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Improved tolerance to successive glucose loads in acromegaly
Improved Tolerance to Successive Loads in Acromegaly C. Abraira
Glucose
and A. M. Lawrence
The mechanism of the Staub-Traugott effect, or facilitated glucose disposal with closely timed successive glucose loads, remains poorly understood. Progressive suppression of growth hormone has been suggested as an explanation. To test this hypothesis, three successive intravenous glucose loads were administered to seven active acromegalic patients and six healthy controls. All subjects showed a clear StaubTraugott effect despite failure of hyper-
glycemia to suppress abnormally high growth hormone levels in the acromegalicr. Except for higher basal and incremental insulin release in the acromegalic patients, patterns of insulin secretion and suppression of free fatty acids were not substantially different from controls. These studies clearly suggest that hyperglycemiainduced suppression of growth hormone is not the cause of the Staub-Tmugott effect.
F
ACILITATED GLUCOSE DISPOSAL, or the Staub-Traugott effect, refers to improved glucose tolerance seen with successive, closely timed oraliJ or intravenous3*4 glucose administration in normal man. The cause for this effect is largely unknown. “Insulinization” of tissues has been suggested as causally related.5 Progressive depression of pituitary factors,5 possibly growth hormone suppression3 has also been suggested to underly the StaubTraugott effect. Growth hormone is known to be diabetogenic6 and prevention of sleep-related growth hormone rise has resulted in improved glucose tolerance in normal volunteers.’ In an attempt to assess the role of growth hormone in the Staub-Traugott effect, successive intravenous glucose loads were administered to patients with active acromegaly and to control subjects. MATERIALS
AND
METHODS
Seven acromegalic patients were studied (age range 29-68; mean age SO). Two patients were recently diagnosed and untreated. All others had received conventional radiation therapy 2-20 yr previously, but each had clinical and laboratory evidence of continued active disease. Six control subjects of comparable age (age range 26-60; mean age 44) were admitted to our Veterans Administration Hospital for study prior to elective surgery. None had a family history of diabetes mellitus or other serious systemic illness. One had epigastric distress diagnosed as esophagitis which had quickly responded to conservative therapy. All subjects received a diet containing at least 200 g of carbohydrate for three days prior to testing, fasted overnight, and rested for approximately 60 min prior to instituting an i.v. glucose test challenge. Indwelling scalp vein needles were inserted in an antecubital vein of each arm between 8:OO and 9:00 a.m.; one was for glucose injection and the other for blood sample withdrawal. The latter was kept open with a solution of heparin and saline (5, U/cc). After baseline samples were obtained, the first intravenous glucose challenge (0.5 g/kg) was infused over a period of 3 min. Postglucose samples were drawn at 5, 15, 25, 35, 45, and 55 min after the beginning of the infusion. Five minutes
From the Veterans Administration Hospital. Hines, The Department of Medicine, University of Illinois Abraham Lincoln School of Medicine, Chicago, and Departments of Medicine and Biochemistry, Loyola University Stritch School of Medicine, Maywood. III. Received for publication March 9.1976. Reprint requests should be addressed to Dr. Carlos Abraira. Hines VA Hospital, Medical Service (1lIC). Hines, Ill. 60141. @ 1977 by Gtune & Stratton, Inc. Metabolism, Vol. 26, No. 3 (March), 1977
207
ABRAIRA
288
AND
LAWRENCE
following the last sample a second glucose challenge was administered with identical timing of sample withdrawals; a similar challenge was administered for a third time at 5 min after the 55-min sample of the second test. The experiment was concluded when the 55-min sample of the third glucose challenge was obtained.
