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Influence of prostaglandins on plasma glucagon levels in the rat
Metabolism Clinical and Experimental VOL. XXV,
NO. 2
PRELIMINARY
FEBRUARY
1976
REPORT
Influence of Prostaglandins on Plasma Glucagon Levels in the Rat L. Sac&
and G. Perez
The effect of PGE, and PGA, intravenous infusion (2/&min) on plasma glucose and glucagon levels was investigated in and pronormal, sympathectomized pranolol-treated rats. POE, infusion significantly increased glucose and glucagon levels, while PGA, had no etTect. Since the dose of POE, used in this study was able to reduce the arterial blood pressure by about 20%,
PGE, acted indirectly through a reflex sympathetic ovemctivity was tested. The increases in plasma glucagon induced by POE, occurred also in sympathectomized or in beta-blocked animals. Thus, it was possible to exclude a sympathetic mediation or a direct stimulation of pancreatic beta-receptors as a likely mechanism of PGE, action.
the possibility that
S
INCE their identification, many studies have been made to clarify the biologic significance of prostaglandins (PGs). Recent studies suggest the existence of a close interrelationship between these compounds and the endocrine system. PGs, in fact, may exert a modulating action on the secretion of various hormones.’ In particular regard to the endocrine pancreas, evidence has been presented in recent years demonstrating the ability of PGs to modulate insulin secretion in vivo, even though a definitive picture cannot be drawn from these studies.2-5 Conversely, less attention has been paid to the possible influence of PGs upon glucagon secretion. Therefore, this work was undertaken in order to study the effects of different PGs on plasma glucagon levels in the normal rat. Experiments were also performed in sympathectomized and beta-
From the Institute of Medical Pathology and Clinical Methodology, II Faculty of Medicine. University of Naples, Italy. Received for publication April 28. I975. Reprint requests should be addressed to Dr. L. Sac&, Istituto di Patologia Medica. via Pansini 5, Napoli. Italy. 0 I976 by Grune & Stratton, Inc. Metabolism, Vol. 25, No. 2 (February), 1976
127
128
SACCA AND PEREZ
adrenergic blocked rats in an attempt to elucidate the mechanism underlying the effect of PGs. It is well-established, in fact, that PGs can modulate adrenergic nervous system actionC9 which, in turn, has profound regulatory effects upon glucagon secretion.‘0-‘3 MATERIALS
AND METHODS
The experiments were conducted in normal and demedullated male rats (weighing about 300 g) which were maintained on commerical pellet diet. Adrenal demedullated rats were purchased from Hormone Assay Laboratories, Chicago, and used 6-8 wk after operation. After overnight fasting (18-20 hr), the animals were anesthetized with sodium thiopental (45 mg/kg, IP), and the trachea was cannulated. Prostaglandins were infused at the constant rate of Z/pg/min for 30 min through a catheter placed in the jugular vein. Crystalline preparations of PGs (Upjohn Co., Kalamazoo, Mich.) were dissolved in 95% ethanol (5 mg/ml), stored at -2O”C, and diluted with saline immediately before the experiment. No animal received more than 10 pl of ethanol throughout the experiment. In control rats, saline was given instead of PGs. Sympathectomized rats were prepared by adrenal medullectomy combined with reserpine (Serpasil, Ciba) which was injected intraperitoneally 20 hr before the experiment in doses of 1.5 mg/kg. In pilot experiments, we found that this procedure was able to reduce by about 75% the hyperglycemic response to the IV injection of a hypotensive dose of sodium nitrite. The pharmacologic blockade of the adrenergic beta-receptors was induced by the IV administration of 5 mg/kg of propranolol (Inderal, Imperial Chemical) 10 min before the beginning of the experiment. This dose of propranolol was reported to prevent the rise of plasma glucagon in response to physical exercise in the rat.14 Arterial blood samples were collected through the carotid artery into chilled tubes containing 1.2 mg of EDTA and 500 U of Trasylol per ml of blood. The total volume of blood removed throughout the experiment was not greater than 1.5 ml, and it was the same in control and treated rats. After centrifugation at 4’C, the supernatant plasma was separated and stored at -20°C until time of assay, not more than 4 wk later. Plasma glucose was determined by the glucose oxidase method (Boehringer, Mannheim, GmbH) and glucagon by radioimmunoassay procedure.