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Plasma glucose response to natural vasopressin in maturity onset diabetics and adult nondiabetics
Plasma
Glucose
Maturity
Response
to Natural
Onset Diabetics By B. V.
Vasopressin
in
and Adult Nondiabetics
SURYANARAYANAANDJOHN R. KENT
Plasma glucose rose following natural vasopressin injection in 9 maturity onset diabetic and 14 adult nondiabetic subjects. The rise was sustained throughout the B-hour test period. No significant changes in plasma insulin and growth hormone occurred. Stimulation of adrenocortical and adrenomedullary secretions
were not essential factors, as the response occurred in bilaterally adrenalectomized subjects. It is suggested that natural vasopressin may have a direct glucose elevating action perhaps mediated via Cyclic AMP activation of hepatic phosphorylase. (Metabolism 18: No. 3, March, 241-247, 1969)
S
INCE 1908 when Borchardtl demonstrated hyperglycemia in rabbits following injection of infundibular extracts, several reports have attested that crude neurohypophyseal extracts, as well as pure or synthetic lysine and arginine vasopressin, are effective in elevating blood glucose in experimental animals.2-5 Very little information is available concerning the effects of vasopressin upon blood glucose in humans except for reports by Knebusch6 and Karp et al.7 in children and adolescents. They reported that blood glucose rises following vasopressin injection. We report here that natural vasopressin administered to maturity onset diabetics and adult non-diabetics also elevates plasma glucose. The relationship of this plasma glucose response to plasma levels of insulin, growth hormone and cortisol is evaluated MATERIALS AND METHODS Twenty-five subjects between the ages of 20 and 76 years were studied. These included 9 male maturity onset diabetics, 14 non-diabetics (12 males and 2 females) and 2 subjects, M.M. (female) and N.S. (male), who had undergone bilateral adrenalectomy for metastatic carcinoma of the breast and Cushing’s Syndrome respectively. All subjects received natural vasopressin,* 10 pressor units (0.5 cc. ), by intramuscular injection between 8 and 10 a.m. after fasting overnight. Pitressin is a natural vasopressin containing a mixture of arginine and lysine vasopressin. Four of the maturity onset diabetic and 4 of the nondiabetic subjects also received 0.5 cc. of normal saline solution by intramuscular From the Medical Research Programs, Long Beach Veterans Administration Hospital, Long Beach, Calif., and the Department of Medicine., University of California College of Medicine, Irvine, Calif. Received for publication November 14, 1968. B. V. SURYANARAYANA, M.B.B.S. (MYSORE) M.R.C.P. (CL. AND ED.), D.T.M.&H. (ENC.) : Fellow in Endocrinology, Long Beach Veterans Administration Hospital, Long Beach, Calif. JOHN R. KENT, M.D.: Assistant Chief, Endocrinology Section, Long Beach Veterans Administtation Hospital, Long Beach, Calif., and Assistant Clinical Professor of Medicine, University of California College of Medicine, Irvine, Calif. * Pitressin: Parke, Davis & Company. Batch GM111 was used in this study.
241
242
SURYANARAYANA
AND KENT
Table L-ControI Values of Plasma Glucose, Insulin and Growth Hormone in Maturity Onset Diabetics and Adult Nondiabetics Imm;;7re;ctive
GlUCOSt3 mg.%
Maturity Onset Diabetics Adult Non-Diabetics
81.11b7.3 (S.E.M.)* (n=9) 63.6?4 (S.E.M.) (n=14)
p units/ml.
61.O_t16.3 (S.E.M.) (n=7) 38.lf 6.7 (S.E.M.) (n=12)
IlIl~UnO~StiV~ Growth Hormone nanogram/ml.
5.222.8
(S.E.M.)
(n=8) 3.821.3 (S.E.M.) (n=ll)
--
* Standard Error of Mean. injection to evaluate the non-specific insulin and growth hormone.