Analytic Methods The first 1.5 cc of blood obtained with each sample was discarded to avoid dilutional error, and the rest of the collection was done with a clean syringe. Blood was drawn into tubes with FluorideVersene additive and into tubes without additives. Plasma was separated and frozen for later glucose and free fatty acid determinations, and serum was separated and frozen at -2o”C, pending analysis of insulin and of growth hormone. Glucose was measured by the autoanalyzer method of H0ffman.s A modified method of the radiochemical method of Ho and Meng was used for determination of free fatty acidss A dextran-coated charcoal method was employed for determination by radioimmunoassay of serum insulin levels. Serum growth hormone was measured by minor modifications of the solid-phase method described by Catt and Tregear.” Glucose tolerance expressed as a disappearance rate (K) was obtained by plotting absolute The plasma glucose regression value was calglucose values semilogarithmically against time.” culated from the 15-min sample since the period O-15 min is generally interpreted as one of equilibration prior to actual glucose uptake in tissues.‘2 Free fatty acid suppression after the second and third glucose loads was calculated by comparing in each subject the mean of free fatty acid levels at 15, 35. and 55 min after each glucose injection, with the mean of similar time determinations after the preceding load. In addition to absolute peaks, insulin response to each glucose load was also compared by summating insulin levels at 5. 15, 25, 35. and 45 min after each load. Results were statistically evaluated using the Wilcoxon rank sum test.” RESULTS
Glucose disposal rates. Mean fasting plasma of acromegalics was slightly nonsignificantly greater of controls (85 & 5 versus 77 The mean initial in the control subjects 1.07 f 0.09, two had diabetic and/or and 0.9). Disappearance rates all acromegalics in this study, however, were either frankly or borderline diabetic (Fig. mean K, of K values for the second and third for both control acromegalic subjects (Fig. For controls, the mean K value increased to 1.85 + 0.33 and finally to 2.56 in the third The improvement in disposal rates K, and K,, and and K, in control subjects, was statistically significant (p < 0.05). Although the increase in the control group, of the diabetic acromegalics also increased significantly the second and third of 0.9 in the second and 1.45 =t 0.18 the third load. (Differences K, and K,, and and K, in acromegalics the course of to suppress, showing little of approximately 30-32 ng/ml in these acromegalic subjects The slight elevation in the first the transitory but marked one patient exhibited during first glucose tolerance to unchanged elevated fasting the second and third
GLUCOSE
289
IN ACROMEGALY
Fig. 1. A: Mean glucose disappearhce rater (K) +iEM of thr;e
20
successive intravenous glucose loads in normal and acromegalic patients. B: Serum growth hormone levels in acromegalic subjects during the same tests (moan + SW).
not determined in our control group, since others3 have shown that after initial depression in growth hormone in normal subjects values remain very low throughout the period of repetitive intravenous glucose challenge. Znsulin responses-controls. Insulin response following the successive glucose loads in normal subjects showed a brisk initial rise with a significantly higher “basal” level at the start of the second and third test periods (p < 0.001) (Fig. 2B). Perhaps coincidentally with improved glucose tolerance, insulin secretory profiles during the second and third tests differed in that insulin rose and tended to remain high during the remainder of the test periods. Additionally, it should be noted that peak insulin levels with the second and third tests showed a progressive increment (peak 3 versus peak 1, p < 0.05; peak 3 versus peak 2,p< 0.05). Insulin release in the acromegalic group Insulin responses-acromegalics. revealed certain not unexpected responses (Fig. 2B). Despite poorer glucose tolerance for acromegalics than for control subjects with each test, total absolute insulin release in each test was significantly greater in the patients with active acromegaly (p < 0.05; Table 1). As with the normal controls, basal insulin values at the beginning of the second and third test periods were sig-
ABRAIRA
AND
LAWRENCE
Fig. 2. A: Mean plasma free fatty acids + SEM in acromegolic and control subjects during three successive i.v. glucose tolerance tests. B: Mean serum insulin levels * SRM, in acromegolic and control subjects during the same tests.
Table 1. Plasma Insulin Responses(pU/ml). Glucose Load
Acromegalics
324 f
Second
513 * 179
183 f 18
952 f 469
196 i
Third Expressed
Controls
First
cts sum of determinations
127
and
11 15
during each glucosetolerancetest,following three successive intro-
venousglucoseloads. Means f SEM. See Materials
107*
Methods
for
method
of calculation.