‘5”6 (The reaction mixture consisted of antiserum 30 K (Diabetes Research Fund, University of Texas (Southwestern) at Dallas) which detects very little glucagon-like immunoreactivity in extracts of intestinal mucosa, glucagon-‘251 (Nuclear Medical Laboratories, Inc., Dallas), and pork glucagon standard (Novo Research Institute) or plasma. In some experiments, the hemodynamic effects of PG infusion at the dose reported above were evaluated. For this purpose, a polyethylene catheter was placed in the abdominal aorta and blood pressure was continuously monitored with a pressure transducer and polygraph. RESULTS
All the results are summarized in Table 1. PGE, infusion in normal rats produced a progressive and significant increase in plasma glucose and glucagon levels, while no appreciable modification was recorded in controls and in rats infused with PGA,. In sympathectomized rats, PGE, maintained unaltered its hyperglycemic effect and produced a remarkable enhancement of glucagon levels which reached, at the end of the infusion, a value 15 times that of the baseline. It should also be noted that in this group of rats, the basal level of glucagon was much lower than in controls (p < 0.01) probably as a consequence of the deprivation of the sympathetic function. In the rats pretreated with propranolol, PGE, exerted a hyperglycemic effect of minor degree in comparison to that of normal rats, while the increase of glucagon concentration was more marked than that recorded in the other two groups receiving the same prostaglandin. As far as the hemodynamic effect of PGs are concerned, PGA, was almost completely ineffective on arterial blood pressure, whereas PGE, produced a rapid fall of about 20% of the basal level without any tendency to recovery until the infusion was discontinued.
PROSTAGLANDINS
129
Table 1. Influence of lntmvenous Infusion of Pmstaglandins (l/pg/min) of Glucose (mg/lOO
on Plasma levels
ml) and Immunoreactive Glucagon (pg/ml).*
Minutes
15
0
30
Glucose
94 f 5
93 f 5
Glucagon
8Oz4z 10
98 f 8
96 f 6
NS
Controls (7)
NS 94 f
NS
Glucose
102zt 8
87&t
97+8
NS
PGA, (4) Glucagon
57+
Glucose
95 f 5
12
50 f 4
NS 6Oi9
NS 118&;6
Glucagon
67 f 9
161 f
33
p < .025 Glucose
80 f 2
136zk 13
Glucogon
27+
158 f 38
PGE, plus sympathectomy (9)
p<.OO5 7
p<.OO5 Glucose
91 f 3
PGE, plus propranolol(5)
110*
7
p < .05 Glucagon
103 f
13
433 f
NS 145*
p < .025
PGE, (8)
7
NS
140
p < .05
11
p < .Ol 208 zt 37 p<.OO5 118zt7 p<.OOl 449 f
135
p<.ool 113*
9
p < .05 691 f
133
p-C.005
*Values are mean f SE. Number of rats is indicated in parentheses. Mean values at 15 and 30 min were compared to the basal values by t test.
DISCUSSION
Our data clearly demonstrate that PGE, infusion increases plasma glucagon levels in the rat, while PGA, is completely ineffective. Since hypotensive doses of PGE, were employed in these studies, it was reasonable to hypothesize that hyperglucagonemia could be evoked by a sympathetic overactivity. In fact, considerable evidence suggests that catecholamines stimulate glucagon secretion in several species including the rat,‘@14and hyperglucagonemia occurs during stressful conditions associated with enhanced catecholamine release.‘7-2’ However, we observed an enhancement of glucagon levels also in sympathectomized rats during PGE, infusion, and therefore, the possibility of an adrenergic mediation of this effect can be excluded. In the light of recent evidence demonstrating that catecholamines induce hyperglucagonemia through the stimulation of the pancreatic beta-adrenergic receptors,‘2*‘4*22v23 we considered it interesting to ascertain if PGE, acted via the same mechanism. The data obtained in the rats pretreated with propranolol allow us to exclude a direct influence of PGE, on the adrenergic receptors of pancreatic alpha-cells. The higher glucagon levels reached in these experiments can be accounted for by the minor hyperglycemic effect exerted by PGE, as compared to that of normal rats infused with the same prostaglandin. Our data are in agreement with and extend the finding reported in a recent abstract, that PGE, increases the release of glucagon from isolated rat pancreas. 24The results of our studies do not permit us to establish whether PGE, acts directly on pancreatic alpha-cells or by an extrapancreatic mechanism. However, based on the observations made in increases in plasma vitro by Pek et al.,24 we conclude that PGE,-induced
