also compared the group of systematic drinkers with NIDDM to a group of NIDDM nondrinkers and a group of normal controls.

PATIENTS AND METHODS Forty-six patients with NIDDM who habitually consumed alcohol (NIDDM-B group) (31 women and 15 men, mean [& SEMI age 67 f 1 years) were admitted to the hospital over a 3-year study period. The patients were referred to the hospital by their family physician for a periodic follow-up of longterm diabetes complications. The body mass index was 28 f 1 kg/m2 and the duration of diabetes was 9 f 1 years. For each patient a detailed history of ethanol intake and dietary habits was obtained by two physicians in two or more interviews. These data were confirmed by a family member. Thirty-five patients with NIDDM who were nonalcohol consumers (NIDDM group) were admitted to the hospital during the same period of time for similar reasons. This group was composed of 20 women and 15 men aged 65 f 3 years. The body mass index of this group was 27 f 3 kg/m2 and the duration of the disease was 8 f 2 years. The control group (NC group) was composed of 40 subjects, matched for age (66 f 4 years) and sex (25 women and 15 men), with a body mass index of 26 f 3 kg/m2. These patients were referred to the hospital for problems unrelated to diabetes. They were either non-alcohol consumers or occasionally consumed alcohol in their diet. None of the subjects included in this study had evidence of hepatic, renal, or myocardial failure or endocrine disease. Twenty-three percent of the NIDDM-B group, 20% of the NIDDM group, and 15% of the NC group had systolic blood pressure values above 150 mm Hg and diastolic blood pressure values above 95 mm Hg. At the time of hospital admission they were undergoing domiciliary treatment for hypertension. All diabetic subjects admitted to the hospital were receiving domiciliary conventional treatment for diabetes. Patients in the NIDDM-B group were receiving the following: six were on diet alone; 13 were taking sulfonylureas; 14 were taking sulfo-

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nylureas and biguanides; three were taking biguanides; one was taking insulin and sulfonylureas; and nine were undergoing insulin therapy. Patients in the NIDDM group were treated as follows: four were on diet alone; 12 were taking sulfonylureas; nine were receiving combined sulfonylurea and biguanide treatment; two were taking biguanides; two were receiving sulfonylurea and insulin therapy; and six were undergoing insulin therapy. The regular diet followed by each subject included in the study consisted of at least 50% carbohydrates. The protocol was approved by the Ethical Committee for Human Investigations. All the subjects had a blood specimen drawn immediately upon arrival at the hospital for the following: hemoglobin; glucose; triglycerides; total cholesterol; high-density lipoprotein (HDL) cholesterol; hemoglobin Ai,; C-peptide; lactate; 3-hydroxybutyrate; free fatty acids (FFA); alcohol; blood urea nitrogen (BUN); aspartate aminotransferase (AST); alanine aminotransferase (ALT); yglutamyl transpeptidase (gGT); and acid-base composition and electrolytes. All the patients were admitted to the ward in the morning. They had all been fasting for at least 10 hours, but for no more than 15 hours. On the first and following days of hospitalization, plasma samples were taken during fasting and at 2-hour postprandial intervals at least five times a day. The subjects were on a standard hospital diet, calorically similar to their regular daily diet. The subjects followed their habitual insulin or oral therapeutic regimen as before hospitalization. Analysis Glucose was assayed with a glucose oxidase method [15]. Triglycerides were determined according to a previously described technique [16]. Total cholesterol and HDL cholesterol were quanta”ated by the methods of Allain et al [17] and Lopes-Virella et al [18]. Hemoglobin Ai, was measured according to the method of Schwartz and colleagues [19]. C-peptide was determined by radioimmunoassay as described previously [20]. Lactate and 3-hydroxybutyrate were assayed by a fluorimetric method [21]. FFA were measured according to a technique reported by Shimuzu et al [22]. BUN was quantitated as previously described [23]. Alcohol levels were assessed by the method of Mather and Assimos [24]. AST, ALT, and gGT were assayed enzymatically as reported by Kessler et al [25]. The blood pH was measured by an ILS 1302 pH meter (Instrument Laboratories, Lexington, Massachusetts). Sodium and potassium were determined with a flame photometer, and chloride was quantitated by an IL 446 chloride analyzer (Instrument Laboratories). January