effects of an injection upon plasma levels of glucose,
Blood samples were drawn from the antecubital vein before and 30, 60 and 120 minutes after injection and collected in E.D.T.A. tubes. Plasma was separated quickly and kept frozen until analysis. Side effects, if any, were recorded. Plasma was analyzed for glucose by the potassium ferricyanide oxidation reduction method adapted for the autoanalyzer,* cortisol by the method of Mattingly,s insulin and growth hormone (GH) by the simultaneous double-antibody procedure of MorganlO RESULTS
Control levels of plasma glucose, insulin and GH and of maturity onset diabetics and adult nondiabetics are shown in Table 1. Table 2 shows changes of the above parameters at each collection period following natural vasopressin injection compared to control levels. The t test for paired experiments was used for this analysis. l1 Table 3 shows plasma glucose and insulin response in two bilaterally adrenalectomized subjects. Glucose Peak rise in plasma glucose from control levels occurred at 30 minutes and was sustained up to 2 hours following natural vasopressin injection in all the subjects studied (Fig. 1). These changes are statistically highly significant (Table 2). Two bilaterally adrenalectomized subjects also showed this plasma glucose response (Table 3). Insulin No significant change in insulin levels was seen except for a small rise at 2 hours in the adult nondiabetics (Table 2). Growth Hemone No significant changes in the levels of GH were noted. Only 1 maturity onset diabetic and 4 adult nondiabetics, inclusive of 1 female, showed a GH rise of more than 5 nanogram/ml. which is considered to be a normal response according to Brostoff et al.12
In 7 subjects comprising both maturity onset diabetics and adult nondiabetics, the mean control cortisol level of 12.6 ,ug/IOOml. t I.1 (S.E.M.) rose to 23.3 ,~g/lOO ml. + 2.2 (S.E.M.) at 30 minutes, 21.9 pg./100 ml. +
Glucose,
)
(S.E.M.)
21.5%7
(S.E.M.)
20.2zk2.8
120’
30’
N.S.
(n=12)
(S.E.M.)
-4.9&3
N.S.
(n=7)
(S.E.M. )
-16.O-cl5.3
-
N.S.
(S.E.M.)
5.2~14.1
N.S.
(S.E.M. )
-16.Or+15.3
60’
p units/ml. 120’
<0.05
(S.E.M.)
7.6k2.6
<0.05
(S.E.M.)
2.8k1.6
N.S.
(n=ll) N.S.
(S.E.M. )
3.oe1.5
(S.E.M.)
N.S.
(S.E.M. )
-0.24-t-1.1
60’
N.S.
(n=8)
(S.E.M. )
0.76-t-1.3
30’
Immunoreactive Growth nanogram/ml.
120’
-
and
N.S.
(S.E.M. )
0.66r1.2
N.S.
(S.E.M. )
-1.721.3
Hormone
in Maturity Onset Diabetics as Compared to Control Values
Injection
-14.025.5
Hormone _ Ilnmunoreactive Insulin
Vasopressin
and Growth
to Natural
using the t test for paired experiments.11
(S.E.M.)
19.022.7
calculated
(n=14)
18.Ok2.7 ( S.E.M.
(S.E.M. )
(n=9)
23.1k5.7
60’
20.6k4.2
30’
“&z
(S.E.M.)’
___-
Insulin
Response
Glucose,
Hormone
in Plasma
and Growth
Changes
Insulin
Nondiabetics.
a Standard Error of Mean. t Significance of differences
p Value
Adult Non-Diabetics
p f Value
Maturity Onset Diabetics
Adult
2.-Plasma
T;~j$$$r
Table
i4
g
z g
244 Table
SURYANAFlAYANA
3.-Plasma
AM)
Glucose and Insulin Response to Natural Vasopressin in Bilaterally Adrenalectomized Subjects Glucose mg.%
Control 0
30’
1. M.M. (F.) 5062 2. N.S. (M.) 52
60’
76 76
76
Time After Injection
Control 12F
0
60 76
50 54
Injection
Insulin p units/ml.
Immunoreactive
Time After Injection
KENT
60’
30’
42 50
120’
50 50
50 60
INJ.
30 *
i
Fig. 1 .-Plasma glucose response to natural vasopressin injection (Inj.) in maturity onset diabetics and adult nondiabetics. Mean + standard error of mean are plotted.
0
30
NONDIABETICS
120
60 MINUTES
3.8 (S.E.M.) at 60 minutes and returned to control levels, 12.7 pg./ 100 ml. + 2.2 (S.E.M.) at 120 minutes. The rise of cortisol in each of these subjects was normal according to the criterion of Brostoff et a1.12 Among the 4 maturity onset diabetic and 4 adult nondiabetic subjects who also received normal saline injections, the mean changes in plasma glucose, insulin and GH were not statistically significant (p > 0.2 for all parameters).