GLUCOSE
291
IN ACROMEGALY
nificantly raised above fasting levels (p < O.Ol), but insulin rises were incrementally increased only during the third test period (p < 0.01). Free fatty acids. Finally, free fatty acid levels were examined during the course of these three tests. In controls, a steady and significant decline in free fatty acid levels was seen with each of the glucose challenges (Fig. 2A). Levels dropped 345 mM/liter during the first test and thereafter an additional 230 mM/liter. Mean fasting levels in both groups were not significantly different. In the acromegalic group, however, a significant early rise from 694 to 1425 mEq/liter was noted in the first 15 min after the initial glucose infusion (p < 0.05). This rise occurred despite a greater than normal insulin elevation, 121 f 68 pU/ml in acromegalics versus 25 + 2 pU/ml in our controls (p < 0.05) (Fig. 2). Following this early free fatty acid rise, however, a steady drop in free fatty acids was then observed throughout the remainder of the succeeding test periods. In fact, the mean fatty acidemia was more significantly suppressed after the second and third loads in acromegalics than in controls (p < 0.05). DISCUSS1ON
The mechanism of facilitated glucose disposal, or the Staub-Traugott effect, actually described initially by Hamman and Hirschman in 1919,14 has been ascribed variously to “insulinization” of tissues, lowering of free fatty acid levels, and/or to suppressed circulating growth hormone titers.‘v5 In our present study, it was observed that a clear Staub-Traugott effect did occur in acromegalic subjects despite failure of hyperglycemia to suppress elevated growth hormone levels and despite initial diabetic glucose disposal rates. We have recently reported what appears to be the unique absence of the Staub-Traugott effect in patients with panhypopituitarism receiving maintenance thyroid, cortisone, and sex steroid replacement and having patterns of peripheral insulin response similar to normals. ” It was suggested that the absence of growth hormone might be in part responsible. From these companion studies in acromegaly it would appear that although the presence of minimally critical amounts of growth hormone may be required for the phenomenon of facilitated glucose disposal, failure of hyperglycemia to lower elevated growth hormone levels does not prevent the Staub-Traugott effect. It may be argued that augmented insulin release in acromegalic subjects might act to counter these high growth hormone levels, since the total insulin response was not only higher in every glucose test but also exhibited greater increments with each glucose stimulus, most significantly after the third load. These observations confirm and complement reports on the priming effect of repetitive pulses of glucose on the potentiation of insulin response in normals.4 Growth hormone increases the insulin response to glucose,16 and, as shown here, this response is potentiated as well after repeated glucose stimulation. However, although an unquestionable Staub-Traugott effect was obtained, the greater insulin release in the second and third tests failed to potentiate glucose tolerance as much as was observed in controls. Hypopituitary patients who failed to demonstrate a Staub-Traugott effect were also noted to demonstrate an initial rise and an incomplete fall in free fatty acids after glucose administration despite a greater than normal insulin rise.15 A similar phenomenon was noted early during the initial 15 min of the first
292
ABRAIRA
AND LAWRENCE
intravenous glucose tolerance test in our patients with active acromegaly. This transient increase in serum free fatty acids, in contrast with reports in acromegalics following oral glucose administration,16 is not readily explainable. However, it might be speculated that known lipolytic effects of growth hormone,” which may be potentiated by the stress-induced rise in catecholsln associated with the initial intravenous manipulation, might be responsible. Conceivably this degree of free fatty acidemia could contribute to insulin resistance and thus generate the observed initial diabetic K values. In fact, the free fatty acids stayed higher than fasting levels until the third load, perhaps reflecting in part the recognized insulin resistance associated with hypersomatotropism. Nevertheless, in contrast to the hypopituitary patients, where free fatty acid levels decline very slowly during repeated glucose loading,” a consistent and steady drop in free fatty acids was seen after the first 15 min in patients with acromegaly and during a time when peripheral glucose disposal (K) was, in fact, improving. One hypothesis on the mechanism of the Staub-Traugott effect3 proposes that it might also depend on the free fatty acid influence on insulin resistance. If free fatty acidemia is lower in the second glucose load than during the first, and still lower during the third glucose tolerance, it cannot be ruled out as a factor in the progressive improvement