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Propranolol and hypertriglyceridemia
Atherosclerosis, 17 (1973) 31-35 0 Elsevier Scientific Publishing Company,
PROPRANOLOL
JOSEPH
31 Amsterdam
- Printed in The Netherlands
AND HYPERTRIGLYCERIDEMIA
J. BARBORIAK*
AND
H. DAVID
FRIEDBERG**
(Received January 7th, 1972)
SUMMARY
Eight subjects with elevated fasting plasma triglyceride levels and type IV hyperlipoproteinemia, who received a 60 g fat meal before and after 2-week treatment with propranolol, showed an enhanced lipemic response to the meal after the treatment. In 6 subjects without fasting hypertriglyceridemia, treatment with propranolol led to a slight but consistent decrease in alimentary lipemia. Plasma cholesterol levels were not affected in either group.
Key words : Hypertriglyceridemia - Postprandial lipemia - Propranolol
INTRODUCTION
Results of animal experiments have suggested that beta adrenergic blocking agents enhance alimentary lipemia 1~~.This lipemic effect of propranolol was especially apparent in rats maintained on a high fat diets. Furthermore, butoxamine, another beta-blocking agent, increased plasma triglyceride levels following chylomicron infusions in dog@. Evidence regarding the effects of beta adrenergic blockade on plasma triglycerides in man is scanty and conflicting. Sailer et al5. and Wegener et aZ.6 reported a reduction in fasting plasma triglycerides with propranolol in short-term studies, however, Lloyd-Mostyn et al.7 could not confirm this. The present report describes the effects of small but therapeutic doses of propranolol on fasting serum lipids and on the lipemic response to a standard fatty meal in man. This work was supported by a grant from the Wisconsin Heart Association. * Professor of Pharmacology, Medical College of Wisconsin, Milwaukee, Wise.; Chief, Biochemistry Section, Research Service, Veterans Administration Center, Wood (Milwaukee), Wise. 53193 (U.S.A.) ** Associate Professor of Medicine, Medical College of Wisconsin, Milwaukee, Wise.; Chief, Coronary Care Unit, Medical Service, Veterans Administration Center, Wood (Milwaukee), Wise. 53193 (U.S.A.)
32
JOSEPH J. BARBORIAK,
H. DAVID FRIEDBERG
METHODS
Fourteen subjects were studied. They included 5 patients in whom propranolol was indicated for angina pectoris, 4 with tachycardia due to the Wolff-ParkinsonWhite syndrome, and 5 normal volunteers with no overt evidence of cardiovascular disease. Three patients had maturity onset diabetes mellitus well controlled by diet alone, 7 were receiving digitalis. During the study the patients remained in the hospital ; the control subjects were ambulatory. Initial blood samples were drawn after an overnight fast. A standardized high fat breakfasts containing, by calculation, about 60 g of fat was then given. Further blood samples were drawn 6 h after the meal. Plasma was separated in a refrigerated centrifuge. Triglyceride and total cholesterol levels and electrophoretic distribution of lipoproteins were determined by the standard techniques+ll. All subjects then received 40 mg propranolol daily in divided doses for 14 days. In one patient, the propranolol dose was gradually increased for medical reasons to 80 mg and in two patients to 160 mg daily. After 2 weeks of treatment with propranolol, i.e. on the 15th day of the experiment, the fat meal and blood sampling were repeated. Direct questioning of all subjects showed no marked changes in dietary habits or physical activity. RESULTS
Plasma triglycerides