Side effects were minimal. Most of the subjects showed facial pallor soon after injection. On direct questioning one third of the subjects mentioned abdominal discomfort of a transient nature and 3 subjects experienced mild rectal tenesmus. DISCUSSION
Cash and Kaplan l3 showed glucose elevating activity of both lysine and arginine vasopressin in rabbits. Similar action in humans was reported by Knebusche in 1967 and subsequently co&med by Karp et al.’ The mechanism by which natural vasopressin elicits this rise in plasma glucose remains unclear. Certain possible mechanisms including a significant portion of the endocrine system known to influence plasma glucose have been evaluated in this study. The data presented indicates that the rise in plasma glucose is independent of changes in plasma cortisol, GH, insulin, and probably epinephrine. Plasma cortisol, as reported by other investigators,l*-l6 rises consistently
PLASMA
GLUCOSE
RESPONSE
245
following injection of synthetic or natural vasopressin in subjects with intact adrenals. The increment of plasma glucose appears to be independent of the cortisol response, since in bilaterally adrenalectomized subjects the rise was identical to that seen in subjects with intact adrenals. WestIr has shown that the glucose elevating effect of glucocorticoids occurs several hours after the administered dose, whereas the plasma glucose response to vasopressin occurs within 30 minutes. The plasma glucose rise also occurred independent of the GH response to natural vasopressin, in agreement with Karp et al7 Augmented GH secretion is, therefore, an unlikely explanation for the glucose rise. The glucose response apparently does require the presence of adequate basal levels of GH, since it has been reported to be absent in patients with isolated GH deficiency.7 No consistent GH response to natural vasopressin was noted in our study in agreement with some authors, 7~~~1~but in disagreement with the report of Gagliardino et al I8 This variability of GH response to vasopressin has been reported with both synthetic lysine and natural vasopressin. No significant rise in plasma insulin was observed in contrast to the small increase reported by Karp et al.7 using lysine vasopressin. WhiIe the administration of glucagon elicits a rise in both plasma glucose and plasma insulin, a more marked insulin response would be expected if vasopressin acted via this indirect mechanism.lg The possibility that the rise in plasma glucose was a consequence of natural vasopressin stimulation of epinephrine release is also unlikely, since the plasma glucose response occurred in bilaterally adrenalectomized subjects with absent adrenomedullary function. Furthermore, a rise in FFA would be expected if the plasma glucose response was attributable to epinephrine. Published reports indicate that FFA either fal17r20-23or remain unchangedz4 after vasopressin administration. It is concluded from this study that the rapid rise of plasma glucose following natural vasopressin administration occurs independent of any effects upon plasma levels of insulin, GH, cortisol or epinephrine. Studies in experimental animals suggest that the glucose response, instead, could be attributable to a direct action of vasopressin. Bergen et al5 showed by direct measurement of hepatic portal gradients that the liver was the source of the plasma glucose increment following intraportal administration of synthetic lysine vasopressin, or natural vasopressin, in fasted unanesthetized dogs. They suggested this could be due to a direct effect of vasopressin upon hepatic phosphorylase, promoting glycogenolysis. In addition, Best and TaylorZ4 have demonstrated, following vasopressin administration, the association of plasma glucose elevation with a fall in hepatic glycogen content. The action of vasopressin upon glucose metabolism at peripheral tissues, or the role of other hormones, such as glucagon, in the plasma glucose response to vasopressin remains to be clarified. However, it is consistent with present evidence to speculate that in man, as in experimental animals, natural vasopressin produces a plasma glucose rise via stimulation of hepatic phosphorylase, perhaps mediated by cyclic adenosine 3’5’-monophosphate. It is
246
SUEIYANARAYANA
noteworthy that both glucagon and epinephrine plasma glucose via this mechanism.25l26
have been
shown
AND KENT
to elevate
ACKNOWLEDGMENTS We thank kindly Dr. Mary A. Root of the Lilly Research Laboratories for supplying Human Insulin Lot 516-734 B3, 25.4 IU/mg. and The Endocrinology Study Section, Division of Research Grants, National Institutes of Health, Bethesda, Maryland, for supplying Human Growth Hormone NIH-GH-HS968C having growth activity 1.45 IU/mg. and prolactin