in tolerance to the successive glucose loads. The Staub-Traugott effect is present in normal3 and diabetic4 subjects and in patients with active acromegaly, but its absence is characteristic of hypopituitarism. Absence of the Staub-Traugott effect in hypopituitarism has tentatively been attributed to impaired induction of key glycolytic and glycogenic enzymes. l5 The presence of the Staub-Traugott phenomenon in acromegalics might be consistent with this hypothesis. Although there is a large body of evidence for growth hormone antagonizing the action of insulin, it seems likely that this diabetogenic hormone also acts at the level of the glucose transport system,‘9.20 while chronic excessive growth hormone levels are accompanied by high liver glycogen and increased utilization and production of glucose in the absorptive state. 2’ Furthermore growth hormone has been shown to increase phosphofructokinase activity. 22‘Thus it appears probable that glycolytic and glycogenic enzymatic induction is largely preserved in acromegaly, as long as adequate insulin secretion is present.23 Finally, an alternate explanation for the absence of facilitated glucose disposal in hypopituitarism is the possibility that the absence of a net growth hormone decrease during hyperglycemia following glucose administration might be causally responsible. 3*5 The present studies, which demonstrate a StaubTraugott effect in acromegaly without growth hormone suppression, clearly suggest that changes in growth hormone levels are not causally related to the Staub-Traugott effect. The requirement for growth hormone secretion in order to elicit a Staub-Traugott effect is, however, not excluded by these findings. REFERENCES I. Dupre J: An intestinal hormone affecting glucose disposal in man. Lancet 2~672-673, 1964 2. Somersalo D: Staub effect on children.
Studies of the blood sugar regulation by means of double and triple glucose tolerance tests. Acta Paediatr 78-83: l-- 126. 1950- 195 I 3. Szabo AJ. Maier .I, Szabo 0, et al: Im-
GLUCOSE
IN ACROMEGALY
proved glucose disappearance following repeated glucose administration. Diabetes 18: 232-237, 1969 4. Metz R, Friedenberg R: Effects of repetitive glucose loads on plasma concentrations of glucose, insulin and free fatty acids: Paradoxical insulin responses in subjects with mild glucose intolerance. J Clin Endocrinol 30:602-608, 1970 5. Soskin S: Role of the endocrines in the regulation of blood sugar. J Clin Endocrinol 475588, 1944 6. Ikkos D and Luft R: “Idiohypophyseal” diabetes mellitus in two hypophysectomised women. Lancet 2:897, 1960 7. Schnure JJ, Raskin P, Lipman R: Growth hormone secretion during sleep: Impairment in glucose tolerance and nonsuppressibility by hyperglycemia. J Clin Endocrinol 33:234-241, 1971 8. Hoffman WS: Rapid photoelectric method for determination of glucose in blood and urine. J Biol Chem 120:51, 1937 9. Ho RJ, Meng HC: A simple and ultrasensitive method for determination of free fatty acids by radiochemical assay. Anal Biochem 31:426, 1969 10. Catt K, Tregear GW: Solid phase radioimmunoassay in antibody coated tubes. Science 158:1570-1571, 1967 I I. Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J l:l507, 1962 12. Butterfield WJH, Abrams ME, Whichelow MJ: The 25 gram intravenous glucose tolerance test: A critical appraisal. Metabolism 20:255, 197 I 13. Armitage P: Statistical Methods in Medical Research. New York, Wiley, 1971, p 398 14. Hamman L, Hirschman II: Studies on
293
blood sugar. IV. Effects upon the blood sugar of the repeated ingestion of glucose. Bull Johns Hopkins Hosp 30:306-308, 1919 15. Abraira C, Graham L, Lawrence AM: Absence of facilitated glucose disposal (StaubTraugott effect) in subjects with hypopituitarism. Metabolism 24: 1145, 1975 16. Beck P, Schach DS, Parker MC et al: Correlative studies of growth hormone and insulin plasma concentrations with metabolic abnormalities in acromegaly. J Lab Clin Med 661366, 1965 17. Raben MS, Hollenberg CM: Effect of growth hormone on plasma fatty acids, J Clin Invest 38:484, 1959 18. Hagen TC, Lawrence AM, Kirsteins L: Growth hormone enhancement of epinephrine induced lipolysis. Excerpta Med 256:36, 1972. 19. Henderson MJ, Morgan HE, Park CR: Regulation of glucose uptake in muscle. V. The effect of growth hormone on glucose transport in the isolated, perfused rat heart. J Biol Chem 236:2157-2161, 1961 20. Zierler KL, Rabinowitz D: Roles of insulin and growth hormone, based on studies of forearm metabolism in man. Medicine (Baltimore) 42:385-402, 1963 21. Altszuler N, Rathgeb J, Winkler B, et al: The effect of growth hormone on carbohydrate and lipid metabolism in the dog. Ann NY Acad Sci 148:44ll458, 1968 22. Krishna Raj R, Ramaiah A, Talwar GP: Effect of growth hormone in vitro on phosphofructokinase activity of rat epididymal adipose tissue. Arch Biochem Biophys 142:61-68, 1971 23. Shreeve WW, Cerasi E, Luft R: Metabolism of Cl4 pyruvate in normal, acromegalic and HGH-treated human subjects. Acta Endocrinol 59:344-352, 1968.