The response of plasma triglyceride levels to propranolol revealed two very distinct patterns (Table 1). In one group of subjects (group A) (7 patients and one control, mean age 50 f 1 year, body weight 18 1 f 7 lbs.) the initial fasting triglyceride levels were all over 150 mg/lOO ml (mean = 217 mg/lOO ml, standard error = 21 mg/lOO ml). The triglyceride level rose by additional 74 & 11 mg/lOO ml at 6 h after the meal. After treatment with propranolol, the initial plasma triglyceride level amounted to 274 f 26 mg/lOO ml (P > 0.05). The 6-h post-meal had risen by 128 f 9 mg/lOO ml. Thus, the standard meal produced a 6-h rise of plasma triglycerides of 74 mg/lOO ml before and 128 mg/lOO ml after propranolol. This difference is statistically significant (t-test, P < 0.01). In the other group (group B) (4 controls and 2 patients, mean age 48 & 6 years, body weight 187 & 31 lbs.) the initial fasting plasma triglyceride levels were all less than 150 mg per 100 ml (mean 108 f 7 mg/lOO ml). The meal-induced rise in plasma triglyceride level at 6 h was 68 f 24 mg/lOO ml before and 33 f 13 mg/lOO ml after propranolol (P < 0.05). Lipoprotein electrophoresis
All subjects in group A showed a distinct pre-beta-lipoprotein band (Type IV hyperlipoproteinemia). At 6 h in the post-treatment study the chylomicron band was present and pre-beta was qualitatively increased. The lipoprotein electrophoresis pattern was normal in all patients in group B. No quantitative measurements of lipoprotein distribution were carried out.
PROPRANOLOL AND HYPERTRIGLYCERIDEMIA
33
TABLE I THE
EFFECT
LEVELS
OF PROPRANOLOL
TREATMENT
ON PLASMA
CHOLESTEROL
AND POSTPRANDIAL
TRIGLYCERIDE
IN MAN
_
Patient
No.
Before propranolol triglycerides pre-meal
6-h increase
cholesterol pre-meal
triglycerides pre-meal
6-h increase
306 152 254 396 326 214 286 256
102 132 157 80 126 138 150 138
170 208 262 280 264 188 -
274 f 26
128 +z 9
229 f 19
101 74 186 183 115 122
-1 26 38 93 13 32
226 128 210 208 169 154
130 f 18
33 f
cholesterol pre-meal
_ A - Group with 1 2 3 4 5 6 7 8 Mean
increasedplasma triglyceride
levels 210” 249 255 234 247 168
298& 186 215 158 216 152 230 158
96 110 82 64 6 64 70 98
-
217 f 21e
14 &I1
227 i
B - Group with normal plasma 1 125 2 84 3 120 4 116 5 88 6 115
triglyceride 15 46 89 170 16 70
Mean
68 zt 24
108 f 7
14
levels 175 136 184 173 176 230 179 f 12
13
193 f
15
& All values in mg/lOO ml. b Only plasmas of 6 patients were available for cholesterol determination. c Mean rt standard error of the mean.
Cholesterol
We found no evidence that plasma total cholesterol levels were affected by propranolol (Table 1). In group A the fasting total cholesterol concentration was 227 f 14 mg/lOO ml before and 229 f 19 mg/lOO ml after propranolol. The corresponding values for group B were 179 f 12 and 193 i_ 15 mg, respectively. No differences in lipid response to the test meal before or after treatment could be related to the presence of diabetes mellitus (2 of the diabetic patients were in the high triglyceride group, one in the low lipid group), or digitalis treatment (4 of the 7 patients were in the high triglyceride group). Two of the patients receiving higher doses of propranolol were in the high triglyceride group; the rise in their plasma triglycerides after 2 weeks of propranolol treatment amounted to 157 and 132 mg/lOO ml, respectively and was thus slightly higher than the average value for the whole group, which was 128 mg/lOO ml. The corresponding triglyceride rise of the third patient with increased propranolol dose was 38 mg/lOO ml.
