0021-972X/90/7006-1732$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 70, No. 6 Printed in U.S.A.
Plasma Concentrations of Growth Hormone during Hyperglycemic Clamp with or without Somatostatin Infusion in Obese Subjects* E. BONORA, P. MOGHETTI, M. ZENERE, M. QUERENA, F. TOSI, A. CORGNATI, AND M. MUGGEO Cattedra di Malattie del Metabolismo and Istituto di Chimica e Microscopia Clinica (A.C.), University of Verona, Verona, Italy
ABSTRACT. It is known that obese subjects have a blunted GH secretory response to stimulation, but little is known about the inhibition of GH secretion in obesity. The present study was designed to evaluate the effects of obesity on the suppression of GH by hyperglycemia and/or somatostatin. Plasma GH concentrations were measured in eight nondiabetic obese subjects and eight nonobese healthy controls during a 4-h hyperglycemic clamp. During the third hour synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min. Baseline plasma GH levels were similar in obese and nonobese subjects (0.9 ±0.1 us. 0.8 ± 0.2 Mg/L; mean ± SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120
G
LUCOSE administration results in a decline in plasma GH concentrations (1, 2). This might be due to a direct effect of hyperglycemia on pituitary cells releasing GH or to a more complex neuroendocrine mechanism. Somatostatin administration also decreases plasma GH levels (1, 2). Indeed, somatostatin is one of the most important physiological modulators of GH secretion. There have been several reports that in human obesity basal plasma GH levels are within the normal range, while the response of GH to a wide variety of stimuli is depressed (3,4). On the contrary, it is not known whether the suppressive effect of hyperglycemia and somatostatin on plasma GH levels is intact in obese subjects. In the present study we compared the plasma concentrations of GH in obese and nonobese subjects during prolonged steady state hyperglycemia (hyperglycemic clamp). The study included a period of combined administration of glucose and somatostatin in order to achieve a maximal inhibition of GH release. Received March 3, 1989. Address all correspondence and requests for reprints to: Dr. Enzo Bonora, Cattedra di Malattie del Metabolismo, Universita di Verona, Ospedale Policlinico I 37134, Verona, Italy. * This work was supported by Grants 85.00502.04 and 86.00102.04 from Consiglio Nazionale delle Ricerche, Italy, and grants from Ministero della Pubblica Istruzione, Italy.
min of the study) plasma GH averaged 0.8 ±0.1 /xg/L in obese patients and 0.4 ± 0.1 fig/L in control subjects (P < 0.01), with a reduction of 6 ± 5% in the former and 35 ± 10% in the latter (P < 0.01). In both groups somatostatin infusion did not result in a further decrease in plasma GH. Discontinuation of the somatostatin infusion resulted in a rise in both groups; the increase was higher in nonobese subjects (8.1 ± 3.8 vs. 2.3 ± 0.9 Mg/L in the period 220-240 min; P = NS). These results suggest that in human obesity, hyperglycemia has a diminished inhibitory effect on GH secretion, and somatostatin administration has no additional effect in either obese or nonobese nondiabetic subjects. (J Clin Endocrinol Metab 70: 1732-1734, 1990)
Materials and Methods Eight nonobese healthy subjects (five males and three females) and eight nondiabetic obese subjects (three males and five females) were studied after they gave their informed consent. All females were premenopausal and in the follicular phase of the menstrual cycle, and none was taking oral contraceptives. The nonobese subjects averaged 31 ± 1 yr of age (mean ± SEM), weighed 68 ± 2 kg, and had a body mass index of 22 ± 1 kg/m2. The obese subjects averaged 37 ± 4 yr of age, weighed 91 ± 5 kg, and had a body mass index of 35 ± 2 kg/ m2. All subjects had normal hepatic and renal function, had not taken any drug for at least 2 months, had no concomitant disease, were not bulemic, were not on a diet, and had maintained a stable body weight over the previous 3 months. Among obese subjects, seven had a normal glucose tolerance, and one had slightly impaired glucose tolerance by conventional criteria (5). Both groups under study included only sedentary people and no conditioned athletes. Two of the subjects in the nonobese and three subjects in the obese group were cigarette smokers, but no subject had a consumption exceeding 10 cigarettes/day. In the morning after an overnight fast, each subject underwent a 4-h hyperglycemic clamp, carried out according to the method of DeFronzo et al. (6). Briefly, the plasma glucose concentration was acutely raised from its fasting value to approximately 11 mmol/L by a priming glucose infusion, and this level of hyperglycemia was then maintained for 4 h by a