Glucose
and A. M. Lawrence
The mechanism of the Staub-Traugott effect, or facilitated glucose disposal with closely timed successive glucose loads, remains poorly understood. Progressive suppression of growth hormone has been suggested as an explanation. To test this hypothesis, three successive intravenous glucose loads were administered to seven active acromegalic patients and six healthy controls. All subjects showed a clear StaubTraugott effect despite failure of hyper-
glycemia to suppress abnormally high growth hormone levels in the acromegalicr. Except for higher basal and incremental insulin release in the acromegalic patients, patterns of insulin secretion and suppression of free fatty acids were not substantially different from controls. These studies clearly suggest that hyperglycemiainduced suppression of growth hormone is not the cause of the Staub-Tmugott effect.
F
ACILITATED GLUCOSE DISPOSAL, or the Staub-Traugott effect, refers to improved glucose tolerance seen with successive, closely timed oraliJ or intravenous3*4 glucose administration in normal man. The cause for this effect is largely unknown. “Insulinization” of tissues has been suggested as causally related.5 Progressive depression of pituitary factors,5 possibly growth hormone suppression3 has also been suggested to underly the StaubTraugott effect. Growth hormone is known to be diabetogenic6 and prevention of sleep-related growth hormone rise has resulted in improved glucose tolerance in normal volunteers.’ In an attempt to assess the role of growth hormone in the Staub-Traugott effect, successive intravenous glucose loads were administered to patients with active acromegaly and to control subjects. MATERIALS
AND
METHODS
Seven acromegalic patients were studied (age range 29-68; mean age SO). Two patients were recently diagnosed and untreated. All others had received conventional radiation therapy 2-20 yr previously, but each had clinical and laboratory evidence of continued active disease. Six control subjects of comparable age (age range 26-60; mean age 44) were admitted to our Veterans Administration Hospital for study prior to elective surgery. None had a family history of diabetes mellitus or other serious systemic illness. One had epigastric distress diagnosed as esophagitis which had quickly responded to conservative therapy. All subjects received a diet containing at least 200 g of carbohydrate for three days prior to testing, fasted overnight, and rested for approximately 60 min prior to instituting an i.v. glucose test challenge. Indwelling scalp vein needles were inserted in an antecubital vein of each arm between 8:OO and 9:00 a.m.; one was for glucose injection and the other for blood sample withdrawal. The latter was kept open with a solution of heparin and saline (5, U/cc). After baseline samples were obtained, the first intravenous glucose challenge (0.5 g/kg) was infused over a period of 3 min. Postglucose samples were drawn at 5, 15, 25, 35, 45, and 55 min after the beginning of the infusion. Five minutes
From the Veterans Administration Hospital. Hines, The Department of Medicine, University of Illinois Abraham Lincoln School of Medicine, Chicago, and Departments of Medicine and Biochemistry, Loyola University Stritch School of Medicine, Maywood. III. Received for publication March 9.1976. Reprint requests should be addressed to Dr. Carlos Abraira. Hines VA Hospital, Medical Service (1lIC). Hines, Ill. 60141. @ 1977 by Gtune & Stratton, Inc. Metabolism, Vol. 26, No. 3 (March), 1977
207
ABRAIRA
288
AND
LAWRENCE
following the last sample a second glucose challenge was administered with identical timing of sample withdrawals; a similar challenge was administered for a third time at 5 min after the 55-min sample of the second test. The experiment was concluded when the 55-min sample of the third glucose challenge was obtained.