130
SACCA
AND
PEREZ
glucagon, which we have observed in vivo, may be due to increased secretion of pancreatic glucagon. REFERENCES 1. Horton EW: Prostaglandins. SpringerVerlag, Berlin, 1972 2. Saccil L, Rengo F, Chiariello M, Condorelli M: Glucose intolerance and impaired insulin secretion by Prostaglandin A, in fasting anesthetized dogs. Endocrinology 92:31, 1973 3. Lefebvre PJ, Luyckx AS: Stimulation of insulin secretion after Prostaglandin PGE, in the anesthetized dog. Biochem Pharmacol 22: 1773,1973 4. Robertson PR, Gavareski DJ, Porte D Jr, Bierman EL: Inhibition of in vivo insulin secretion by Prostaglandin E,. J Clin Invest 54:310, 1974 5. Sac& L, Perez G, Rengo F, Pascucci I, Condorelli M: Reduction of circulating insulin levels during the infusion of different Prostaglandins in the rat. Acta Endocrinol (Kbh) 79: 266, 1975 6. Hedqvist P: Prostaglandin E compounds and sympathetic neuromuscular transmission. Ann NY Acad Sci 180:410, 1971 7. Hedqvist P: Prostaglandin mediated control of sympathetic neuroeffector transmission. Adv Biosci 9:46 I, 1973 8. Hedqvist P: Autonomic neurotransmission, in Ramwell PW (ed): The Prostaglandins vol 1. Plenum, New York, 1973, p 101 9. Hedqvist P: Prostaglandin action on noradrenaline release and mechanical responses in the stimulated guinea pig vas deferens. Acta Physiol Stand 90:86, 1974 10. Leclerq-Meyer V, Brisson G, Malaisse W: Effect of adrenaline and glucose on release of glucagon and insulin in vitro. Nature (New Biol) 231:248, 1971 11. Frohman LA, Bernardis LL: Effect of hypothalamic stimulation on plasma glucose, insulin, and glucagon levels. Am J Physiol 221: 1596, 1971 12. Eaton RP, Conway M, Buckman M: Role of alpha-adrenergic blockade on alanineinduced hyperglucagonemia. Metabolism 21: 371, 1972
13. Gerich J, Karam J, Forsham P: Stimulation of glucagon secretion by epinephrine in man. J Clin Endocrinol Metab 37:479, 1973 14. Luyckx AS, Lefebvre PJ: Mechanism involved in the exercise-induced increase in glucagon secretion in rats. Diabetes 23:81, 1974 15. Aguilar-Parada E, Eisentraut AM, Unger RH: Effect of starvation on plasma pancreatic glucagon in normal man. Diabetes 18:717, 1969 16. Unger RH: Instructions for glucagon radioimmunoassay, obtained with purchase of glucagon antibody. 17. Rocha DM, Santeusanio F, Faloona GR, Unger RH: Abnormal pancreatic alpha-cell function in bacterial infections. N Engl J Med 288:700, 1973 18. Lindsey CA, Wilmore DW, Moylan JA, Faloona GR, Unger RH: Glucagon and the insulin:glucagon (I/G) ratio in burns and trauma. Clin Res 20:802, 1972 19. Lanido S, Segal P, Esrig B: Secretion of endogenous immunoreactive glucagon following acute myocardial infarction in man: Its role in the pathogenesis of post-infarction hyperglycemia. Am J Cardiol 31:144, 1973 20. Feiig P, Wahren J, Hendler R, Ahlborg G: Plasma glucagon levels in exercising man. N Engl J Med 287: 184, 1972 21. Bottger I, Schlein EM, Faloona GR, Knochel JP, Unger RH: The effect of exercise on glucagon secretion. J Clin Endocrinol Metab 35:I 17. 1972 22. lversen J: Adrenergic receptors for the secretion of glucagon and insulin from the isolated, perfused canine pancreas. J Clin Invest 52:2102, 1973 23. Lindsey CA, Faloona GR: Adrenergic blockade in shock-induced hyperglucagonemia. Diabetes 22(Suppl 1):301, 1973 24. Pek S, Tai TY, Elster A, Fajans SS: Augmentation by Prostaglandins of glucagon (IRG) and insulin (IRI) release from isolated rat pancreas. Clin Res 22:619, 1974
NO. 2
PRELIMINARY
FEBRUARY
1976
REPORT
Influence of Prostaglandins on Plasma Glucagon Levels in the Rat L. Sac&
and G. Perez
The effect of PGE, and PGA, intravenous infusion (2/&min) on plasma glucose and glucagon levels was investigated in and pronormal, sympathectomized pranolol-treated rats. POE, infusion significantly increased glucose and glucagon levels, while PGA, had no etTect. Since the dose of POE, used in this study was able to reduce the arterial blood pressure by about 20%,
PGE, acted indirectly through a reflex sympathetic ovemctivity was tested. The increases in plasma glucagon induced by POE, occurred also in sympathectomized or in beta-blocked animals. Thus, it was possible to exclude a sympathetic mediation or a direct stimulation of pancreatic beta-receptors as a likely mechanism of PGE, action.