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HYPERGLYCEMIA, SOMATOSTATIN, AND GH
1733
variable glucose infusion. Synthetic cyclic somatostatin-14 (Stilamin, Serono, Rome, Italy) was infused in the third hour of the study at the rate of 2.5 nmol/min (250 Mg/h). Plasma for GH concentration measurements was obtained in the basal state and at 10-min intervals throughout the study. GH was assayed by a double antibody RIA (7) with reagents purchased from Sorin (Saluggia, Italy). In our laboratory the sensitivity of the assay (i.e. the amount of plasma GH producing a 5% displacement of tracer from antibody) was 0.125 Mg/L, and the concentrations of plasma GH ranging from 0.125-1.0 Mg/L were on a portion of the sigmoid competition curve steep enough to ensure good precision. Indeed, intra- and interassay coefficients of variation were, respectively, 8.7% and 9.9% at 0.5 Mg/L, and 5.3% and 7.1% at 5 Mg/L. All samples from the same subject were run in duplicate in the same assay, with a total of four assays. Care was taken to have an equal number of nonobese and obese subjects in each assay. Results were analyzed by the Student's t test for paired and unpaired data as well as by two-way analysis of variance. Data are presented as the mean ± SEM.
Results In the fasting state, plasma glucose averaged 4.8 ± 0.1 mmol/L among nonobese subjects and 4.9 ± 0.2 mmol/ L among obese patients. During the period between 20240 min of the study, plasma glucose averaged 11.2 ± 0.3 mmol/L in nonobese subjects (coefficient of variation, 9%) and 11.3 ± 0.2 mmol/L in obese patients (coefficient of variation, 7%). The amount of glucose required to maintain steady state hyperglycemia was significantly lower for obese than nonobese subjects, whether glucose was infused alone (20-120 and 180-240 min) or with somatostatin (120-180 min; data not shown). In the fasting state, obese and nonobese subjects had similar plasma GH concentrations (0.9 ± 0 . 1 vs. 0.8 ± 0.2 jug/L; P = NS). When the plasma glucose concentration was raised to approximately 11.2 mmol/L, the plasma GH concentration fell significantly (P < 0.05) in the nonobese, but not in the obese subjects (Fig. 1). In particular, during the 100- to 120-min period of the study, plasma GH averaged 0.8 ± 0 . 1 jug/L in obese patients and 0.5 ± 0.1 /ig/L in nonobese subjects (P < 0.01). The decline from basal levels was 6 ± 5% in obese and 35 ± 10% in nonobese subjects (P < 0.01). All plasma GH concentrations for nonobese subjects fell within the detection limits of the assay. During somatostatin administration, while stable hyperglycemia was maintained by glucose infusion, the plasma GH concentration did not change in either obese or nonobese subjects. In the 160- to 180-min period, GH averaged 0.8 ± 0.2 /ug/L in the former and 0.4 ±0.1 ng/ L in the latter group (P < 0.01). After interrupting somatostatin infusion, plasma GH levels rose significantly (P < 0.05) in both groups, averaging 3.8 ± 0.9
somatostatin.
120
210
240
TIME (min)
FIG. 1. Plasma GH concentrations during a 4-h hyperglycemic clamp in obese (T • • T) and nonobese (•-•) subjects. In the period between 120-180 min, somatostatin (2.5 nmol/min) was infused.
L in obese and Ml ± 3.8 ixg/L in nonobese subjects, during the 220-1 1240-min period. This difference, even though remarkaj i, did not reach statistical significance (0.05 < P < 0 . 1 > Analysis of vrt tnce showed that for the study period as a whole, pla^ la GH levels in nonobese and obese subjects were chif Jrent (P < 0.01). This difference was also apparent when the three study periods were analyzed separately: 60-120 min (P < 0.01), 120-180 min (P < 0.01), and 180-240 min (P < 0.05).
