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Role of glucagon in perinatal glucose homeostasis
Role of Glucagon in Perinatal Glucose Homeostasis Mark A. Sperling, Luiz A. Grajwer, Rosemary Leake, and Delbert A. Fisher
A
RAPID RISE in plasma immunoreactive glucagon (IRG) concentration, maximal with 2 hr of life occurs in newborn rats, t lambs) and humans 3,4 following delivery. Simultaneously, there is a fall in blood glucose in newborn rats and humans, but not newborn lambs, so that mechanisms other than hypoglycemia alone must be acting as the stimulus. A second rise in fasting plasma IRG occurs in humans between day 1 and day 3 of life, and is associated with a return of glucose to euglycemic levels, while plasma insulin (IRI) concentrations remain low and unchanged throughout) This hormonal profile bears some resemblance to the situation existent in juvenile diabetes. 5 Again, analogous to diabetes, plasma IRG concentrations in newborn infants cannot be suppressed by glucose alone, but can be suppressed by simultaneous glucose plus insulin infusion,6 and stimulated by orally or intravenously administered amino acids, with a resultant rise in blood glucose concentration) '7 In contrast, infants of diabetic mothers who have a high prevalence of neonatal hypoglycemia have relatively high plasma IRI, and a markedly attenuated neonatal surge in plasma IRG; 4'8 plasma IRG can be suppressed by glucose alone 6 and is stimulated minimally by amino acids without a significant rise in glucose concentration) Thus, glucagon may be an important factor in perinatal glucose homeostasis. To further examine the potential role of glucagon in neonatal glucose homeostasis, we have infused cyclic somatostatin (SRIF) 50 ~zg as a bolus followed by 200/~g/hr for 2 hr, into fasting newborn lambs aged 24-72 hr. SRIF was administered alone during the first hour; during the second hour glucagon (5 ng/ Kg/min) or insulin (0.1 U / K g / h r ) was simultaneously infused. Plasma IRI, IRG, and glucose were determined in samples collected sequentially prior to, during, and following SRIF infusion. The results are summarized in Table 1. SRIF alone lowered plasma IRG and IRI to approximately 30% of basal; when both hormones were suppressed glucose fell. During reinfusion of glucagon, plasma IRG rose by circa 200 pg/ml, glucose values stabilized but IRI also tended to rise. Cessation of glucagon with SRIF infusion resulted in a fall in IRG, a further rise in IRI, and a significant fall in glucose. When insulin 0.1 U / K g / h r was substituted for glucagon during the second hour of SRIF infusion, plasma IRI was maintained at 80 # U / m l and glucose fell precipitously to plasma concentrations of less than 10 mg/dl. Finally, glucagon 50 ng/Kg/min was infused during the second hour of SRIF. Plasma IRG rose to a peak of 4500 pg/ml. And despite a rise in IRI to a peak of circa 100 #U/ml, simulating the levels of IRI achieved during insulin infusion when glucagon remained supFrom the Department of Pediatrics, Harbor General Hospital Campus, UCLA School of Medicine, Torrance, Calif. SuppoJ'ted in part by USPHS Grant HD-07087. Dr. Sperling is a recipient, Research Career Development A ward from the USPHS l K04 HDO0029. Reprint requests should be addressed to Mark A, Sperling, M.D., Department o f Pediatrics, Harbor General Hospital Campus, UCLA School of Medicine, Torrance, Calif. 90509. 9 1976 by Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 11, Suppl. 1 {November), 1976
1385
1386
SPERLING ET AL. Table 1. Changes During SRIF Infusion Minutes
0-60
60-120
A Glucagon, pg/ml
-54.0
~-SEM Alnsulin,#U/ml
9.5t -- 9
70* 16
• A Glucose, mg/dl
3.0 ~ - 12.