the possibility that
S
INCE their identification, many studies have been made to clarify the biologic significance of prostaglandins (PGs). Recent studies suggest the existence of a close interrelationship between these compounds and the endocrine system. PGs, in fact, may exert a modulating action on the secretion of various hormones.’ In particular regard to the endocrine pancreas, evidence has been presented in recent years demonstrating the ability of PGs to modulate insulin secretion in vivo, even though a definitive picture cannot be drawn from these studies.2-5 Conversely, less attention has been paid to the possible influence of PGs upon glucagon secretion. Therefore, this work was undertaken in order to study the effects of different PGs on plasma glucagon levels in the normal rat. Experiments were also performed in sympathectomized and beta-
From the Institute of Medical Pathology and Clinical Methodology, II Faculty of Medicine. University of Naples, Italy. Received for publication April 28. I975. Reprint requests should be addressed to Dr. L. Sac&, Istituto di Patologia Medica. via Pansini 5, Napoli. Italy. 0 I976 by Grune & Stratton, Inc. Metabolism, Vol. 25, No. 2 (February), 1976
127
128
SACCA AND PEREZ
adrenergic blocked rats in an attempt to elucidate the mechanism underlying the effect of PGs. It is well-established, in fact, that PGs can modulate adrenergic nervous system actionC9 which, in turn, has profound regulatory effects upon glucagon secretion.‘0-‘3 MATERIALS
AND METHODS
The experiments were conducted in normal and demedullated male rats (weighing about 300 g) which were maintained on commerical pellet diet. Adrenal demedullated rats were purchased from Hormone Assay Laboratories, Chicago, and used 6-8 wk after operation. After overnight fasting (18-20 hr), the animals were anesthetized with sodium thiopental (45 mg/kg, IP), and the trachea was cannulated. Prostaglandins were infused at the constant rate of Z/pg/min for 30 min through a catheter placed in the jugular vein. Crystalline preparations of PGs (Upjohn Co., Kalamazoo, Mich.) were dissolved in 95% ethanol (5 mg/ml), stored at -2O”C, and diluted with saline immediately before the experiment. No animal received more than 10 pl of ethanol throughout the experiment. In control rats, saline was given instead of PGs. Sympathectomized rats were prepared by adrenal medullectomy combined with reserpine (Serpasil, Ciba) which was injected intraperitoneally 20 hr before the experiment in doses of 1.5 mg/kg. In pilot experiments, we found that this procedure was able to reduce by about 75% the hyperglycemic response to the IV injection of a hypotensive dose of sodium nitrite. The pharmacologic blockade of the adrenergic beta-receptors was induced by the IV administration of 5 mg/kg of propranolol (Inderal, Imperial Chemical) 10 min before the beginning of the experiment. This dose of propranolol was reported to prevent the rise of plasma glucagon in response to physical exercise in the rat.14 Arterial blood samples were collected through the carotid artery into chilled tubes containing 1.2 mg of EDTA and 500 U of Trasylol per ml of blood. The total volume of blood removed throughout the experiment was not greater than 1.5 ml, and it was the same in control and treated rats. After centrifugation at 4’C, the supernatant plasma was separated and stored at -20°C until time of assay, not more than 4 wk later. Plasma glucose was determined by the glucose oxidase method (Boehringer, Mannheim, GmbH) and glucagon by radioimmunoassay procedure.‘5”6 (The reaction mixture consisted of antiserum 30 K (Diabetes Research Fund, University of Texas (Southwestern) at Dallas) which detects very little glucagon-like immunoreactivity in extracts of intestinal mucosa, glucagon-‘251 (Nuclear Medical Laboratories, Inc., Dallas), and pork glucagon standard (Novo Research Institute) or plasma. In some experiments, the hemodynamic effects of PG infusion at the dose reported above were evaluated. For this purpose, a polyethylene catheter was placed in the abdominal aorta and blood pressure was continuously monitored with a pressure transducer and polygraph. RESULTS