Discussion There are several studies demonstrating that obese subjects have blunted plasma GH responses to stimuli such as hypoglycemia, arginine, L-dopa, and exercise (3, 4). In contrast, there are few data about the impact of obesity on experimental GH suppression. To our knowledge, no data are available comparing plasma GH levels in obese and nonobese subjects during the iv administration of glucose or somatostatin. In the present study we compared plasma GH levels in obese and nonobese subjects during a hyperglycemic clamp, with or without combined somatostatin infusion. Our results indicate that in nondiabetic obese patients hyperglycemia does not decrease plasma GH levels to the same degree as in nonobese controls. Indeed, although hyperglycemia decreased plasma GH levels in nonobese subjects by 35%, the plasma GH levels of obese subjects
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1734
BONORA ET AL.
did not significantly change during the iv glucose infusion. Since insulin per se has no suppressive effect on GH release (8-10), the reduction of plasma GH observed in nonobese subjects can be attributed to hyperglycemia, rather than to glucose-induced hyperinsulinemia. Hyperglycemic clamp is a technique that allows generation of an increase in plasma glucose levels that is virtually identical in all subjects under examination. The increase over basal in plasma glucose concentration is predetermined by the operator. With the priming glucose infusion used in the present study, the hyperglycemic level is approximately 11 mmol/L. This level is 30-40% higher than that encountered in man under physiological conditions, i.e. after a meal. Thus, it remains to be determined if in obesity a more modest increase above basal in plasma glucose results in an impaired suppression of plasma GH levels. In regard to this, to our knowledge no data comparing postprandial plasma GH levels in obese and nonobese subjects are available in the literature. Our data suggest that in either nonobese or obese subjects somatostatin has no additive effect to that of hyperglycemia. Indeed, during hyperglycemia no change in plasma GH concentrations was detected when somatostatin was infused at a rate that usually generates supraphysiological plasma somatostatin concentrations (11). The impaired rise in plasma GH levels observed in obese subjects after somatostatin withdrawal is consistent with the well known blunting of GH release observed in obese subjects during exercise or hypoglycemia, or after the administration of arginine or L-dopa (3, 4). However, the increase in plasma GH levels that followed the discontinuation of somatostatin is difficult to explain, since somatostatin had no apparent effect on GH release during its administration with glucose. Perhaps somatostatin administration, although unable to further
JCE & M • 1990 Vol 70 • No 6
decrease plasma GH levels, interferred with the processes involved in GH secretion, so that the interruption of its infusion was immediately followed by a remarkable release of GH. In conclusion, this study suggests that 1) in human obesity, the GH-secreting cells or the hypothalamic cells involved in the regulation of GH secretion do not respond normally to hyperglycemia; and 2) somatostatin administration has no effect above that of hyperglycemia to inhibit GH release. The increase in plasma GH levels observed after somatostatin withdrawal remains to be elucidated. References 1. Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD, Broadus AE, Frohman L, eds. Endocrinology and metabolism. New York: McGraw-Hill; 1987;247-337. 2. Daughaday WH. The anterior pituitary. In: Wilson JD, Foster DW, eds. William's textbook of endocrinology. Philadelphia: Saunders; 1985;568-613. 3. Rabinowitz D. Some endocrine and metabolic aspects of obesity. Annu Rev Med. 1970;21:241-58. 4. Glass AR, Burman KD, Dahms WT, Boehm TM. Endocrine function in human obesity. Metabolism. 1981;30:89-104 5. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-57. 6. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214-23. 7. Boden G, Soeldner JS. A sensitive double antibody radioimmunoassay for HGH: levels of serum HGH following rapid tolbutamide infusion. Diabetologia. 1967;3:413-21. 8. Meneilly GS, Elahi D, Minaker KL, Rowe JW. Somatostatin does not alter insulin-mediated glucose disposal. J Clin Endocrinol Metab. l987;65:364-7. 9. Sharp PS, Mohan V, Maneschi F, et al. Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp. Metabolism. 1987;36:71-5. 10. Webb S, Wass LJAH, Llorens A, et al. Studies on the mechanisms of somatostatin release after insulin induced hypoglycemia in man. Clin Endocrinol (Oxf). 1984;21:667-75. 11. Adrian TE, Barnes AJ, Long RG, et al. The effect of somatostatin analogs on secretion of growth, pancreatic and gastrointestinal hormones in man. J Clin Endocrinol Metab. 1981;53:675-81.