Analytic Methods The first 1.5 cc of blood obtained with each sample was discarded to avoid dilutional error, and the rest of the collection was done with a clean syringe. Blood was drawn into tubes with FluorideVersene additive and into tubes without additives. Plasma was separated and frozen for later glucose and free fatty acid determinations, and serum was separated and frozen at -2o”C, pending analysis of insulin and of growth hormone. Glucose was measured by the autoanalyzer method of H0ffman.s A modified method of the radiochemical method of Ho and Meng was used for determination of free fatty acidss A dextran-coated charcoal method was employed for determination by radioimmunoassay of serum insulin levels. Serum growth hormone was measured by minor modifications of the solid-phase method described by Catt and Tregear.” Glucose tolerance expressed as a disappearance rate (K) was obtained by plotting absolute The plasma glucose regression value was calglucose values semilogarithmically against time.” culated from the 15-min sample since the period O-15 min is generally interpreted as one of equilibration prior to actual glucose uptake in tissues.‘2 Free fatty acid suppression after the second and third glucose loads was calculated by comparing in each subject the mean of free fatty acid levels at 15, 35. and 55 min after each glucose injection, with the mean of similar time determinations after the preceding load. In addition to absolute peaks, insulin response to each glucose load was also compared by summating insulin levels at 5. 15, 25, 35. and 45 min after each load. Results were statistically evaluated using the Wilcoxon rank sum test.” RESULTS
Glucose disposal rates. Mean fasting plasma of acromegalics was slightly nonsignificantly greater of controls (85 & 5 versus 77 The mean initial in the control subjects 1.07 f 0.09, two had diabetic and/or and 0.9). Disappearance rates all acromegalics in this study, however, were either frankly or borderline diabetic (Fig. mean K, of K values for the second and third for both control acromegalic subjects (Fig. For controls, the mean K value increased to 1.85 + 0.33 and finally to 2.56 in the third The improvement in disposal rates K, and K,, and and K, in control subjects, was statistically significant (p < 0.05). Although the increase in the control group, of the diabetic acromegalics also increased significantly the second and third of 0.9 in the second and 1.45 =t 0.18 the third load. (Differences K, and K,, and and K, in acromegalics the course of to suppress, showing little of approximately 30-32 ng/ml in these acromegalic subjects The slight elevation in the first the transitory but marked one patient exhibited during first glucose tolerance to unchanged elevated fasting the second and third
GLUCOSE
289
IN ACROMEGALY
Fig. 1. A: Mean glucose disappearhce rater (K) +iEM of thr;e
20
successive intravenous glucose loads in normal and acromegalic patients. B: Serum growth hormone levels in acromegalic subjects during the same tests (moan + SW).
not determined in our control group, since others3 have shown that after initial depression in growth hormone in normal subjects values remain very low throughout the period of repetitive intravenous glucose challenge. Znsulin responses-controls. Insulin response following the successive glucose loads in normal subjects showed a brisk initial rise with a significantly higher “basal” level at the start of the second and third test periods (p < 0.001) (Fig. 2B). Perhaps coincidentally with improved glucose tolerance, insulin secretory profiles during the second and third tests differed in that insulin rose and tended to remain high during the remainder of the test periods. Additionally, it should be noted that peak insulin levels with the second and third tests showed a progressive increment (peak 3 versus peak 1, p < 0.05; peak 3 versus peak 2,p< 0.05). Insulin release in the acromegalic group Insulin responses-acromegalics. revealed certain not unexpected responses (Fig. 2B). Despite poorer glucose tolerance for acromegalics than for control subjects with each test, total absolute insulin release in each test was significantly greater in the patients with active acromegaly (p < 0.05; Table 1). As with the normal controls, basal insulin values at the beginning of the second and third test periods were sig-
ABRAIRA
AND
LAWRENCE
Fig. 2. A: Mean plasma free fatty acids + SEM in acromegolic and control subjects during three successive i.v. glucose tolerance tests. B: Mean serum insulin levels * SRM, in acromegolic and control subjects during the same tests.