JOSEPH J. BARBORIAK,
H. DAVID FRIEDBERG
DISCUSSION
This study shows that treatment with propranolol enhances alimentary lipemia and reduces fat tolerance in subjects with elevated fasting plasma triglyceride levels and increased pre-beta lipoproteins. Our data also suggest a small but not statistically significant increase in fasting plasma triglyceride levels after only a 2-week exposure to the drug. Similar small but statistically not significant increases in fasting plasma triglycerides have been observed by Lloyd-Mostyn et al.7 in patients receiving three different beta-adrenergic blocking agents for 2 week periods. The absence of any information on the lipoprotein type of patients in the two other studies516 makes it difficult to explain the differences between their findings and the results of LloydMostyn et al.7 and the present study. In normal subjects we found a small but statistically significant reduction of alimentary lipemia after treatment. As reported in other studies’, the levels of plasma cholesterol were not affected by the propranolol. The metabolic background of the lipemic response to propranolol is not clear. It may be related to the fact that propranolol inhibits the release of insulin12,13 which is believed to be necessary for clearing of circulating triglyceridesl4J15. Further, propranolol may affect the extrahepatic processing of absorbed dietary fat1s117 by blocking the release of free fatty acids from the adipose tissues and thus may retard the return of plasma lipids to their fasting levels. Finally, propranolol may enhance the known tendency of patients with elevated fasting plasma triglycerides to prolong the retention of the absorbed dietary fat in the circulationlsyl9. Studies of longer duration are needed to find out whether beta blockade leads to a sustained change in triglyceride levels. The clinical significance of the propranolol-induced enhancement of alimentary lipemia in some hyperlipemic patients is speculative. While lipemia of even short duration may be associated with changes in blood coagulation 20, the extent and importance of such changes in patients with coronary disease remains to be clarified. ACKNOWLEDGEMENTS
The authors wish to thank Miss F. P. Kelley, Chief, Dietetic Service for her help in planning the diet and Mrs. Gertrude Scribner and Miss Jacqueline Owenby for their technical assistance.
REFERENCES 1 BARBORIAK, J. J., R. C. MEADE, J. OWENBY AND R. A. STIGLITZ, Blockers
of free fatty acid
release and postprandial lipemia, Arch. Int. Pharmacodyn. Ther., 176 (1967) 249. 2 FRIEDMAN, M., AND C. 0. BYERS, Epinephrine-induced reduction of postprandial lipemia in the rat, Amer. J. Physiol., 213 (1967) 829. 3 BARBORIAK, J. J., AND R. C. MEADE, Fatty acid release and alimentary lipemia, Pharmacologist, 12 (1970) 219.
PROPRANOLOL AND HYPERTRIGLYCERIDEMIA
35
4 REGAN, T. J., H. A. OLDEWURTEL,A. MARKOV, AND W. M. BURKE, Free fatty acid release from tissue stores during chyle infusion, J. Appl. Physiol., 28 (1970) 444. 5 SAILER, S., F. SANDHOFER,R. BOLZANO, F. DIENSTLAND H. BRAUNSTEINER, Uber die Wirkung eines Beta-blockers (Propranolol) auf den Umsatz der freien Fettsluren in Plasmatriglyceride beim Mensch, Klin. Wochenschr., 45 (1967) 670. 6 WEGENER,M., W. GEBHARDTAND R. CLOTTEN,Blutfette nach medikamentijser BetarezeptorenBlockade, Dtsch. Med. Wochenschr., 94 (1969) 904. 7 LLOYD-M• STYN, R. H., D. LEFEVRE,P. S. LORD. E. DOIG AND D. M. KRIKLER,The effect of betaadrenergic blocking agents on serum lipids, Atherosclerosis, 14 (1971) 283. 8 BARBORIAK,J. J., AND R. C. MEADE, Enhancement of alimentary lipemia by preprandial alcohol,
Amer. J. Med. Sci., 255 (1962) 245. 9 VAN HANDEL, E., AND D. B. ZILVERSMIT,Micromethod glycerides, J. Lab. C/in. Med., 50 (1957) 152.