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Vol. 70, No. 6 Printed in U.S.A.
Plasma Concentrations of Growth Hormone during Hyperglycemic Clamp with or without Somatostatin Infusion in Obese Subjects* E. BONORA, P. MOGHETTI, M. ZENERE, M. QUERENA, F. TOSI, A. CORGNATI, AND M. MUGGEO Cattedra di Malattie del Metabolismo and Istituto di Chimica e Microscopia Clinica (A.C.), University of Verona, Verona, Italy
ABSTRACT. It is known that obese subjects have a blunted GH secretory response to stimulation, but little is known about the inhibition of GH secretion in obesity. The present study was designed to evaluate the effects of obesity on the suppression of GH by hyperglycemia and/or somatostatin. Plasma GH concentrations were measured in eight nondiabetic obese subjects and eight nonobese healthy controls during a 4-h hyperglycemic clamp. During the third hour synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min. Baseline plasma GH levels were similar in obese and nonobese subjects (0.9 ±0.1 us. 0.8 ± 0.2 Mg/L; mean ± SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120
G
LUCOSE administration results in a decline in plasma GH concentrations (1, 2). This might be due to a direct effect of hyperglycemia on pituitary cells releasing GH or to a more complex neuroendocrine mechanism. Somatostatin administration also decreases plasma GH levels (1, 2). Indeed, somatostatin is one of the most important physiological modulators of GH secretion. There have been several reports that in human obesity basal plasma GH levels are within the normal range, while the response of GH to a wide variety of stimuli is depressed (3,4). On the contrary, it is not known whether the suppressive effect of hyperglycemia and somatostatin on plasma GH levels is intact in obese subjects. In the present study we compared the plasma concentrations of GH in obese and nonobese subjects during prolonged steady state hyperglycemia (hyperglycemic clamp). The study included a period of combined administration of glucose and somatostatin in order to achieve a maximal inhibition of GH release. Received March 3, 1989. Address all correspondence and requests for reprints to: Dr. Enzo Bonora, Cattedra di Malattie del Metabolismo, Universita di Verona, Ospedale Policlinico I 37134, Verona, Italy. * This work was supported by Grants 85.00502.04 and 86.00102.04 from Consiglio Nazionale delle Ricerche, Italy, and grants from Ministero della Pubblica Istruzione, Italy.
min of the study) plasma GH averaged 0.8 ±0.1 /xg/L in obese patients and 0.4 ± 0.1 fig/L in control subjects (P < 0.01), with a reduction of 6 ± 5% in the former and 35 ± 10% in the latter (P < 0.01). In both groups somatostatin infusion did not result in a further decrease in plasma GH. Discontinuation of the somatostatin infusion resulted in a rise in both groups; the increase was higher in nonobese subjects (8.1 ± 3.8 vs. 2.3 ± 0.9 Mg/L in the period 220-240 min; P = NS). These results suggest that in human obesity, hyperglycemia has a diminished inhibitory effect on GH secretion, and somatostatin administration has no additional effect in either obese or nonobese nondiabetic subjects. (J Clin Endocrinol Metab 70: 1732-1734, 1990)
Materials and Methods Eight nonobese healthy subjects (five males and three females) and eight nondiabetic obese subjects (three males and five females) were studied after they gave their informed consent. All females were premenopausal and in the follicular phase of the menstrual cycle, and none was taking oral contraceptives. The nonobese subjects averaged 31 ± 1 yr of age (mean ± SEM), weighed 68 ± 2 kg, and had a body mass index of 22 ± 1 kg/m2. The obese subjects averaged 37 ± 4 yr of age, weighed 91 ± 5 kg, and had a body mass index of 35 ± 2 kg/ m2. All subjects had normal hepatic and renal function, had not taken any drug for at least 2 months, had no concomitant disease, were not bulemic, were not on a diet, and had maintained a stable body weight over the previous 3 months. Among obese subjects, seven had a normal glucose tolerance, and one had slightly impaired glucose tolerance by conventional criteria (5). Both groups under study included only sedentary people and no conditioned athletes. Two of the subjects in the nonobese and three subjects in the obese group were cigarette smokers, but no subject had a consumption exceeding 10 cigarettes/day. In the morning after an overnight fast, each subject underwent a 4-h hyperglycemic clamp, carried out according to the method of DeFronzo et al. (6). Briefly, the plasma glucose concentration was acutely raised from its fasting value to approximately 11 mmol/L by a priming glucose infusion, and this level of hyperglycemia was then maintained for 4 h by a