Table 1. Plasma Insulin Responses(pU/ml). Glucose Load
Acromegalics
324 f
Second
513 * 179
183 f 18
952 f 469
196 i
Third Expressed
Controls
First
cts sum of determinations
127
and
11 15
during each glucosetolerancetest,following three successive intro-
venousglucoseloads. Means f SEM. See Materials
107*
Methods
for
method
of calculation.
GLUCOSE
291
IN ACROMEGALY
nificantly raised above fasting levels (p < O.Ol), but insulin rises were incrementally increased only during the third test period (p < 0.01). Free fatty acids. Finally, free fatty acid levels were examined during the course of these three tests. In controls, a steady and significant decline in free fatty acid levels was seen with each of the glucose challenges (Fig. 2A). Levels dropped 345 mM/liter during the first test and thereafter an additional 230 mM/liter. Mean fasting levels in both groups were not significantly different. In the acromegalic group, however, a significant early rise from 694 to 1425 mEq/liter was noted in the first 15 min after the initial glucose infusion (p < 0.05). This rise occurred despite a greater than normal insulin elevation, 121 f 68 pU/ml in acromegalics versus 25 + 2 pU/ml in our controls (p < 0.05) (Fig. 2). Following this early free fatty acid rise, however, a steady drop in free fatty acids was then observed throughout the remainder of the succeeding test periods. In fact, the mean fatty acidemia was more significantly suppressed after the second and third loads in acromegalics than in controls (p < 0.05). DISCUSS1ON
The mechanism of facilitated glucose disposal, or the Staub-Traugott effect, actually described initially by Hamman and Hirschman in 1919,14 has been ascribed variously to “insulinization” of tissues, lowering of free fatty acid levels, and/or to suppressed circulating growth hormone titers.‘v5 In our present study, it was observed that a clear Staub-Traugott effect did occur in acromegalic subjects despite failure of hyperglycemia to suppress elevated growth hormone levels and despite initial diabetic glucose disposal rates. We have recently reported what appears to be the unique absence of the Staub-Traugott effect in patients with panhypopituitarism receiving maintenance thyroid, cortisone, and sex steroid replacement and having patterns of peripheral insulin response similar to normals. ” It was suggested that the absence of growth hormone might be in part responsible. From these companion studies in acromegaly it would appear that although the presence of minimally critical amounts of growth hormone may be required for the phenomenon of facilitated glucose disposal, failure of hyperglycemia to lower elevated growth hormone levels does not prevent the Staub-Traugott effect. It may be argued that augmented insulin release in acromegalic subjects might act to counter these high growth hormone levels, since the total insulin response was not only higher in every glucose test but also exhibited greater increments with each glucose stimulus, most significantly after the third load. These observations confirm and complement reports on the priming effect of repetitive pulses of glucose on the potentiation of insulin response in normals.4 Growth hormone increases the insulin response to glucose,16 and, as shown here, this response is potentiated as well after repeated glucose stimulation. However, although an unquestionable Staub-Traugott effect was obtained, the greater insulin release in the second and third tests failed to potentiate glucose tolerance as much as was observed in controls. Hypopituitary patients who failed to demonstrate a Staub-Traugott effect were also noted to demonstrate an initial rise and an incomplete fall in free fatty acids after glucose administration despite a greater than normal insulin rise.15 A similar phenomenon was noted early during the initial 15 min of the first
292
ABRAIRA
AND LAWRENCE