All the results are summarized in Table 1. PGE, infusion in normal rats produced a progressive and significant increase in plasma glucose and glucagon levels, while no appreciable modification was recorded in controls and in rats infused with PGA,. In sympathectomized rats, PGE, maintained unaltered its hyperglycemic effect and produced a remarkable enhancement of glucagon levels which reached, at the end of the infusion, a value 15 times that of the baseline. It should also be noted that in this group of rats, the basal level of glucagon was much lower than in controls (p < 0.01) probably as a consequence of the deprivation of the sympathetic function. In the rats pretreated with propranolol, PGE, exerted a hyperglycemic effect of minor degree in comparison to that of normal rats, while the increase of glucagon concentration was more marked than that recorded in the other two groups receiving the same prostaglandin. As far as the hemodynamic effect of PGs are concerned, PGA, was almost completely ineffective on arterial blood pressure, whereas PGE, produced a rapid fall of about 20% of the basal level without any tendency to recovery until the infusion was discontinued.
PROSTAGLANDINS
129
Table 1. Influence of lntmvenous Infusion of Pmstaglandins (l/pg/min) of Glucose (mg/lOO
on Plasma levels
ml) and Immunoreactive Glucagon (pg/ml).*
Minutes
15
0
30
Glucose
94 f 5
93 f 5
Glucagon
8Oz4z 10
98 f 8
96 f 6
NS
Controls (7)
NS 94 f
NS
Glucose
102zt 8
87&t
97+8
NS
PGA, (4) Glucagon
57+
Glucose
95 f 5
12
50 f 4
NS 6Oi9
NS 118&;6
Glucagon
67 f 9
161 f
33
p < .025 Glucose
80 f 2
136zk 13
Glucogon
27+
158 f 38
PGE, plus sympathectomy (9)
p<.OO5 7
p<.OO5 Glucose
91 f 3
PGE, plus propranolol(5)
110*
7
p < .05 Glucagon
103 f
13
433 f
NS 145*
p < .025
PGE, (8)
7
NS
140
p < .05
11
p < .Ol 208 zt 37 p<.OO5 118zt7 p<.OOl 449 f
135
p<.ool 113*
9
p < .05 691 f
133
p-C.005
*Values are mean f SE. Number of rats is indicated in parentheses. Mean values at 15 and 30 min were compared to the basal values by t test.
DISCUSSION
Our data clearly demonstrate that PGE, infusion increases plasma glucagon levels in the rat, while PGA, is completely ineffective. Since hypotensive doses of PGE, were employed in these studies, it was reasonable to hypothesize that hyperglucagonemia could be evoked by a sympathetic overactivity. In fact, considerable evidence suggests that catecholamines stimulate glucagon secretion in several species including the rat,‘@14and hyperglucagonemia occurs during stressful conditions associated with enhanced catecholamine release.‘7-2’ However, we observed an enhancement of glucagon levels also in sympathectomized rats during PGE, infusion, and therefore, the possibility of an adrenergic mediation of this effect can be excluded. In the light of recent evidence demonstrating that catecholamines induce hyperglucagonemia through the stimulation of the pancreatic beta-adrenergic receptors,‘2*‘4*22v23 we considered it interesting to ascertain if PGE, acted via the same mechanism. The data obtained in the rats pretreated with propranolol allow us to exclude a direct influence of PGE, on the adrenergic receptors of pancreatic alpha-cells. The higher glucagon levels reached in these experiments can be accounted for by the minor hyperglycemic effect exerted by PGE, as compared to that of normal rats infused with the same prostaglandin. Our data are in agreement with and extend the finding reported in a recent abstract, that PGE, increases the release of glucagon from isolated rat pancreas. 24The results of our studies do not permit us to establish whether PGE, acts directly on pancreatic alpha-cells or by an extrapancreatic mechanism. However, based on the observations made in increases in plasma vitro by Pek et al.,24 we conclude that PGE,-induced