1732
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HYPERGLYCEMIA, SOMATOSTATIN, AND GH
1733
variable glucose infusion. Synthetic cyclic somatostatin-14 (Stilamin, Serono, Rome, Italy) was infused in the third hour of the study at the rate of 2.5 nmol/min (250 Mg/h). Plasma for GH concentration measurements was obtained in the basal state and at 10-min intervals throughout the study. GH was assayed by a double antibody RIA (7) with reagents purchased from Sorin (Saluggia, Italy). In our laboratory the sensitivity of the assay (i.e. the amount of plasma GH producing a 5% displacement of tracer from antibody) was 0.125 Mg/L, and the concentrations of plasma GH ranging from 0.125-1.0 Mg/L were on a portion of the sigmoid competition curve steep enough to ensure good precision. Indeed, intra- and interassay coefficients of variation were, respectively, 8.7% and 9.9% at 0.5 Mg/L, and 5.3% and 7.1% at 5 Mg/L. All samples from the same subject were run in duplicate in the same assay, with a total of four assays. Care was taken to have an equal number of nonobese and obese subjects in each assay. Results were analyzed by the Student's t test for paired and unpaired data as well as by two-way analysis of variance. Data are presented as the mean ± SEM.
Results In the fasting state, plasma glucose averaged 4.8 ± 0.1 mmol/L among nonobese subjects and 4.9 ± 0.2 mmol/ L among obese patients. During the period between 20240 min of the study, plasma glucose averaged 11.2 ± 0.3 mmol/L in nonobese subjects (coefficient of variation, 9%) and 11.3 ± 0.2 mmol/L in obese patients (coefficient of variation, 7%). The amount of glucose required to maintain steady state hyperglycemia was significantly lower for obese than nonobese subjects, whether glucose was infused alone (20-120 and 180-240 min) or with somatostatin (120-180 min; data not shown). In the fasting state, obese and nonobese subjects had similar plasma GH concentrations (0.9 ± 0 . 1 vs. 0.8 ± 0.2 jug/L; P = NS). When the plasma glucose concentration was raised to approximately 11.2 mmol/L, the plasma GH concentration fell significantly (P < 0.05) in the nonobese, but not in the obese subjects (Fig. 1). In particular, during the 100- to 120-min period of the study, plasma GH averaged 0.8 ± 0 . 1 jug/L in obese patients and 0.5 ± 0.1 /ig/L in nonobese subjects (P < 0.01). The decline from basal levels was 6 ± 5% in obese and 35 ± 10% in nonobese subjects (P < 0.01). All plasma GH concentrations for nonobese subjects fell within the detection limits of the assay. During somatostatin administration, while stable hyperglycemia was maintained by glucose infusion, the plasma GH concentration did not change in either obese or nonobese subjects. In the 160- to 180-min period, GH averaged 0.8 ± 0.2 /ug/L in the former and 0.4 ±0.1 ng/ L in the latter group (P < 0.01). After interrupting somatostatin infusion, plasma GH levels rose significantly (P < 0.05) in both groups, averaging 3.8 ± 0.9
somatostatin.
120
210
240
TIME (min)
FIG. 1. Plasma GH concentrations during a 4-h hyperglycemic clamp in obese (T • • T) and nonobese (•-•) subjects. In the period between 120-180 min, somatostatin (2.5 nmol/min) was infused.
L in obese and Ml ± 3.8 ixg/L in nonobese subjects, during the 220-1 1240-min period. This difference, even though remarkaj i, did not reach statistical significance (0.05 < P < 0 . 1 > Analysis of vrt tnce showed that for the study period as a whole, pla^ la GH levels in nonobese and obese subjects were chif Jrent (P < 0.01). This difference was also apparent when the three study periods were analyzed separately: 60-120 min (P < 0.01), 120-180 min (P < 0.01), and 180-240 min (P < 0.05).