for direct determination
of serum tri-
10 BABSON,A. L., P. 0. SHAPIROAND G. E. PHILLIPS,A new assay for cholesterol and cholesterol ester in serum which is not affected by bilirubin, Clin. Chirn. Acta, 7 (1962) 800. 11 LEES,R. S., AND F. T. HATCH, Sharper separation of lipoprotein species by paper electrophoresis in albumin-containing buffer, J. Lab. Ckn. Med., 61 (1963) 518. 12 CERASI, E., F. EFFENDICAND R. LUFT, Role of adrenergic receptors in glucose-induced insulin secretion in man, Lancet, i (1969) 301. 13 KOTLER, M. N., L. A. BERMANAND A. H. RUBINSTEIN,Hypoglycemia precipitated by propranolol, Luncet, ii (1966) 1389. 14 BAGDADE,J. D., D. PORTE,JR. AND E. L. BIERMAN,Acute insulin withdrawal in the regulation of plasma triglyceride removal in diabetic subjects, Diabetes, 17 (1968) 127. 15 NIKKILA, E. A., Control of plasma and liver triglyceride kinetics by carbohydrate metabolism and insulin. In: R. PAOLETTIAND D. KR~TCHEVSKY (Eds.), Advances in Lipid Research, Academic Press, New York, 1969, Vol. 7, p. 97. 16 FELTS, J. M., AND P. M. MAYES, Lack of uptake and oxidation of chylomicron triglyceride to carbon dioxide and ketone bodies by perfused rat liver, Nature (London), 206 (1965) 195. 17 MAYES, P. M., AND J. M. FELTS, Regulation of fat metabolism in the liver, Nature (London),
215 (1967) 716. 18 NESTEL,P. M., Relationship between plasma triglycerides and removal of chylomicrons, J. Ckn. Invest., 43 (1964) 943. 19 DENBOROUGH,M. A., Alimentary lipemia in ischaemic heart disease, Clin. Sci., 25 (1963) 115. 20 RENAUD, S., AND F. LECOMPTE,Hypercoagulability induced by hyperlipemia in rat, rabbit and man. Role of platelet factor 3, Circ. Res., 27 (1970) 1003.
PROPRANOLOL
JOSEPH
31 Amsterdam
- Printed in The Netherlands
AND HYPERTRIGLYCERIDEMIA
J. BARBORIAK*
AND
H. DAVID
FRIEDBERG**
(Received January 7th, 1972)
SUMMARY
Eight subjects with elevated fasting plasma triglyceride levels and type IV hyperlipoproteinemia, who received a 60 g fat meal before and after 2-week treatment with propranolol, showed an enhanced lipemic response to the meal after the treatment. In 6 subjects without fasting hypertriglyceridemia, treatment with propranolol led to a slight but consistent decrease in alimentary lipemia. Plasma cholesterol levels were not affected in either group.
Key words : Hypertriglyceridemia - Postprandial lipemia - Propranolol
INTRODUCTION
Results of animal experiments have suggested that beta adrenergic blocking agents enhance alimentary lipemia 1~~.This lipemic effect of propranolol was especially apparent in rats maintained on a high fat diets. Furthermore, butoxamine, another beta-blocking agent, increased plasma triglyceride levels following chylomicron infusions in dog@. Evidence regarding the effects of beta adrenergic blockade on plasma triglycerides in man is scanty and conflicting. Sailer et al5. and Wegener et aZ.6 reported a reduction in fasting plasma triglycerides with propranolol in short-term studies, however, Lloyd-Mostyn et al.7 could not confirm this. The present report describes the effects of small but therapeutic doses of propranolol on fasting serum lipids and on the lipemic response to a standard fatty meal in man. This work was supported by a grant from the Wisconsin Heart Association. * Professor of Pharmacology, Medical College of Wisconsin, Milwaukee, Wise.; Chief, Biochemistry Section, Research Service, Veterans Administration Center, Wood (Milwaukee), Wise. 53193 (U.S.A.) ** Associate Professor of Medicine, Medical College of Wisconsin, Milwaukee, Wise.; Chief, Coronary Care Unit, Medical Service, Veterans Administration Center, Wood (Milwaukee), Wise. 53193 (U.S.A.)