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TABLE I Findings on Admission in the Diabetic Patients and Normal Control Subjects NIDDMD Alcohol intake (g/day) Plasma alcohol (mg/dL) AST (U/L)

NIDDM

45*4

3.08 3~0.92 31f2

25zk3 91 f 1 77 f 20*

i&y;) gGT (‘J/L)

NC

-

-

27:3 23 i 3 91f2 24ic3

26f4 24-+2 90f3 21f4

CV = mean corpuscular volume. p <0.05 compared with NIDDM and NC.

Figure 2. Top panel, mean (zL SEM) hemoglobin AI, in the NIDDM-B (white bar), NIDDM (crosshatched bar), and NC (hatched bar) groups. Bottom panel, mean (* SEM) C-peptide concentration on admission in the NIDDM-B (white bar), NIDDM (crosshatched bar), and NC (hatched bar) groups. * Statistically NC values.

(p <0.05)

significant

as compared

to NIDDM

and

Admission Acid-Base and Electrolyte Values I

8

I

I

I

0

1

2

3

4

I

I

5

6

1

1ADMlSSlDN

I (-+ SEM) fasting plasma glucose concentration on the day of admission to the hospital and on the following days in the NIDDM-B (open circles), NIDDM (solid circles), and NC (solid triangles) groups. Bottom panei, mean (f SEM) 2 hours postprandial plasma glucose concentration on the day of admission to the hospital and on the following days in the NIDDM-B (open circles), NIDDM (solid circles), and NC (solid triangles) groups. * Statistically (p <0.05) significant as compared to NIDDM and NC values.

~~~7~~~

7?JgT

IfIji;

Figure 1. Top panel, mean

The results are expressed as mean f SEM. Comparisons among groups were performed with Student’s t-test. Linear regressions and analysis of variance and covariance were performed according to conventional statistical methods. 72

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TCO2 = total carbon dioxide: Na = sodium: K = potassium; Cl = chloride.

RESULTS Alcohol intake in the NIDDM-B group was 45 f 4 g/day. At the time of hospital admission, the plasma alcohol level was 3.08 f 0.92 mg/dL. No significant differences were detected for AST, ALT, and mean corpuscular volume, as shown in Table I. The level of gGT was significantly higher in the NIDDM-B group (77 f 20 U/L) than in the NIDDM (24 f 3 U/ L) and NC (21 f 4 U/L) groups (p X0.05). On admission to the hospital, fasting plasma glu-

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TABLE III Fasting Metabolite Values on Admission and After 1 Week of Alcohol Withdrawal

Lactate (pm/L) 3-Hydroxybutyrate

&M/L)

FFA @M/L) Tryglycerides

(mM/L)

Total cholesterol

(mM/L)

HDL cholesterol

(mM/L)

Admission Withdrawal Admission Withdrawal Admission Withdrawal Admission Withdrawal Admission Withdrawal Admission Withdrawal

NIDDM-B

NIDDM

NC

1,321 f 251”

1,113*303* 993 k 202**

809 f 216 783 f 186

134f21’

104f 31

954 zk 198** 350 If: 41 *t 146 f 76** 790 f 47’f

127 i 36*

94 f 29

575 f 38* 526 f 30’ 1.51* 0.11* 1.50 f 0.09’ 5.7 f 0.2 5.6 f 0.3

543 6 42$* 1.61 & 0.13’ 1.53f0.16”

5.7 250.2 5.5 f 0.3 1.3fO.l 1.3f0.2

441 f 52 406 f 38 1.38 f 0.09 1.24f0.11

5.4 f 0.2 5.3 f 0.2

1.3fO.l 1.2f0.2

1.3ztO.l 1.3fO.l

* p <0.05 compared with NC. t p <0.05 compared with NIDDM. * p <0.05 compared with admission value.

case (Figure 1) was significantly higher in the NIDDM-B group (9.10 f 0.52 mM/L) than in the NIDDM group (7.83 f 0.27 mM/L; p <0.05). On the day of admission, the postprandial glucose concentration was significantly higher in the NIDDM-B group (10.65 f 0.72 mM/L) than in the NIDDM group (8.52 f 0.92 mM/L; p
and FFA than the NC group (104 f 31 PM/L and 441 f 52 PM/L, respectively). No differences were found in total and HDL cholesterol between the NIDDM-B and NIDDM populations (Table III). Higher triglyceride concentrations were observed in both diabetic groups, as compared to the NC group. We found a significant positive correlation (Figure 3) between age and hemoglobin Ai, in the NIDDM-B group (y = 1.30 + 0.08x; r = 0.47; p