130
SACCA
AND
PEREZ
glucagon, which we have observed in vivo, may be due to increased secretion of pancreatic glucagon. REFERENCES 1. Horton EW: Prostaglandins. SpringerVerlag, Berlin, 1972 2. Saccil L, Rengo F, Chiariello M, Condorelli M: Glucose intolerance and impaired insulin secretion by Prostaglandin A, in fasting anesthetized dogs. Endocrinology 92:31, 1973 3. Lefebvre PJ, Luyckx AS: Stimulation of insulin secretion after Prostaglandin PGE, in the anesthetized dog. Biochem Pharmacol 22: 1773,1973 4. Robertson PR, Gavareski DJ, Porte D Jr, Bierman EL: Inhibition of in vivo insulin secretion by Prostaglandin E,. J Clin Invest 54:310, 1974 5. Sac& L, Perez G, Rengo F, Pascucci I, Condorelli M: Reduction of circulating insulin levels during the infusion of different Prostaglandins in the rat. Acta Endocrinol (Kbh) 79: 266, 1975 6. Hedqvist P: Prostaglandin E compounds and sympathetic neuromuscular transmission. Ann NY Acad Sci 180:410, 1971 7. Hedqvist P: Prostaglandin mediated control of sympathetic neuroeffector transmission. Adv Biosci 9:46 I, 1973 8. Hedqvist P: Autonomic neurotransmission, in Ramwell PW (ed): The Prostaglandins vol 1. Plenum, New York, 1973, p 101 9. Hedqvist P: Prostaglandin action on noradrenaline release and mechanical responses in the stimulated guinea pig vas deferens. Acta Physiol Stand 90:86, 1974 10. Leclerq-Meyer V, Brisson G, Malaisse W: Effect of adrenaline and glucose on release of glucagon and insulin in vitro. Nature (New Biol) 231:248, 1971 11. Frohman LA, Bernardis LL: Effect of hypothalamic stimulation on plasma glucose, insulin, and glucagon levels. Am J Physiol 221: 1596, 1971 12. Eaton RP, Conway M, Buckman M: Role of alpha-adrenergic blockade on alanineinduced hyperglucagonemia. Metabolism 21: 371, 1972
13. Gerich J, Karam J, Forsham P: Stimulation of glucagon secretion by epinephrine in man. J Clin Endocrinol Metab 37:479, 1973 14. Luyckx AS, Lefebvre PJ: Mechanism involved in the exercise-induced increase in glucagon secretion in rats. Diabetes 23:81, 1974 15. Aguilar-Parada E, Eisentraut AM, Unger RH: Effect of starvation on plasma pancreatic glucagon in normal man. Diabetes 18:717, 1969 16. Unger RH: Instructions for glucagon radioimmunoassay, obtained with purchase of glucagon antibody. 17. Rocha DM, Santeusanio F, Faloona GR, Unger RH: Abnormal pancreatic alpha-cell function in bacterial infections. N Engl J Med 288:700, 1973 18. Lindsey CA, Wilmore DW, Moylan JA, Faloona GR, Unger RH: Glucagon and the insulin:glucagon (I/G) ratio in burns and trauma. Clin Res 20:802, 1972 19. Lanido S, Segal P, Esrig B: Secretion of endogenous immunoreactive glucagon following acute myocardial infarction in man: Its role in the pathogenesis of post-infarction hyperglycemia. Am J Cardiol 31:144, 1973 20. Feiig P, Wahren J, Hendler R, Ahlborg G: Plasma glucagon levels in exercising man. N Engl J Med 287: 184, 1972 21. Bottger I, Schlein EM, Faloona GR, Knochel JP, Unger RH: The effect of exercise on glucagon secretion. J Clin Endocrinol Metab 35:I 17. 1972 22. lversen J: Adrenergic receptors for the secretion of glucagon and insulin from the isolated, perfused canine pancreas. J Clin Invest 52:2102, 1973 23. Lindsey CA, Faloona GR: Adrenergic blockade in shock-induced hyperglucagonemia. Diabetes 22(Suppl 1):301, 1973 24. Pek S, Tai TY, Elster A, Fajans SS: Augmentation by Prostaglandins of glucagon (IRG) and insulin (IRI) release from isolated rat pancreas. Clin Res 22:619, 1974