32
JOSEPH J. BARBORIAK,
H. DAVID FRIEDBERG
METHODS
Fourteen subjects were studied. They included 5 patients in whom propranolol was indicated for angina pectoris, 4 with tachycardia due to the Wolff-ParkinsonWhite syndrome, and 5 normal volunteers with no overt evidence of cardiovascular disease. Three patients had maturity onset diabetes mellitus well controlled by diet alone, 7 were receiving digitalis. During the study the patients remained in the hospital ; the control subjects were ambulatory. Initial blood samples were drawn after an overnight fast. A standardized high fat breakfasts containing, by calculation, about 60 g of fat was then given. Further blood samples were drawn 6 h after the meal. Plasma was separated in a refrigerated centrifuge. Triglyceride and total cholesterol levels and electrophoretic distribution of lipoproteins were determined by the standard techniques+ll. All subjects then received 40 mg propranolol daily in divided doses for 14 days. In one patient, the propranolol dose was gradually increased for medical reasons to 80 mg and in two patients to 160 mg daily. After 2 weeks of treatment with propranolol, i.e. on the 15th day of the experiment, the fat meal and blood sampling were repeated. Direct questioning of all subjects showed no marked changes in dietary habits or physical activity. RESULTS
Plasma triglycerides
The response of plasma triglyceride levels to propranolol revealed two very distinct patterns (Table 1). In one group of subjects (group A) (7 patients and one control, mean age 50 f 1 year, body weight 18 1 f 7 lbs.) the initial fasting triglyceride levels were all over 150 mg/lOO ml (mean = 217 mg/lOO ml, standard error = 21 mg/lOO ml). The triglyceride level rose by additional 74 & 11 mg/lOO ml at 6 h after the meal. After treatment with propranolol, the initial plasma triglyceride level amounted to 274 f 26 mg/lOO ml (P > 0.05). The 6-h post-meal had risen by 128 f 9 mg/lOO ml. Thus, the standard meal produced a 6-h rise of plasma triglycerides of 74 mg/lOO ml before and 128 mg/lOO ml after propranolol. This difference is statistically significant (t-test, P < 0.01). In the other group (group B) (4 controls and 2 patients, mean age 48 & 6 years, body weight 187 & 31 lbs.) the initial fasting plasma triglyceride levels were all less than 150 mg per 100 ml (mean 108 f 7 mg/lOO ml). The meal-induced rise in plasma triglyceride level at 6 h was 68 f 24 mg/lOO ml before and 33 f 13 mg/lOO ml after propranolol (P < 0.05). Lipoprotein electrophoresis
All subjects in group A showed a distinct pre-beta-lipoprotein band (Type IV hyperlipoproteinemia). At 6 h in the post-treatment study the chylomicron band was present and pre-beta was qualitatively increased. The lipoprotein electrophoresis pattern was normal in all patients in group B. No quantitative measurements of lipoprotein distribution were carried out.
PROPRANOLOL AND HYPERTRIGLYCERIDEMIA
33
TABLE I THE
EFFECT
LEVELS
OF PROPRANOLOL
TREATMENT
ON PLASMA
CHOLESTEROL
AND POSTPRANDIAL
TRIGLYCERIDE
IN MAN
_
Patient
No.
