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Evanescent effects of hypo- and hyperglucagonemia on blood glucose homeostasis
Evanescent Effects of Hypo- and Hyperglucagonemia on Blood Glucose Homeostasis Robert Sherwin, John Wahren, and Philip Felig ECENT STUDIES from our laboratory involving physiologic increments in plasma glucagon have demonstrated the primary role of insulin deficiency rather than glucagon excess in the pathogenesis of the diabetic state. 1 Those observations seemed at variance with previous studies demonstrating that somatostatin-induced hypoglucagonemia lowers fasting blood glucose levels (during the course of a 1-2 hr infusion) despite concomitant hypoinsulinemia.2'3 In addition, earlier studies had shown that infusion of pharmacologic amounts ofglucagon (50 ng/kg/min) results in a persistent increase in splanchnic glucose production.4 The current studies were consequently undertaken to evaluate the effects of on-going administration of somatostatin on blood glucose regulation, and to examine the effects of physiologic increments in plasma glucagon (300 pg/ml) on splanchnic glucose production. The results demonstrate that hypo- and hyperglucagonemia have only a transient action on blood glucose regulatio n .
R
SOMATOSTATIN-INDUCED HYPOGLUCAGONEMIA
To examine the effects of prolonged glucagon suppression on glucose homeostasis, somatostatin (0.15-0.20 t~g/kg/min) was administered to eleven normal conscious dogs for 6-8 hr. Somatostatin resulted in a persistent decline in plasma glucagon (50%-60~) and insulin (30~-35~). Plasma glucose demonstrated an initial fall of 20%-25% which was maximal after 45-120 min. However, when the somatostatin infusion was continued beyond 2 hr the hypoglycemic effect waned and hyperglycemia invariably occurred despite persistent suppression of glucagon. Plasma glucose increased within 4-6 hr to 130-150 rag/100 ml, an increase of 30 60 rag/100 ml above fasting levels (p < 0.001) (Fig. 1). When exogenous insulin (0.15 mU/kg/min) was given so as to restore plasma insulin to preinfusion values, plasma glucose promptly fell to basal levels despite continued somatostatin infusion. Furthermore, when the prolonged infusion of somatostatin was discontinued, plasma glucagon and insulin rapidly increased above basal levels whereas plasma glucose declined to preinfusion values (Fig. 1). Prevention of somatostatin-induced hypoglycemia by infusion of IV glucose for 3 hri failed to prevent the delayed hyperglycemia, indicating that this effect was not dependent on the prior induction of hypoFrom the Department of Internal Medicine, Yale University School o f Medicine, New Haven, Conn. and the Department of Clinical Physiology at the Serafimer Hospital and Karolinska Institute, Stockholm, Sweden. Supported in part by Grants A M 13526 and RR 125 from the National Institutes of Health and Grants 19X-3108 and 19X-722 from the Swedish Medical Research Council. Dr. Felig is recipient of a Research Career Development A ward (A M 70 219)from the National Institutes of Health. Reprint requests should be addressed to Robert Sherwin, M.D., Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn. 06520. 9 1976 by Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 11, Suppl. 1 (November), 1976
1381
1382
SHERWIN, WAHREN, AND FELIG
150
'=
SRIF
120 PLASMA GLUCOSE (mg/lOOml) 90
I
60
J
I
I
L
I 120
I PLASMA 60 INSULIN (~U/ml) 40
GLUCAGONIt
20
0
I
2 3 4 TIME (hrs)
5
6
7
Fig. 1. Rebound fasting hyperglycemia during proPLASMA longed infusion of somatoGLUCAGON s t a t i n (SRIF) in a normal, 60 (pg/ml) conscious dog. Upon cessation of the somatostatin in30 fusion, blood glucose fails to normal in association with a rise in plasma insulin and glucagon.