11.8 -

9.8 ap : 4

g

X8-

5.8 -

3.8 I

30

80 AGE

igure 3. Linear regression analysis globin Al, in NIDDM-B subjects. The 1.30 + 0.08x; r = 0.47; p
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(years)

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age and hemoof the line is y =

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1

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I

I

I

I 7.33

1 137

I 7.41

I

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were noted between the age of the subjects in the NIDDM-B group and the fasting plasma glucose level on admission (r = 0.16; p = 0.2737), or between the duration of diabetes and the fasting plasma glucose level (r = 0.14; p = 0.3628). In the NIDDM-B group, we observed a significant negative correlation (Figure 4) between the triglyceride concentration and pH (y = 7913 -t -1056x; r = -0.39; p <0.005). We also found a significant negative correlation (Figure 5) between the triglyceride concentration and the estimated plasma anion gap ([sodium + potassium] - [chloride + total carbon dioxide]). A positive correlation was demonstrated between FFA and 3-hydroxybutyrate in the NIDDM-B group and in the NIDDM group, as shown in Figure 6. In the NIDDM-B group, no statistically significant correlation was found between pH and 3-hydroxybutyrate (r = 0.2436; p = 0.2436), or between triglycerides and fasting plasma glucose (r = 0.22; p = 0.1404).

6.67 t’-

0

5.64 5.64 -

4.51 00 3.36 -

225

-

1.13 -

O-

I 725

I 7.29

I 745

PH

COMMENTS

Figure 4. Linear regression analysis between triglyceride concentration (TG) and pi-l in NIDDM-6 subjects immediately on admission to the hospital. The equation of the line is y = 7913 + -1056x; r = -0.39; p <0.005.

667’

’

0

564 t

0

2

336

0

4

6 aniongap

16

12 (mEq/

20

t214

II

Figure 5. Linear regression analysis between triglyceride concentration (TG) and the estimated anion gap in NIDDM-B subjects immediately on admission to the hospital. The equation of the line is y = 0.89 + 7.24x; r = 0.33; p <0.023.

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In Europe, alcoholic beverages, particularly wine, are an integral part of the daily diet, especially in persons with NIDDM. Since these individuals show impaired insulin secretion and biologic action [26], the subject of alcohol in the diabetic diet needs to be addressed. This is the first report that focuses on the effects of customary alcohol consumption in a large group of persons with NIDDM, and also surveys the time course of plasma glucose concentrations after alcohol withdrawal. In this study, we have shown that chronic alcohol consumption significantly worsens short- and long-term metabolic control in elderly patients with NIDDM. This observation disagrees with the previous report of Walsh and O’Sullivan [13], who were not able to detect impaired glucose metabolism after an acute alcohol load in subjects with NIDDM. Our study is the first to show that alcohol consumption, even moderate, such as that present in the daily diet of our NIDDM-B group, has diabetogenic action. Alcohol interferes with insulin secretion [6] and decreases hormone biologic action in insulin-dependent tissues [9,27]. The fact that, at the time of admission to the hospital, the plasma alcohol concentrations in our NIDDM-B group were very low suggests that the detrimental effect of alcohol on insulin action is seen not only during and immediately after alcohol ingestion, and hence during its highest plasma concentrations, but lasts for several hours even in the presence of waning plasma levels. This observation supports the findings of Lomeo and colleagues [ll], who showed that alcohol inter-