intravenous glucose tolerance test in our patients with active acromegaly. This transient increase in serum free fatty acids, in contrast with reports in acromegalics following oral glucose administration,16 is not readily explainable. However, it might be speculated that known lipolytic effects of growth hormone,” which may be potentiated by the stress-induced rise in catecholsln associated with the initial intravenous manipulation, might be responsible. Conceivably this degree of free fatty acidemia could contribute to insulin resistance and thus generate the observed initial diabetic K values. In fact, the free fatty acids stayed higher than fasting levels until the third load, perhaps reflecting in part the recognized insulin resistance associated with hypersomatotropism. Nevertheless, in contrast to the hypopituitary patients, where free fatty acid levels decline very slowly during repeated glucose loading,” a consistent and steady drop in free fatty acids was seen after the first 15 min in patients with acromegaly and during a time when peripheral glucose disposal (K) was, in fact, improving. One hypothesis on the mechanism of the Staub-Traugott effect3 proposes that it might also depend on the free fatty acid influence on insulin resistance. If free fatty acidemia is lower in the second glucose load than during the first, and still lower during the third glucose tolerance, it cannot be ruled out as a factor in the progressive improvement in tolerance to the successive glucose loads. The Staub-Traugott effect is present in normal3 and diabetic4 subjects and in patients with active acromegaly, but its absence is characteristic of hypopituitarism. Absence of the Staub-Traugott effect in hypopituitarism has tentatively been attributed to impaired induction of key glycolytic and glycogenic enzymes. l5 The presence of the Staub-Traugott phenomenon in acromegalics might be consistent with this hypothesis. Although there is a large body of evidence for growth hormone antagonizing the action of insulin, it seems likely that this diabetogenic hormone also acts at the level of the glucose transport system,‘9.20 while chronic excessive growth hormone levels are accompanied by high liver glycogen and increased utilization and production of glucose in the absorptive state. 2’ Furthermore growth hormone has been shown to increase phosphofructokinase activity. 22‘Thus it appears probable that glycolytic and glycogenic enzymatic induction is largely preserved in acromegaly, as long as adequate insulin secretion is present.23 Finally, an alternate explanation for the absence of facilitated glucose disposal in hypopituitarism is the possibility that the absence of a net growth hormone decrease during hyperglycemia following glucose administration might be causally responsible. 3*5 The present studies, which demonstrate a StaubTraugott effect in acromegaly without growth hormone suppression, clearly suggest that changes in growth hormone levels are not causally related to the Staub-Traugott effect. The requirement for growth hormone secretion in order to elicit a Staub-Traugott effect is, however, not excluded by these findings. REFERENCES I. Dupre J: An intestinal hormone affecting glucose disposal in man. Lancet 2~672-673, 1964 2. Somersalo D: Staub effect on children.
Studies of the blood sugar regulation by means of double and triple glucose tolerance tests. Acta Paediatr 78-83: l-- 126. 1950- 195 I 3. Szabo AJ. Maier .I, Szabo 0, et al: Im-
GLUCOSE
IN ACROMEGALY
proved glucose disappearance following repeated glucose administration. Diabetes 18: 232-237, 1969 4. Metz R, Friedenberg R: Effects of repetitive glucose loads on plasma concentrations of glucose, insulin and free fatty acids: Paradoxical insulin responses in subjects with mild glucose intolerance. J Clin Endocrinol 30:602-608, 1970 5. Soskin S: Role of the endocrines in the regulation of blood sugar. J Clin Endocrinol 475588, 1944 6. Ikkos D and Luft R: “Idiohypophyseal” diabetes mellitus in two hypophysectomised women. Lancet 2:897, 1960 7. Schnure JJ, Raskin P, Lipman R: Growth hormone secretion during sleep: Impairment in glucose tolerance and nonsuppressibility by hyperglycemia. J Clin Endocrinol 33:234-241, 1971 8. Hoffman WS: Rapid photoelectric method for determination of glucose in blood and urine. J Biol Chem 120:51, 1937 9. Ho RJ, Meng HC: A simple and ultrasensitive method for determination of free fatty acids by radiochemical assay. Anal Biochem 31:426, 1969 10. Catt K, Tregear GW: Solid phase radioimmunoassay in antibody coated tubes. Science 158:1570-1571, 1967 I I. Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J l:l507, 1962 12. Butterfield WJH, Abrams ME, Whichelow MJ: The 25 gram intravenous glucose tolerance test: A critical appraisal. Metabolism 20:255, 197 I 13. Armitage P: Statistical Methods in Medical Research. New York, Wiley, 1971, p 398 14. Hamman L, Hirschman II: Studies on
293
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