Before propranolol triglycerides pre-meal
6-h increase
cholesterol pre-meal
triglycerides pre-meal
6-h increase
306 152 254 396 326 214 286 256
102 132 157 80 126 138 150 138
170 208 262 280 264 188 -
274 f 26
128 +z 9
229 f 19
101 74 186 183 115 122
-1 26 38 93 13 32
226 128 210 208 169 154
130 f 18
33 f
cholesterol pre-meal
_ A - Group with 1 2 3 4 5 6 7 8 Mean
increasedplasma triglyceride
levels 210” 249 255 234 247 168
298& 186 215 158 216 152 230 158
96 110 82 64 6 64 70 98
-
217 f 21e
14 &I1
227 i
B - Group with normal plasma 1 125 2 84 3 120 4 116 5 88 6 115
triglyceride 15 46 89 170 16 70
Mean
68 zt 24
108 f 7
14
levels 175 136 184 173 176 230 179 f 12
13
193 f
15
& All values in mg/lOO ml. b Only plasmas of 6 patients were available for cholesterol determination. c Mean rt standard error of the mean.
Cholesterol
We found no evidence that plasma total cholesterol levels were affected by propranolol (Table 1). In group A the fasting total cholesterol concentration was 227 f 14 mg/lOO ml before and 229 f 19 mg/lOO ml after propranolol. The corresponding values for group B were 179 f 12 and 193 i_ 15 mg, respectively. No differences in lipid response to the test meal before or after treatment could be related to the presence of diabetes mellitus (2 of the diabetic patients were in the high triglyceride group, one in the low lipid group), or digitalis treatment (4 of the 7 patients were in the high triglyceride group). Two of the patients receiving higher doses of propranolol were in the high triglyceride group; the rise in their plasma triglycerides after 2 weeks of propranolol treatment amounted to 157 and 132 mg/lOO ml, respectively and was thus slightly higher than the average value for the whole group, which was 128 mg/lOO ml. The corresponding triglyceride rise of the third patient with increased propranolol dose was 38 mg/lOO ml.
JOSEPH J. BARBORIAK,
H. DAVID FRIEDBERG
DISCUSSION
This study shows that treatment with propranolol enhances alimentary lipemia and reduces fat tolerance in subjects with elevated fasting plasma triglyceride levels and increased pre-beta lipoproteins. Our data also suggest a small but not statistically significant increase in fasting plasma triglyceride levels after only a 2-week exposure to the drug. Similar small but statistically not significant increases in fasting plasma triglycerides have been observed by Lloyd-Mostyn et al.7 in patients receiving three different beta-adrenergic blocking agents for 2 week periods. The absence of any information on the lipoprotein type of patients in the two other studies516 makes it difficult to explain the differences between their findings and the results of LloydMostyn et al.7 and the present study. In normal subjects we found a small but statistically significant reduction of alimentary lipemia after treatment. As reported in other studies’, the levels of plasma cholesterol were not affected by the propranolol. The metabolic background of the lipemic response to propranolol is not clear. It may be related to the fact that propranolol inhibits the release of insulin12,13 which is believed to be necessary for clearing of circulating triglyceridesl4J15. Further, propranolol may affect the extrahepatic processing of absorbed dietary fat1s117 by blocking the release of free fatty acids from the adipose tissues and thus may retard the return of plasma lipids to their fasting levels. Finally, propranolol may enhance the known tendency of patients with elevated fasting plasma triglycerides to prolong the retention of the absorbed dietary fat in the circulationlsyl9. Studies of longer duration are needed to find out whether beta blockade leads to a sustained change in triglyceride levels. The clinical significance of the propranolol-induced enhancement of alimentary lipemia in some hyperlipemic patients is speculative. While lipemia of even short duration may be associated with changes in blood coagulation 20, the extent and importance of such changes in patients with coronary disease remains to be clarified. ACKNOWLEDGEMENTS
The authors wish to thank Miss F. P. Kelley, Chief, Dietetic Service for her help in planning the diet and Mrs. Gertrude Scribner and Miss Jacqueline Owenby for their technical assistance.
REFERENCES 1 BARBORIAK, J. J., R. C. MEADE, J. OWENBY AND R. A. STIGLITZ, Blockers
of free fatty acid
release and postprandial lipemia, Arch. Int. Pharmacodyn. Ther., 176 (1967) 249. 2 FRIEDMAN, M., AND C. 0. BYERS, Epinephrine-induced reduction of postprandial lipemia in the rat, Amer. J. Physiol., 213 (1967) 829. 3 BARBORIAK, J. J., AND R. C. MEADE, Fatty acid release and alimentary lipemia, Pharmacologist, 12 (1970) 219.