activity
6.5 IU/mg.
REFERENCES 1. Borchardt, L.: Die Hypophysenglykosurie und ihre Beziehung zum Diabetes bei der Akromegalie. Ztschr. Klin. Med. 66:332, 1908. 2. Draper, W. B., and Hill, R. M.: Pituitary extract and the CO, combining power of the blood plasma. Proc. Sot. Exp. Biol. Med. 27:33, 1929. 3. Geiling, E. M. K., and Eddy, C. A.: Hyperglycemic effect of vasopressin, oxytocin and pituitrin. Proc. Sot. Exper. Biol. Med. 26:146, 1928. 4. Bacq, Z. M., and Dworkin,
S.:
Heart
rate after sympathectomy and vagotomy and blood sugar as affected by posterior hypophyseal extracts ( pitressin and pitocin) . Amer. J. Physiol. 95:605, 1930. 5. Bergen, S. S., Jr., Sullivan, B., Hilton, J. G., Willis, S. W., Jr., and Van Itallie, T. B.: Glycogenolytic effect of vasopressin in the canine liver. Amer. J. Physiol. 199: 136, 1960. 6. Knebusch, R. E.: Die Wirkung Lysin-vassopressin auf die Konzentration
von der
11-Hydroxycorteroide im Plasma endodrin gesunder Kinder: Ein Test der Hypophysenfunktion. Helv. Paediat. Acta 12:376, 1967. 7. Karp, M., Pertzelan, A., Doron, M., Kowadlo-Silbergeld, A., and Laron, Z.: Changes in blood glucose and plasma inhormone, sulin, free fatty acids, growth and II-hydroxycorticosteroids during intramuscular vasopressin tests in children and adolescents. Acta Endocr. 58:545, 1968. 8. Hoffman, W. S.: Rapid photoelectric method for determination of glucose in blood and urine. J. Biol. Chem. 120:51, 1937. 9. Mattingly, D.: A simple fluorometric method for estimation of free ll-hydroxycorticoids in human plasma. J. Clin. Path. 15:374, 1962. IO. Morgan, human insulin
C. R.: Immunoassay of and growth hormone simul-
taneously using I-131 and I-125 tracers. Proc. SOC. Exp. Biol. Med. 123:230, 1966. 11. Batson, H. C.: An Introduction to Statistics in the Medical Sciences, Vol. 16. Minneapolis, Burgess Publishing Co., 1963. 12. Brostoff, J., James, V. H. T., and Landon, J. : Plasma corticosteroid and growth hormone response to lysine-vasopressin in man. J. Clin. Endocr. 28:511, 1968. 13. Cash, W. D., and Kaplan, M. H.: A comparison of the effects of B-lysine1-deamino-B-lysine vasopressin vasopressin, and 1-acetyl-B-vasopressin on the blood glucose level in rabbits. Endocrinology 74: 803, 19644. 14. Gwinup, G.: Test for pituitary function using vasopressin. Lancet 2:572, 1965. 15. Tucci, J. R., Espiner, E. A., Jagger, P. I., Lauler, D. P., and Thorn, G. W.: Vasopressin in the evaluation of pituitaryadrenal
function.
Ann.
Int.
Med.
69:191,
1968. 16. Czarny, D., James, V. H. T., Landon, J. J., and Greenwood, F. C.: Corticosteroid and growth hormone response to synthetic lysine-vasopressin, natural vasopressin, saline solution, and venepuncture. Lancet 1: 126, 1968. 17. West, K. M.: Response of the blood glucose to glucocorticoids in man-Determination of the hyperglycemic potencies of glucocorticoids. Diabetes 822, 1959. 18. Gagliardino, J. J., Bailey, J. D., and of vasopressin on Martin, J. M.: Effect serum-levels of human growth hormone. Lancet 1: 1357, 1967. 19. Mirski, I. A.: Relative effects of insulin, oxytocin and vasopressin on the free fatty acid concentration of the plasma of nondiabetic and diabetic dogs. Endocrinology 73:613, 1963. Effect of oxytocin, vasopressin, 20. -: and related peptides on plasma free fatty acids. Amer. J. Physiol. 204:842, 1963.
PLASMA
V.:
GLUCOSE
247
RESPONSE
21. Balasse, E., Rasio, E., Action insulino-mimetique
and Conard, de la vaso-
pressin chez le chien. Arch. Int. Pharmacodyn. 161:392, 1966. 22. Dang-Tran, L., and Douste-Blazy, L.: Influence de la vasopressine sur les lipides plasmatiques. Comptes Rendus des Seance de la Soviete de Biologie. 160: 2473, 1966. 23. Librik, L., and Clayton, G. W.: The measurement of plasma nonesterified fatty acid levels following ACTH release in man. Metabolism 12:790, 1963.