METABOLIC

feres with insulin biologic action through the activity of two novel metabolites: 2,3-butanediol and 1,2propanediol. Since the plasma C-peptide concentrations in our NIDDM-B and NIDDM groups immediately on admission to the hospital were comparable, it seems that the increased plasma glucose concentrations observed in persons with NIDDM are mostly due to the ability of ethanol to inhibit the peripheral biologic action of insulin, rather than to its ability to inhibit B-ceil secretion. Furthermore, as shown in Figure 1, alcohol affects not only fasting but also, as expected, postprandial glucose concentrations. Yet this interfering effect of ethanol and its metabolites on insulin biologic action completely waned 3 days after admission of our patients to the hospital. It is interesting to note, as shown in Figure 3, that there was a progressive worsening of metabolic control with age. This factor makes elderly patients with NIDDM particularly exposed to the negative effects of alcohol on glucose metabolism. It is well known that alcohol oxidation increases the ratio of reduced nicotinamide-adenine dinucleotide (NADH) to nicotinamide-adenine dinucleotide (NAD); hence there is an increased production of lactate in the liver [28,29] and in the peripheral tissues 1301 as well as increased production of 3hydroxybutyrate [31]. However, in this study, the NIDDM-3 group did not show higher lactate concentrations than the NIDDM group. Furthermore, lactate was not increased among those who were receiving biguanide treatment (data not shown). These data support the findings of Halperin and coworkers [32], who observed that lactic acid production was significantly increased by alcohol administration only in the presence of severe clinical circumstances, such as sepsis or hypoxia. In our NIDDM-B group, even though the liver and the peripheral tissues may have produced an increasing amount of lactic acid secondary to diminished mitochondrial oxidation of pyruvate, this anion was probably still efficiently cleared by the peripheral tissues. On the contrary, 3-hydroxybutyrate concentrations were significantly higher in the NIDDM-B group. This could be due both to the effect of increased concentrations of FFA and to the increased NADH/NAD ratio. The higher levels of FFA observed in the NIDDM-B group were probably due to the presence of alcohol-induced insulin resistance, since high levels of FFA are seen only after heavy ethanol intake [33]. Concentrations of 3-hydroxybutyrate in both diabetic groups were closely related to circulating FFA, as shown by the positive correlation in Figure 6. Interestingly, the slope of

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l

500-

0 0

t 1000

500 FFA

, 1500

f 2000

WWII

Figure 6. Linear regression analysis between FFA and 3-hydroxybutyrate concentrations in NIDDM-B (solid circles) and NIDDM (open circles) subjects immediately on admission to the hospital. The equation of the line in NIDDM-B subjects is y = -52.8 + 0.51x; r = 0.59; p
regression between the concentrations of FFA and 3-hydroxybutyrate in the NIDDM-B group was significantly different (p <0.05) from that observed in the NIDDM group. This observation suggests a more efficient synthesis of ketone bodies from FFA in the NIDDM-B group. This could be the result of the combined effects of increased inflow of FFA to the liver and the presence of insulin resistance, even though decreased peripheral 3-hydroxybutyrate clearance might play a role, as previously shown using isotopic tracer methods [34]. After 7 days of alcohol withdrawal, circulating levels of both FFA and 3-hydroxybutyrate were similar to those in nondrinking diabetic subjects. This