PROPRANOLOL AND HYPERTRIGLYCERIDEMIA
35
4 REGAN, T. J., H. A. OLDEWURTEL,A. MARKOV, AND W. M. BURKE, Free fatty acid release from tissue stores during chyle infusion, J. Appl. Physiol., 28 (1970) 444. 5 SAILER, S., F. SANDHOFER,R. BOLZANO, F. DIENSTLAND H. BRAUNSTEINER, Uber die Wirkung eines Beta-blockers (Propranolol) auf den Umsatz der freien Fettsluren in Plasmatriglyceride beim Mensch, Klin. Wochenschr., 45 (1967) 670. 6 WEGENER,M., W. GEBHARDTAND R. CLOTTEN,Blutfette nach medikamentijser BetarezeptorenBlockade, Dtsch. Med. Wochenschr., 94 (1969) 904. 7 LLOYD-M• STYN, R. H., D. LEFEVRE,P. S. LORD. E. DOIG AND D. M. KRIKLER,The effect of betaadrenergic blocking agents on serum lipids, Atherosclerosis, 14 (1971) 283. 8 BARBORIAK,J. J., AND R. C. MEADE, Enhancement of alimentary lipemia by preprandial alcohol,
Amer. J. Med. Sci., 255 (1962) 245. 9 VAN HANDEL, E., AND D. B. ZILVERSMIT,Micromethod glycerides, J. Lab. C/in. Med., 50 (1957) 152.
for direct determination
of serum tri-
10 BABSON,A. L., P. 0. SHAPIROAND G. E. PHILLIPS,A new assay for cholesterol and cholesterol ester in serum which is not affected by bilirubin, Clin. Chirn. Acta, 7 (1962) 800. 11 LEES,R. S., AND F. T. HATCH, Sharper separation of lipoprotein species by paper electrophoresis in albumin-containing buffer, J. Lab. Ckn. Med., 61 (1963) 518. 12 CERASI, E., F. EFFENDICAND R. LUFT, Role of adrenergic receptors in glucose-induced insulin secretion in man, Lancet, i (1969) 301. 13 KOTLER, M. N., L. A. BERMANAND A. H. RUBINSTEIN,Hypoglycemia precipitated by propranolol, Luncet, ii (1966) 1389. 14 BAGDADE,J. D., D. PORTE,JR. AND E. L. BIERMAN,Acute insulin withdrawal in the regulation of plasma triglyceride removal in diabetic subjects, Diabetes, 17 (1968) 127. 15 NIKKILA, E. A., Control of plasma and liver triglyceride kinetics by carbohydrate metabolism and insulin. In: R. PAOLETTIAND D. KR~TCHEVSKY (Eds.), Advances in Lipid Research, Academic Press, New York, 1969, Vol. 7, p. 97. 16 FELTS, J. M., AND P. M. MAYES, Lack of uptake and oxidation of chylomicron triglyceride to carbon dioxide and ketone bodies by perfused rat liver, Nature (London), 206 (1965) 195. 17 MAYES, P. M., AND J. M. FELTS, Regulation of fat metabolism in the liver, Nature (London),
215 (1967) 716. 18 NESTEL,P. M., Relationship between plasma triglycerides and removal of chylomicrons, J. Ckn. Invest., 43 (1964) 943. 19 DENBOROUGH,M. A., Alimentary lipemia in ischaemic heart disease, Clin. Sci., 25 (1963) 115. 20 RENAUD, S., AND F. LECOMPTE,Hypercoagulability induced by hyperlipemia in rat, rabbit and man. Role of platelet factor 3, Circ. Res., 27 (1970) 1003.