GO
glycemia. Infusion of 3H-glucose demonstrated that endogenous glucose production initially declined by 40~-50~ (p < 0.01), but later increased to basal or above basal levels as hyperglycemia developed. Hyperglycemia induced by prolonged somatostatin infusion was thus associated with decreased peripheral glucose utilization rates in conjunction with inappropriately increased glucose production rates (15~o 20~ above baseline values). Administration of somatostatin (9-10 #g/rain) to five healthy normal humans resulted in precisely the same response as observed in the dogs. Rebound hyperglycemia up to 140 150 mg/100 ml occurred at 4-5 hr despite persistent suppression of glucagon secretion. These studies thus indicate that in the face of ongoing suppression of glucagon secretion by somatostatin, rebound fasting hyperglycemia and an increase in hepatic glucose production occur within 4 6 hr. The fasting hyperglycemia responds to administration of exogenous insulin (in physiologic replacement doses) or to cessation of the somatostatin infusion and restoration of endogenous insulin secretion. RESPONSE TO PHYSIOLOGIC HYPERGLUCAGONEMIA
To examine the effects of physiologic increments in plasma glucagon on hepatic glucose production, crystalline glucagon was infused in six normal, healthy subjects in a dose of 3 ng/kg/min, resulting in plasma glucagon increments of 309 -4- 25 pg/ml. Splanchnic glucose output (measured by arterialhepatic venous differences and blood flow determinations rose from basal levels of0.86 • 0.15 m mole/min to peak levels of 2.22 -4- 0.43 at 7-8 rain. Despite ongoing infusion of glucagon, splanchnic glucose output returned to baseline by 30 min (Fig. 2). This rapid return of splanchnic glucose production to baseline occurred in the face of stable insulin levels. 5 In four insulin-dependent diabetic subjects, the increment in splanchnic glucose production was comparable to
HYPO- A N D HYPERGLUCAGONEMIA
1383
~.0
SPLANCHNIC 2 . 0 GLUCOSE
Fig. 2. Transient effect of physiologic hyperglucagonemia on splanchnic glucose output in normal man. Glucagon was infused in a dose of 3 n g / k g / m i n . Based on the data of Felig et al. 5
OUTPUT m mol/min
I 0
o t-L'F-', I -20-10
0
I
I
~
15 TIME
i 30
J
t 45
(min)
controls and a similar rapid return to baseline was observed. Thus physiologic increments in plasma glucagon have only a transient stimulatory affect on splanchnic glucose production. This evanscent effect occurs in the face of stable insulin levels and is demonstrable in insulin-dependent diabetics. SUMMARY
AND
CONCLUSIONS
H y p o g l u c a g o n e m i a ( i n d u c e d by s o m a t o s t a t i n ) a n d h y p e r g l u c a g o n e m i a (ind u c e d by infusion o f p h y s i o l o g i c a m o u n t s o f g l u c a g o n ) h a v e o n l y e v a n e s c e n t effects on b l o o d g l u c o s e r e g u l a t i o n . D e s p i t e o n - g o i n g g l u c a g o n s u p p r e s s i o n by s o m a t o s t a t i n , fasting h y p e r g l y c e m i a d e v e l o p s within 4 6 hr o f insulin s u p p r e s sion, i n d i c a t i n g t h a t (1) b a s a l g l u c a g o n s e c r e t i o n is n o t essential for the develo p m e n t o f the d i a b e t i c state; a n d (2) insulin-deficiency ( r a t h e r t h a n altered g l u c a g o n secretion) is the d o m i n a n t l o n g - t e r m f a c t o r d e t e r m i n i n g glucose h o m e o s t a s i s in the diabetic. W i t h respect to h y p e r g l u c a g o n e m i a , o n l y a transient i n c r e a s e in s p l a n c h n i c g l u c o s e o u t p u t is o b s e r v e d in n o r m a l a n d d i a b e t i c s u b j e c t s in r e s p o n s e to p h y s i o l o g i c i n c r e m e n t s in this h o r m o n e . T h e e x a g g e r a t e d h y p e r g l y c e m i c effect o f g l u c a g o n o b s e r v e d in d i a b e t i c s ~ is t h u s a c o n s e q u e n c e o f t h e failure to m e t a b o l i z e the g l u c o s e t r a n s i e n t l y released i n t o the systemic c i r c u l a t i o n in r e s p o n s e to the g l u c a g o n r a t h e r t h a n a result o f p e r s i s t e n t s t i m u l a tion o f h e p a t i c glucose p r o d u c t i o n . T h e s e o b s e r v a t i o n s t h u s f u r t h e r u n d e r s c o r e the e s s e n t i a l i t y o f insulin deficiency in the d i a b e t o g e n i c a c t i o n o f g l u c a g o n . REFERENCES
1. Sherwin RS, Fisher M, Hendler R, Felig P: Hyperglucagonemia and blood glucose regulation in normal, obese, and diabetic subjects. N Engl J Med 294:455-461, 1976 2. Alford FP, Bloom SR, Nabarro JDN, Hall R, Besser GM, Coy DH, Kastin A J, Schally V: Glucagon control of fasting glucose in man. Lancet 2:974 977, 1974 3. Gerich JE, Lorenzi M, Bier DM, et al: Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mellitus.