9 14
4*
13
a_SEM
208
120-150 -87 40 12 6 - 16 5*
*p < 0.05. 1-p < 0.01. SRIF bolus plus infusion: 0-120 min. Glucagon infused: 60-120 min.
pressed, these high c o n c e n t r a t i o n s of i n s u l i n a n d g l u c a g o n were associated with a rise in glucose to 150 m g / d l . These p r e l i m i n a r y results suggest t h a t in fasting n e w b o r n lambs, as in fasting m a n , 9 g l u c a g o n p a r t i c i p a t e s significantly in glucose h o m e o s t a s i s , since glucose falls when both i n s u l i n a n d g l u c a g o n are suppressed to a similar extent. M o r e over, the ratio of i n s u l i n to g l u c a g o n a p p e a r s to m o d u l a t e glucose c o n c e n t r a tion in n e w b o r n fasting lambs. I n c o n j u n c t i o n with the o b s e r v a t i o n s in h u m a n n e w b o r n infants, the results also suggest that the n e o n a t a l surge in I R G , in association with coexistent low I R I , m a y be a n i m p o r t a n t event in the adjustm e n t s of glucose h o m e o s t a s i s s u r r o u n d i n g p e r i n a t a l life. REFERENCES
1. Girard JR, Cuendet GS, Marliss EB, Kervran A, Rieutort M, Assan R: Fuels, hormones and liver metabolism at term and during the early postnatal period in the rat. J Clin Invest 52:3190-3200, 1973 2. Sperling MA, Grajwer LA, Leake RD, Fisher DA: Metabolic effects of somatostatin (SRIF) in newborn lambs. Pediatr Res 10:415, 1976 (Abst) 3. Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA: Spontaneous and amino acid stimulated glucagon secretion in the immediate post-natal period; relation to glucose and insulin. J Clin Invest 53:1159 1166, 1974 4. Bloom SR, Johnston DI: Failure of glucagon release in infants of diabetic mothers. Br Med J 4:453-454, 1972 5. Unger RH: Alpha-and-beta-cell interrela-
tionships in health and disease. Metabolism 23:581-591, 1974 6. Massi-Benedetti F, Falorni A, Luyckx A, Lefebvre P: Inhibition of glucagon secretion in the human newborn by simultaneous administration of glucose and insulin. Horm Metab Res 6:392-396, 1974 7. Fiser RH, Williams PR, Fisher DA, DeLamater PV, Sperling MA, Oh W: The effect of oral alanine on blood glucose and glucagon in the human newborn infant. Pediatrics 56: 78-81, 1975 8. Williams PR, Sperling MA, Racasa Z: Evidence indicating glucagon suppression in infants of insulin dependent diabetic mothers. Pediatr Res 10:416, 1976 (Abst) 9. Afford FP, Bloom SR, Nabarro JDN, Hall R, et al: Glucagon control of fasting glucose in man. Lancet 2:974, 1974
A
RAPID RISE in plasma immunoreactive glucagon (IRG) concentration, maximal with 2 hr of life occurs in newborn rats, t lambs) and humans 3,4 following delivery. Simultaneously, there is a fall in blood glucose in newborn rats and humans, but not newborn lambs, so that mechanisms other than hypoglycemia alone must be acting as the stimulus. A second rise in fasting plasma IRG occurs in humans between day 1 and day 3 of life, and is associated with a return of glucose to euglycemic levels, while plasma insulin (IRI) concentrations remain low and unchanged throughout) This hormonal profile bears some resemblance to the situation existent in juvenile diabetes. 5 Again, analogous to diabetes, plasma IRG concentrations in newborn infants cannot be suppressed by glucose alone, but can be suppressed by simultaneous glucose plus insulin infusion,6 and stimulated by orally or intravenously administered amino acids, with a resultant rise in blood glucose concentration) '7 In contrast, infants of diabetic mothers who have a high prevalence of neonatal hypoglycemia have relatively high plasma IRI, and a markedly attenuated neonatal surge in plasma IRG; 4'8 plasma IRG can be suppressed by glucose alone 6 and is stimulated minimally by amino acids without a significant rise in glucose concentration) Thus, glucagon may be an important factor in perinatal glucose homeostasis. To further examine the potential role of glucagon in neonatal glucose homeostasis, we have infused cyclic somatostatin (SRIF) 50 ~zg as a bolus followed by 200/~g/hr for 2 hr, into fasting newborn lambs aged 24-72 hr. SRIF was administered alone during the first hour; during the second hour glucagon (5 ng/ Kg/min) or insulin (0.1 U / K g / h r ) was simultaneously infused. Plasma IRI, IRG, and glucose were determined in samples collected sequentially prior to, during, and following SRIF infusion. The results are summarized in Table 1. SRIF alone lowered plasma IRG and IRI to approximately 30% of basal; when both hormones were suppressed glucose fell. During reinfusion of glucagon, plasma IRG rose by circa 200 pg/ml, glucose values stabilized but IRI also tended to rise. Cessation of glucagon with SRIF infusion resulted in a fall in IRG, a further rise in IRI, and a significant fall in glucose. When insulin 0.1 U / K g / h r was substituted for glucagon during the second hour of SRIF infusion, plasma IRI was maintained at 80 # U / m l and glucose fell precipitously to plasma concentrations of less than 10 mg/dl. Finally, glucagon 50 ng/Kg/min was infused during the second hour of SRIF. Plasma IRG rose to a peak of 4500 pg/ml. And despite a rise in IRI to a peak of circa 100 #U/ml, simulating the levels of IRI achieved during insulin infusion when glucagon remained supFrom the Department of Pediatrics, Harbor General Hospital Campus, UCLA School of Medicine, Torrance, Calif. SuppoJ'ted in part by USPHS Grant HD-07087. Dr. Sperling is a recipient, Research Career Development A ward from the USPHS l K04 HDO0029. Reprint requests should be addressed to Mark A, Sperling, M.D., Department o f Pediatrics, Harbor General Hospital Campus, UCLA School of Medicine, Torrance, Calif. 90509. 9 1976 by Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 11, Suppl. 1 {November), 1976
1385
1386
SPERLING ET AL. Table 1. Changes During SRIF Infusion Minutes
0-60
60-120
A Glucagon, pg/ml
-54.0
~-SEM Alnsulin,#U/ml
9.5t -- 9
70* 16
• A Glucose, mg/dl
3.0 ~ - 12.
9 14
4*
13
a_SEM
208
120-150 -87 40 12 6 - 16 5*
*p < 0.05. 1-p < 0.01. SRIF bolus plus infusion: 0-120 min. Glucagon infused: 60-120 min.
pressed, these high c o n c e n t r a t i o n s of i n s u l i n a n d g l u c a g o n were associated with a rise in glucose to 150 m g / d l . These p r e l i m i n a r y results suggest t h a t in fasting n e w b o r n lambs, as in fasting m a n , 9 g l u c a g o n p a r t i c i p a t e s significantly in glucose h o m e o s t a s i s , since glucose falls when both i n s u l i n a n d g l u c a g o n are suppressed to a similar extent. M o r e over, the ratio of i n s u l i n to g l u c a g o n a p p e a r s to m o d u l a t e glucose c o n c e n t r a tion in n e w b o r n fasting lambs. I n c o n j u n c t i o n with the o b s e r v a t i o n s in h u m a n n e w b o r n infants, the results also suggest that the n e o n a t a l surge in I R G , in association with coexistent low I R I , m a y be a n i m p o r t a n t event in the adjustm e n t s of glucose h o m e o s t a s i s s u r r o u n d i n g p e r i n a t a l life. REFERENCES
1. Girard JR, Cuendet GS, Marliss EB, Kervran A, Rieutort M, Assan R: Fuels, hormones and liver metabolism at term and during the early postnatal period in the rat. J Clin Invest 52:3190-3200, 1973 2. Sperling MA, Grajwer LA, Leake RD, Fisher DA: Metabolic effects of somatostatin (SRIF) in newborn lambs. Pediatr Res 10:415, 1976 (Abst) 3. Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA: Spontaneous and amino acid stimulated glucagon secretion in the immediate post-natal period; relation to glucose and insulin. J Clin Invest 53:1159 1166, 1974 4. Bloom SR, Johnston DI: Failure of glucagon release in infants of diabetic mothers. Br Med J 4:453-454, 1972 5. Unger RH: Alpha-and-beta-cell interrela-
tionships in health and disease. Metabolism 23:581-591, 1974 6. Massi-Benedetti F, Falorni A, Luyckx A, Lefebvre P: Inhibition of glucagon secretion in the human newborn by simultaneous administration of glucose and insulin. Horm Metab Res 6:392-396, 1974 7. Fiser RH, Williams PR, Fisher DA, DeLamater PV, Sperling MA, Oh W: The effect of oral alanine on blood glucose and glucagon in the human newborn infant. Pediatrics 56: 78-81, 1975 8. Williams PR, Sperling MA, Racasa Z: Evidence indicating glucagon suppression in infants of insulin dependent diabetic mothers. Pediatr Res 10:416, 1976 (Abst) 9. Afford FP, Bloom SR, Nabarro JDN, Hall R, et al: Glucagon control of fasting glucose in man. Lancet 2:974, 1974