further underscores the efficiency of alcohol intake by sustaining both lipolysis and ketogenesis. Although alcohol intake has been known to cause an increase in plasma triglycerides [35], we did not observe a clear-cut increase in the triglyceride concentration in the NIDDM-B group. However, the highly significant negative correlation between pH and triglycerides, as well as the correlation between the estimated anion gap and triglycerides, in the NIDDM-B subjects suggests that even a small increase in the blood proton content could interfere with normal insulin action, as previously shown in vitro by Van Putten and colleagues [36]. They found that lowering the physiologic pH induces a decrease in insulin binding. The close relationship between pH and triglyceride synthesis is further supported by the fact that there was no correlation between glucose and triglyceride levels. This decreased insulin action could sustain a decreased triglyceride clearance by lipoprotein lipase and could

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glucose tolerance in normal and non-insulin dependent diabetic subjects. Alcoholism (NY) 1988; 12: 727-30. 15. Huggett AS, Nixon DA. Use of glucose oxidase, peroxidase and 0-dianisidine in the determination of blood and urine glucose. Lancet 1957; 2: 368-70. 16. Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973; 19: 476-82. 17. Allain CC, Poon LS, Chan CS. Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20: 470-5. i8. Lopes-Virella MF. Stone P, Ellis S, Colwell JA. Cholesterol determiriation in high-density lipoprotein separated by three different methods. Clin Chem 1977;

explain the severe hypertriglyceridemia observed during heavy alcohol intake. In conclusion, alcohol intake causes deterioration in long- and short-term glucose metabolism in aged persons with NIDDM. These patients are at particular risk since they also show a progressive decline in metabolic control with age. Alcohol consumption leads to increased lipolysis and ketogenesis, probably mediated by alcohol-induced insulin resistance. Increased triglyceride concentration also seems to be related to sotie degree of insulin resistance, induced by decreased blood pH. The data presented in this study emphasize the importance of limiting alcohol consumption, at least in elderly individuals with NIDDM, and stress the necessity of strictly monitoring metabolic control when alcohol is an important cbnstituent of the diet.

23: 882-4. 19. Schwartz HC, King KC, Schwartz AL, Edmund D. Schwartz R. Effect of pregnancy on hemoglobin Ale in normal gestational diabetic and diabetic women. Diabetes 1976; 25: 1118-22. 20. Kuzuya T, Saito T, Yoshida S, Matsuda A. Human C-peptide immunoreactive (CPR) in blood and urine. Evaluation of a radioimmunoassay method and its clinical applications. Diabetologia 1976; 12: 511-8. 21. Lloyd B, Burrin J, Smythe P, Alberti KG. Enzymic fluorometric continuousflow assay for blood glucose, lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem 1978; 24: 1724-9. 22. Shimuzu S, lnque K, Tani Y, Yamada H. Enzymatic microdetermination of serum free fatty acids. Anal Biochem 1979; 98: 341-5. 23. Marsh WH, Fingenut B, Miller H. Automated and manual direct methods for the determination of blood urea. Clin Chem 1965; 11: 624-7. 24. Mather A, Assimos A. Evaluation of gas-liquid chromatography in assays for blood volatiles. Clin Chem 1965; 11: 1023-35. 25. Kessler G, Rush R, Leon L, Delea A, Cupiola R. Automate 340 nm measurement of SGOT, SGPT, and LDH. In: Advances in automated analysis. Technicon International Congress. Vol 1. Miami: Thurman Associates, 1970: 67-74. 26. Olefsky JM. Garvey WT, Henry RR, Brillon D, Matthaei S, Freidemberg GR. Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. Am J Med 1988; 85 (Suppl 5A): 86-105. 27. Avogaro A, Duner E, Marescotti MC, et al. Metabolic effects of moderate alcohol intake with meals in insulin-dependent diabetics controlled by artificial endocrine pancreas (AEP) and in normal subjects. Metab Clin Exp Res 1983; 32:

ACKNOWLEDGMENT We are deeply grateful linguistic support.

to Mrs. Cheryl

Shulgin Maggiani for the inestimable

REFERENCES 1. Phillips GE, Safrit HF. Alcoholic diabetes: induction of glucose intolerance with alcohol. JAMA 1971; 217: 1513-9. 2. Nilikila EA, Taskinen MR. Ettianol-induced alterations of glucose tolerance, postglucose hypoglycemia, and insulin secretion in normal, obese, and diabetic subjects. Diabetes 1975; 24: 933-43. 3. Shanley BC, Robertson EJ. Joubert SM, North-Coombes JD. Effect of alcohol on glucose tolerance. Lancet 1972; 1: 1232. 4. Dornhorst A, Ouyang A. Effect of alcohol on glucose tolerance. Lancet 1971;

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M, Bock J, Ben-Ezra J, Antony M, Danzig J, Gage JS. Plasma lactate and 3-hydroxybutyrate levels in patients with acute ethanol intoxication. Am J Med 1986: 80: 191-5. 29. Avogaro A, Cibin M, Croatto T. Rizzo A, Gallimberti L, Tiengo A. Alcohol intake and withdrawal: effects on branched chain aminoacids and alanine. Alcoholism (NY) 1986; 10: 300-4. 30. Duner E, Avogaro A, Marescotti MC, et al. Intermediary metabolite profiles during euglycemic glucose-insulin clamp: effects of ethanol. Ric Clin Lab 1986; 16: 471-9. 31. Fulop M, Hoberman HD. Alcohol ketosis. Diabetes 1975; 24: 785-90. 32. Halperin ML, Hammeke M, Josse RG, Jungas RL. Metabolic acidosis in the alcoholic: a pathophysiologic approach. Metabolism 1983; 32: 308-15. 33. Lieber CS. Metabolic derangements induced by alcohol. Annu Rev Med 1967; 18: 35-43. 34. Nosadini R, Avogaro A, Trevisan R, et al. Acetoacetate and 3-hydroxybutyrate kinetics in obese and insulin-dependent diabetic humans. Am J Physiol 1985; 248: R611-20. 35. Ginsberg H, Olefsky J, Farquhar JW, Reaven GM. Moderate ethanol ingestion and plasma triglyceride levels. A study in normal and hypertriglyceridemic persons. Ann Intern Med 1974; 80: 143-9. 36.Van Putten JPM, Wieringa T, Krans HMJ. Low pH and ketoacids induce insulin receptor binding and postbinding alterations in cultured 3T3 adipocytes. Diabetes 1985; 34: 744-50.

2: 957-9. 5. Sereny G, Endrenyi L. Mechanism and significance of carbohydrate intolerance. Metabolism 1978; 27: 1041-6. 6. Tiengo A, Valerio A, h;lolinari M, Meneghel A, Lapolla A. Effect of ethanol, acetaldehyde, and acetate on insulin and glucagon secretion in the perfused rat pancreas. Diabetes 1981; 30: 705-9. 7. Holley DC, Bagby GJ, Curry DL. Ethanol-induced interrelationships in the rat studied in vitro and in viva: evidence for direct ethanol inhibition of biphasic glucose-induced insulin secretion. Metabolism 1981; 30: 894-9. 8. Avogaro A, Fontana P. Valerio A, et al. Alcohol impairs insulin sensitivity in normal subjects. Diabetes, Res 1987; 5: 23-7. 9. Yki-Jarvinen H. Nikkila EA. -Ethanol decreases glucose utilization in healthy man. J Clin Endocrinol Metab 1985; 61: 941-5. 10. Shelmet JJ, Reichard GA, Skutches CL, Hoeldtke RD, Owen OE, Boden G. Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance. J Clin Invest 1988; 81: 1137-45. ll.Lomeo F, Khokhner MA, Dandona P. Ethanol and its novel metabolites inhibit insulin action on adipocytes. Diabetes 1988; 37: 912-5. 12. McDonald J. Alcohol and diabetes. Diabetes Care 1980; 3: 629-37. 13. Walsh CH, O’Sullivan DJ. Effect of moderate alcohol intake on control of diabetes. Diabetes 1974; 23: 440-2. 14. Singh SP, Kumar Y, Snyder AK, Ellyin FE, Gilden JL. Effect of alcohol on

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