24. Best, C. H., and Taylor, N. B.: A Physiological Basis of Medical Practice: A Text in Applied Physiology (ed. 7). London, Bailliere, Tindall and Cox, 1961. 25. Sutherland, E. W., and Rall, T. W.: The relation of adenosine-3’,5’-phosphate and phosphorylase to the actions of catecholamines and other hormones. Pharmacol. Rev. 12:265, 1960. 26. Levine, R. A.: Effect of glycogenolytic agents on phosphorylase activity of perfused rat liver. Amer. J. Physiol. 208:317, 1965.
Glucose
Maturity
Response
to Natural
Onset Diabetics By B. V.
Vasopressin
in
and Adult Nondiabetics
SURYANARAYANAANDJOHN R. KENT
Plasma glucose rose following natural vasopressin injection in 9 maturity onset diabetic and 14 adult nondiabetic subjects. The rise was sustained throughout the B-hour test period. No significant changes in plasma insulin and growth hormone occurred. Stimulation of adrenocortical and adrenomedullary secretions
were not essential factors, as the response occurred in bilaterally adrenalectomized subjects. It is suggested that natural vasopressin may have a direct glucose elevating action perhaps mediated via Cyclic AMP activation of hepatic phosphorylase. (Metabolism 18: No. 3, March, 241-247, 1969)
S
INCE 1908 when Borchardtl demonstrated hyperglycemia in rabbits following injection of infundibular extracts, several reports have attested that crude neurohypophyseal extracts, as well as pure or synthetic lysine and arginine vasopressin, are effective in elevating blood glucose in experimental animals.2-5 Very little information is available concerning the effects of vasopressin upon blood glucose in humans except for reports by Knebusch6 and Karp et al.7 in children and adolescents. They reported that blood glucose rises following vasopressin injection. We report here that natural vasopressin administered to maturity onset diabetics and adult non-diabetics also elevates plasma glucose. The relationship of this plasma glucose response to plasma levels of insulin, growth hormone and cortisol is evaluated MATERIALS AND METHODS Twenty-five subjects between the ages of 20 and 76 years were studied. These included 9 male maturity onset diabetics, 14 non-diabetics (12 males and 2 females) and 2 subjects, M.M. (female) and N.S. (male), who had undergone bilateral adrenalectomy for metastatic carcinoma of the breast and Cushing’s Syndrome respectively. All subjects received natural vasopressin,* 10 pressor units (0.5 cc. ), by intramuscular injection between 8 and 10 a.m. after fasting overnight. Pitressin is a natural vasopressin containing a mixture of arginine and lysine vasopressin. Four of the maturity onset diabetic and 4 of the nondiabetic subjects also received 0.5 cc. of normal saline solution by intramuscular From the Medical Research Programs, Long Beach Veterans Administration Hospital, Long Beach, Calif., and the Department of Medicine., University of California College of Medicine, Irvine, Calif. Received for publication November 14, 1968. B. V. SURYANARAYANA, M.B.B.S. (MYSORE) M.R.C.P. (CL. AND ED.), D.T.M.&H. (ENC.) : Fellow in Endocrinology, Long Beach Veterans Administration Hospital, Long Beach, Calif. JOHN R. KENT, M.D.: Assistant Chief, Endocrinology Section, Long Beach Veterans Administtation Hospital, Long Beach, Calif., and Assistant Clinical Professor of Medicine, University of California College of Medicine, Irvine, Calif. * Pitressin: Parke, Davis & Company. Batch GM111 was used in this study.
241
242
SURYANARAYANA
AND KENT
Table L-ControI Values of Plasma Glucose, Insulin and Growth Hormone in Maturity Onset Diabetics and Adult Nondiabetics Imm;;7re;ctive
GlUCOSt3 mg.%
Maturity Onset Diabetics Adult Non-Diabetics
81.11b7.3 (S.E.M.)* (n=9) 63.6?4 (S.E.M.) (n=14)
p units/ml.
61.O_t16.3 (S.E.M.) (n=7) 38.lf 6.7 (S.E.M.) (n=12)
IlIl~UnO~StiV~ Growth Hormone nanogram/ml.
5.222.8
(S.E.M.)