Discussion There are several studies demonstrating that obese subjects have blunted plasma GH responses to stimuli such as hypoglycemia, arginine, L-dopa, and exercise (3, 4). In contrast, there are few data about the impact of obesity on experimental GH suppression. To our knowledge, no data are available comparing plasma GH levels in obese and nonobese subjects during the iv administration of glucose or somatostatin. In the present study we compared plasma GH levels in obese and nonobese subjects during a hyperglycemic clamp, with or without combined somatostatin infusion. Our results indicate that in nondiabetic obese patients hyperglycemia does not decrease plasma GH levels to the same degree as in nonobese controls. Indeed, although hyperglycemia decreased plasma GH levels in nonobese subjects by 35%, the plasma GH levels of obese subjects
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1734
BONORA ET AL.
did not significantly change during the iv glucose infusion. Since insulin per se has no suppressive effect on GH release (8-10), the reduction of plasma GH observed in nonobese subjects can be attributed to hyperglycemia, rather than to glucose-induced hyperinsulinemia. Hyperglycemic clamp is a technique that allows generation of an increase in plasma glucose levels that is virtually identical in all subjects under examination. The increase over basal in plasma glucose concentration is predetermined by the operator. With the priming glucose infusion used in the present study, the hyperglycemic level is approximately 11 mmol/L. This level is 30-40% higher than that encountered in man under physiological conditions, i.e. after a meal. Thus, it remains to be determined if in obesity a more modest increase above basal in plasma glucose results in an impaired suppression of plasma GH levels. In regard to this, to our knowledge no data comparing postprandial plasma GH levels in obese and nonobese subjects are available in the literature. Our data suggest that in either nonobese or obese subjects somatostatin has no additive effect to that of hyperglycemia. Indeed, during hyperglycemia no change in plasma GH concentrations was detected when somatostatin was infused at a rate that usually generates supraphysiological plasma somatostatin concentrations (11). The impaired rise in plasma GH levels observed in obese subjects after somatostatin withdrawal is consistent with the well known blunting of GH release observed in obese subjects during exercise or hypoglycemia, or after the administration of arginine or L-dopa (3, 4). However, the increase in plasma GH levels that followed the discontinuation of somatostatin is difficult to explain, since somatostatin had no apparent effect on GH release during its administration with glucose. Perhaps somatostatin administration, although unable to further
JCE & M • 1990 Vol 70 • No 6
decrease plasma GH levels, interferred with the processes involved in GH secretion, so that the interruption of its infusion was immediately followed by a remarkable release of GH. In conclusion, this study suggests that 1) in human obesity, the GH-secreting cells or the hypothalamic cells involved in the regulation of GH secretion do not respond normally to hyperglycemia; and 2) somatostatin administration has no effect above that of hyperglycemia to inhibit GH release. The increase in plasma GH levels observed after somatostatin withdrawal remains to be elucidated. References 1. Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD, Broadus AE, Frohman L, eds. Endocrinology and metabolism. New York: McGraw-Hill; 1987;247-337. 2. Daughaday WH. The anterior pituitary. In: Wilson JD, Foster DW, eds. William's textbook of endocrinology. Philadelphia: Saunders; 1985;568-613. 3. Rabinowitz D. Some endocrine and metabolic aspects of obesity. Annu Rev Med. 1970;21:241-58. 4. Glass AR, Burman KD, Dahms WT, Boehm TM. Endocrine function in human obesity. Metabolism. 1981;30:89-104 5. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-57. 6. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214-23. 7. Boden G, Soeldner JS. A sensitive double antibody radioimmunoassay for HGH: levels of serum HGH following rapid tolbutamide infusion. Diabetologia. 1967;3:413-21. 8. Meneilly GS, Elahi D, Minaker KL, Rowe JW. Somatostatin does not alter insulin-mediated glucose disposal. J Clin Endocrinol Metab. l987;65:364-7. 9. Sharp PS, Mohan V, Maneschi F, et al. Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp. Metabolism. 1987;36:71-5. 10. Webb S, Wass LJAH, Llorens A, et al. Studies on the mechanisms of somatostatin release after insulin induced hypoglycemia in man. Clin Endocrinol (Oxf). 1984;21:667-75. 11. Adrian TE, Barnes AJ, Long RG, et al. The effect of somatostatin analogs on secretion of growth, pancreatic and gastrointestinal hormones in man. J Clin Endocrinol Metab. 1981;53:675-81.
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