Pathophysiologic and therapeutic implications. N Engl J Med 291:544 547, 1974 4. Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW: Effect of glucagon on net splanchnic cyclic AMP production in normal and diabetic man. J Clin Invest 53:198 204, 1974 5. Felig P, Wahren J, Hendler R: Influence of physiologic hyperglucagonemia on basal and insulin inhibited splanchnic glucose output in man. J Clin Invest Sept, 1976
R
SOMATOSTATIN-INDUCED HYPOGLUCAGONEMIA
To examine the effects of prolonged glucagon suppression on glucose homeostasis, somatostatin (0.15-0.20 t~g/kg/min) was administered to eleven normal conscious dogs for 6-8 hr. Somatostatin resulted in a persistent decline in plasma glucagon (50%-60~) and insulin (30~-35~). Plasma glucose demonstrated an initial fall of 20%-25% which was maximal after 45-120 min. However, when the somatostatin infusion was continued beyond 2 hr the hypoglycemic effect waned and hyperglycemia invariably occurred despite persistent suppression of glucagon. Plasma glucose increased within 4-6 hr to 130-150 rag/100 ml, an increase of 30 60 rag/100 ml above fasting levels (p < 0.001) (Fig. 1). When exogenous insulin (0.15 mU/kg/min) was given so as to restore plasma insulin to preinfusion values, plasma glucose promptly fell to basal levels despite continued somatostatin infusion. Furthermore, when the prolonged infusion of somatostatin was discontinued, plasma glucagon and insulin rapidly increased above basal levels whereas plasma glucose declined to preinfusion values (Fig. 1). Prevention of somatostatin-induced hypoglycemia by infusion of IV glucose for 3 hri failed to prevent the delayed hyperglycemia, indicating that this effect was not dependent on the prior induction of hypoFrom the Department of Internal Medicine, Yale University School o f Medicine, New Haven, Conn. and the Department of Clinical Physiology at the Serafimer Hospital and Karolinska Institute, Stockholm, Sweden. Supported in part by Grants A M 13526 and RR 125 from the National Institutes of Health and Grants 19X-3108 and 19X-722 from the Swedish Medical Research Council. Dr. Felig is recipient of a Research Career Development A ward (A M 70 219)from the National Institutes of Health. Reprint requests should be addressed to Robert Sherwin, M.D., Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn. 06520. 9 1976 by Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 11, Suppl. 1 (November), 1976
1381
1382
SHERWIN, WAHREN, AND FELIG
150
'=
SRIF
120 PLASMA GLUCOSE (mg/lOOml) 90
I
60
J
I
I
L
I 120
I PLASMA 60 INSULIN (~U/ml) 40
GLUCAGONIt
20
0
I
2 3 4 TIME (hrs)
5
6
7
Fig. 1. Rebound fasting hyperglycemia during proPLASMA longed infusion of somatoGLUCAGON s t a t i n (SRIF) in a normal, 60 (pg/ml) conscious dog. Upon cessation of the somatostatin in30 fusion, blood glucose fails to normal in association with a rise in plasma insulin and glucagon.