(n=8) 3.821.3 (S.E.M.) (n=ll)
--
* Standard Error of Mean. injection to evaluate the non-specific insulin and growth hormone.
effects of an injection upon plasma levels of glucose,
Blood samples were drawn from the antecubital vein before and 30, 60 and 120 minutes after injection and collected in E.D.T.A. tubes. Plasma was separated quickly and kept frozen until analysis. Side effects, if any, were recorded. Plasma was analyzed for glucose by the potassium ferricyanide oxidation reduction method adapted for the autoanalyzer,* cortisol by the method of Mattingly,s insulin and growth hormone (GH) by the simultaneous double-antibody procedure of MorganlO RESULTS
Control levels of plasma glucose, insulin and GH and of maturity onset diabetics and adult nondiabetics are shown in Table 1. Table 2 shows changes of the above parameters at each collection period following natural vasopressin injection compared to control levels. The t test for paired experiments was used for this analysis. l1 Table 3 shows plasma glucose and insulin response in two bilaterally adrenalectomized subjects. Glucose Peak rise in plasma glucose from control levels occurred at 30 minutes and was sustained up to 2 hours following natural vasopressin injection in all the subjects studied (Fig. 1). These changes are statistically highly significant (Table 2). Two bilaterally adrenalectomized subjects also showed this plasma glucose response (Table 3). Insulin No significant change in insulin levels was seen except for a small rise at 2 hours in the adult nondiabetics (Table 2). Growth Hemone No significant changes in the levels of GH were noted. Only 1 maturity onset diabetic and 4 adult nondiabetics, inclusive of 1 female, showed a GH rise of more than 5 nanogram/ml. which is considered to be a normal response according to Brostoff et al.12
In 7 subjects comprising both maturity onset diabetics and adult nondiabetics, the mean control cortisol level of 12.6 ,ug/IOOml. t I.1 (S.E.M.) rose to 23.3 ,~g/lOO ml. + 2.2 (S.E.M.) at 30 minutes, 21.9 pg./100 ml. +
Glucose,
)
(S.E.M.)
21.5%7
(S.E.M.)
20.2zk2.8
120’
30’
N.S.
(n=12)
(S.E.M.)
-4.9&3
N.S.
(n=7)
(S.E.M. )
-16.O-cl5.3
-
N.S.
(S.E.M.)
5.2~14.1
N.S.
(S.E.M. )
-16.Or+15.3
60’
p units/ml. 120’
<0.05
(S.E.M.)
7.6k2.6
<0.05
(S.E.M.)
2.8k1.6
N.S.
(n=ll) N.S.
(S.E.M. )
3.oe1.5
(S.E.M.)
N.S.
(S.E.M. )
-0.24-t-1.1
60’
N.S.
(n=8)
(S.E.M. )
0.76-t-1.3
30’
Immunoreactive Growth nanogram/ml.
120’
-
and
N.S.
(S.E.M. )
0.66r1.2
N.S.
(S.E.M. )
-1.721.3
Hormone
in Maturity Onset Diabetics as Compared to Control Values
Injection
-14.025.5
Hormone _ Ilnmunoreactive Insulin
Vasopressin
and Growth
to Natural
using the t test for paired experiments.11
(S.E.M.)
19.022.7
calculated
(n=14)
18.Ok2.7 ( S.E.M.
(S.E.M. )
(n=9)
23.1k5.7
60’
20.6k4.2
30’
“&z
(S.E.M.)’
___-
Insulin
Response
Glucose,
Hormone
in Plasma
and Growth
Changes
Insulin
Nondiabetics.
a Standard Error of Mean. t Significance of differences
p Value
Adult Non-Diabetics
p f Value
Maturity Onset Diabetics
Adult
2.-Plasma
T;~j$$$r
Table
i4
g
z g
244 Table
SURYANAFlAYANA
3.-Plasma
AM)
Glucose and Insulin Response to Natural Vasopressin in Bilaterally Adrenalectomized Subjects Glucose mg.%
Control 0
30’
1. M.M. (F.) 5062 2. N.S. (M.) 52
60’
76 76
76
Time After Injection
Control 12F
0
60 76
50 54
Injection
Insulin p units/ml.
Immunoreactive
Time After Injection
KENT
60’
30’
42 50
120’
50 50
50 60
INJ.
30 *
i
Fig. 1 .-Plasma glucose response to natural vasopressin injection (Inj.) in maturity onset diabetics and adult nondiabetics. Mean + standard error of mean are plotted.
0
30
NONDIABETICS
120
60 MINUTES
3.8 (S.E.M.) at 60 minutes and returned to control levels, 12.7 pg./ 100 ml. + 2.2 (S.E.M.) at 120 minutes. The rise of cortisol in each of these subjects was normal according to the criterion of Brostoff et a1.12 Among the 4 maturity onset diabetic and 4 adult nondiabetic subjects who also received normal saline injections, the mean changes in plasma glucose, insulin and GH were not statistically significant (p > 0.2 for all parameters).
Side effects were minimal. Most of the subjects showed facial pallor soon after injection. On direct questioning one third of the subjects mentioned abdominal discomfort of a transient nature and 3 subjects experienced mild rectal tenesmus. DISCUSSION
Cash and Kaplan l3 showed glucose elevating activity of both lysine and arginine vasopressin in rabbits. Similar action in humans was reported by Knebusche in 1967 and subsequently co&med by Karp et al.’ The mechanism by which natural vasopressin elicits this rise in plasma glucose remains unclear. Certain possible mechanisms including a significant portion of the endocrine system known to influence plasma glucose have been evaluated in this study. The data presented indicates that the rise in plasma glucose is independent of changes in plasma cortisol, GH, insulin, and probably epinephrine. Plasma cortisol, as reported by other investigators,l*-l6 rises consistently
PLASMA
GLUCOSE
RESPONSE
245
following injection of synthetic or natural vasopressin in subjects with intact adrenals. The increment of plasma glucose appears to be independent of the cortisol response, since in bilaterally adrenalectomized subjects the rise was identical to that seen in subjects with intact adrenals. WestIr has shown that the glucose elevating effect of glucocorticoids occurs several hours after the administered dose, whereas the plasma glucose response to vasopressin occurs within 30 minutes. The plasma glucose rise also occurred independent of the GH response to natural vasopressin, in agreement with Karp et al7 Augmented GH secretion is, therefore, an unlikely explanation for the glucose rise. The glucose response apparently does require the presence of adequate basal levels of GH, since it has been reported to be absent in patients with isolated GH deficiency.7 No consistent GH response to natural vasopressin was noted in our study in agreement with some authors, 7~~~1~but in disagreement with the report of Gagliardino et al I8 This variability of GH response to vasopressin has been reported with both synthetic lysine and natural vasopressin. No significant rise in plasma insulin was observed in contrast to the small increase reported by Karp et al.7 using lysine vasopressin. WhiIe the administration of glucagon elicits a rise in both plasma glucose and plasma insulin, a more marked insulin response would be expected if vasopressin acted via this indirect mechanism.lg The possibility that the rise in plasma glucose was a consequence of natural vasopressin stimulation of epinephrine release is also unlikely, since the plasma glucose response occurred in bilaterally adrenalectomized subjects with absent adrenomedullary function. Furthermore, a rise in FFA would be expected if the plasma glucose response was attributable to epinephrine. Published reports indicate that FFA either fal17r20-23or remain unchangedz4 after vasopressin administration. It is concluded from this study that the rapid rise of plasma glucose following natural vasopressin administration occurs independent of any effects upon plasma levels of insulin, GH, cortisol or epinephrine. Studies in experimental animals suggest that the glucose response, instead, could be attributable to a direct action of vasopressin. Bergen et al5 showed by direct measurement of hepatic portal gradients that the liver was the source of the plasma glucose increment following intraportal administration of synthetic lysine vasopressin, or natural vasopressin, in fasted unanesthetized dogs. They suggested this could be due to a direct effect of vasopressin upon hepatic phosphorylase, promoting glycogenolysis. In addition, Best and TaylorZ4 have demonstrated, following vasopressin administration, the association of plasma glucose elevation with a fall in hepatic glycogen content. The action of vasopressin upon glucose metabolism at peripheral tissues, or the role of other hormones, such as glucagon, in the plasma glucose response to vasopressin remains to be clarified. However, it is consistent with present evidence to speculate that in man, as in experimental animals, natural vasopressin produces a plasma glucose rise via stimulation of hepatic phosphorylase, perhaps mediated by cyclic adenosine 3’5’-monophosphate. It is
246
SUEIYANARAYANA
noteworthy that both glucagon and epinephrine plasma glucose via this mechanism.25l26
have been
shown
AND KENT
to elevate
ACKNOWLEDGMENTS We thank kindly Dr. Mary A. Root of the Lilly Research Laboratories for supplying Human Insulin Lot 516-734 B3, 25.4 IU/mg. and The Endocrinology Study Section, Division of Research Grants, National Institutes of Health, Bethesda, Maryland, for supplying Human Growth Hormone NIH-GH-HS968C having growth activity 1.45 IU/mg. and prolactin