GO
glycemia. Infusion of 3H-glucose demonstrated that endogenous glucose production initially declined by 40~-50~ (p < 0.01), but later increased to basal or above basal levels as hyperglycemia developed. Hyperglycemia induced by prolonged somatostatin infusion was thus associated with decreased peripheral glucose utilization rates in conjunction with inappropriately increased glucose production rates (15~o 20~ above baseline values). Administration of somatostatin (9-10 #g/rain) to five healthy normal humans resulted in precisely the same response as observed in the dogs. Rebound hyperglycemia up to 140 150 mg/100 ml occurred at 4-5 hr despite persistent suppression of glucagon secretion. These studies thus indicate that in the face of ongoing suppression of glucagon secretion by somatostatin, rebound fasting hyperglycemia and an increase in hepatic glucose production occur within 4 6 hr. The fasting hyperglycemia responds to administration of exogenous insulin (in physiologic replacement doses) or to cessation of the somatostatin infusion and restoration of endogenous insulin secretion. RESPONSE TO PHYSIOLOGIC HYPERGLUCAGONEMIA
To examine the effects of physiologic increments in plasma glucagon on hepatic glucose production, crystalline glucagon was infused in six normal, healthy subjects in a dose of 3 ng/kg/min, resulting in plasma glucagon increments of 309 -4- 25 pg/ml. Splanchnic glucose output (measured by arterialhepatic venous differences and blood flow determinations rose from basal levels of0.86 • 0.15 m mole/min to peak levels of 2.22 -4- 0.43 at 7-8 rain. Despite ongoing infusion of glucagon, splanchnic glucose output returned to baseline by 30 min (Fig. 2). This rapid return of splanchnic glucose production to baseline occurred in the face of stable insulin levels. 5 In four insulin-dependent diabetic subjects, the increment in splanchnic glucose production was comparable to
HYPO- A N D HYPERGLUCAGONEMIA
1383
~.0
SPLANCHNIC 2 . 0 GLUCOSE
Fig. 2. Transient effect of physiologic hyperglucagonemia on splanchnic glucose output in normal man. Glucagon was infused in a dose of 3 n g / k g / m i n . Based on the data of Felig et al. 5
OUTPUT m mol/min
I 0
o t-L'F-', I -20-10
0
I
I
~
15 TIME
i 30
J
t 45
(min)
controls and a similar rapid return to baseline was observed. Thus physiologic increments in plasma glucagon have only a transient stimulatory affect on splanchnic glucose production. This evanscent effect occurs in the face of stable insulin levels and is demonstrable in insulin-dependent diabetics. SUMMARY
AND
CONCLUSIONS
H y p o g l u c a g o n e m i a ( i n d u c e d by s o m a t o s t a t i n ) a n d h y p e r g l u c a g o n e m i a (ind u c e d by infusion o f p h y s i o l o g i c a m o u n t s o f g l u c a g o n ) h a v e o n l y e v a n e s c e n t effects on b l o o d g l u c o s e r e g u l a t i o n . D e s p i t e o n - g o i n g g l u c a g o n s u p p r e s s i o n by s o m a t o s t a t i n , fasting h y p e r g l y c e m i a d e v e l o p s within 4 6 hr o f insulin s u p p r e s sion, i n d i c a t i n g t h a t (1) b a s a l g l u c a g o n s e c r e t i o n is n o t essential for the develo p m e n t o f the d i a b e t i c state; a n d (2) insulin-deficiency ( r a t h e r t h a n altered g l u c a g o n secretion) is the d o m i n a n t l o n g - t e r m f a c t o r d e t e r m i n i n g glucose h o m e o s t a s i s in the diabetic. W i t h respect to h y p e r g l u c a g o n e m i a , o n l y a transient i n c r e a s e in s p l a n c h n i c g l u c o s e o u t p u t is o b s e r v e d in n o r m a l a n d d i a b e t i c s u b j e c t s in r e s p o n s e to p h y s i o l o g i c i n c r e m e n t s in this h o r m o n e . T h e e x a g g e r a t e d h y p e r g l y c e m i c effect o f g l u c a g o n o b s e r v e d in d i a b e t i c s ~ is t h u s a c o n s e q u e n c e o f t h e failure to m e t a b o l i z e the g l u c o s e t r a n s i e n t l y released i n t o the systemic c i r c u l a t i o n in r e s p o n s e to the g l u c a g o n r a t h e r t h a n a result o f p e r s i s t e n t s t i m u l a tion o f h e p a t i c glucose p r o d u c t i o n . T h e s e o b s e r v a t i o n s t h u s f u r t h e r u n d e r s c o r e the e s s e n t i a l i t y o f insulin deficiency in the d i a b e t o g e n i c a c t i o n o f g l u c a g o n . REFERENCES
1. Sherwin RS, Fisher M, Hendler R, Felig P: Hyperglucagonemia and blood glucose regulation in normal, obese, and diabetic subjects. N Engl J Med 294:455-461, 1976 2. Alford FP, Bloom SR, Nabarro JDN, Hall R, Besser GM, Coy DH, Kastin A J, Schally V: Glucagon control of fasting glucose in man. Lancet 2:974 977, 1974 3. Gerich JE, Lorenzi M, Bier DM, et al: Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mellitus.
Pathophysiologic and therapeutic implications. N Engl J Med 291:544 547, 1974 4. Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW: Effect of glucagon on net splanchnic cyclic AMP production in normal and diabetic man. J Clin Invest 53:198 204, 1974 5. Felig P, Wahren J, Hendler R: Influence of physiologic hyperglucagonemia on basal and insulin inhibited splanchnic glucose output in man. J Clin Invest Sept, 1976