activity
6.5 IU/mg.
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S.:
Heart
rate after sympathectomy and vagotomy and blood sugar as affected by posterior hypophyseal extracts ( pitressin and pitocin) . Amer. J. Physiol. 95:605, 1930. 5. Bergen, S. S., Jr., Sullivan, B., Hilton, J. G., Willis, S. W., Jr., and Van Itallie, T. B.: Glycogenolytic effect of vasopressin in the canine liver. Amer. J. Physiol. 199: 136, 1960. 6. Knebusch, R. E.: Die Wirkung Lysin-vassopressin auf die Konzentration
von der
11-Hydroxycorteroide im Plasma endodrin gesunder Kinder: Ein Test der Hypophysenfunktion. Helv. Paediat. Acta 12:376, 1967. 7. Karp, M., Pertzelan, A., Doron, M., Kowadlo-Silbergeld, A., and Laron, Z.: Changes in blood glucose and plasma inhormone, sulin, free fatty acids, growth and II-hydroxycorticosteroids during intramuscular vasopressin tests in children and adolescents. Acta Endocr. 58:545, 1968. 8. Hoffman, W. S.: Rapid photoelectric method for determination of glucose in blood and urine. J. Biol. Chem. 120:51, 1937. 9. Mattingly, D.: A simple fluorometric method for estimation of free ll-hydroxycorticoids in human plasma. J. Clin. Path. 15:374, 1962. IO. Morgan, human insulin
C. R.: Immunoassay of and growth hormone simul-
taneously using I-131 and I-125 tracers. Proc. SOC. Exp. Biol. Med. 123:230, 1966. 11. Batson, H. C.: An Introduction to Statistics in the Medical Sciences, Vol. 16. Minneapolis, Burgess Publishing Co., 1963. 12. Brostoff, J., James, V. H. T., and Landon, J. : Plasma corticosteroid and growth hormone response to lysine-vasopressin in man. J. Clin. Endocr. 28:511, 1968. 13. Cash, W. D., and Kaplan, M. H.: A comparison of the effects of B-lysine1-deamino-B-lysine vasopressin vasopressin, and 1-acetyl-B-vasopressin on the blood glucose level in rabbits. Endocrinology 74: 803, 19644. 14. Gwinup, G.: Test for pituitary function using vasopressin. Lancet 2:572, 1965. 15. Tucci, J. R., Espiner, E. A., Jagger, P. I., Lauler, D. P., and Thorn, G. W.: Vasopressin in the evaluation of pituitaryadrenal
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Int.
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69:191,
1968. 16. Czarny, D., James, V. H. T., Landon, J. J., and Greenwood, F. C.: Corticosteroid and growth hormone response to synthetic lysine-vasopressin, natural vasopressin, saline solution, and venepuncture. Lancet 1: 126, 1968. 17. West, K. M.: Response of the blood glucose to glucocorticoids in man-Determination of the hyperglycemic potencies of glucocorticoids. Diabetes 822, 1959. 18. Gagliardino, J. J., Bailey, J. D., and of vasopressin on Martin, J. M.: Effect serum-levels of human growth hormone. Lancet 1: 1357, 1967. 19. Mirski, I. A.: Relative effects of insulin, oxytocin and vasopressin on the free fatty acid concentration of the plasma of nondiabetic and diabetic dogs. Endocrinology 73:613, 1963. Effect of oxytocin, vasopressin, 20. -: and related peptides on plasma free fatty acids. Amer. J. Physiol. 204:842, 1963.
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V.:
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21. Balasse, E., Rasio, E., Action insulino-mimetique
and Conard, de la vaso-
pressin chez le chien. Arch. Int. Pharmacodyn. 161:392, 1966. 22. Dang-Tran, L., and Douste-Blazy, L.: Influence de la vasopressine sur les lipides plasmatiques. Comptes Rendus des Seance de la Soviete de Biologie. 160: 2473, 1966. 23. Librik, L., and Clayton, G. W.: The measurement of plasma nonesterified fatty acid levels following ACTH release in man. Metabolism 12:790, 1963.
24. Best, C. H., and Taylor, N. B.: A Physiological Basis of Medical Practice: A Text in Applied Physiology (ed. 7). London, Bailliere, Tindall and Cox, 1961. 25. Sutherland, E. W., and Rall, T. W.: The relation of adenosine-3’,5’-phosphate and phosphorylase to the actions of catecholamines and other hormones. Pharmacol. Rev. 12:265, 1960. 26. Levine, R. A.: Effect of glycogenolytic agents on phosphorylase activity of perfused rat liver. Amer. J. Physiol. 208:317, 1965.