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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2261-2265
Copyright © 1997 by The Endocrine Society

Experimental Studies

In Obesity, Glucose Load Loses Its Early Inhibitory, But Maintains Its Late Stimulatory, Effect on Somatotrope Secretion1

S. Grottoli, M. Procopio, M. Maccario, M. Zini, S. E. Oleandri, F. Tassone, R. Valcavi and E. Ghigo

Division of Endocrinology, Department of Internal Medicine, University of Torino, Torino; Second Division of Medicine and Endocrinology, Arcispedale of Santa Maria Nuova (M.Z., R.V.), Reggio Emilia, Italy

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so A.M. Dogliotti 14, 10126 Torino, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Glucose load has a biphasic effect on GH secretion. In fact, in normal subjects, glucose load has a prompt inhibitory and a late stimulatory effect on both spontaneous and GHRH-induced GH levels. The mechanism underlying the inhibitory effect is probably mediated by the increase in hypothalamic somatostatin, whereas that underlying the stimulatory effect is unclear. On the other hand, in obesity, a reduced somatotrope responsiveness to all GH secretagogues is well known, whereas recently, we found that glucose load, but not pirenzepine and somatostatin, fails to inhibit the GHRH-induced GH rise. Thus, the inhibitory effect of hyperglycemia on GH secretion is selectively lacking in obesity. The aim of the present study was to verify whether in obesity the late stimulatory effect of glucose on GH secretion is preserved. We studied 15 female obese patients (OB; age, 33.9 ± 2.6 yr; body mass index, 36.4 ± 1.5 kg/m2; waist/hip ratio, 0.9 ± 0.1) and 12 normal female subjects (NS; 26.5 ± 1.0 yr; 21.4 ± 0.3 kg/m2) as controls. Two studies were performed. In study A (six OB and six NS) we evaluated the somatotrope response to GHRH (1 µg/kg, iv, at 0 min) alone or preceded by oral glucose (OGTT; 100 g, orally, at -45 min). In study B (nine OB and six NS) we studied the somatotrope response to OGTT (100 g, orally, at 0 min), saline plus GHRH (1 µg/kg, iv, at 150 min), and OGTT plus GHRH. In study A, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT blunted the GHRH-induced GH rise in NS (0–90 min area under the curve, 318.9 ± 39.1 vs. 696.3 ± 110.8 µg/min·L; P < 0.05), but failed to modify it in OB (289.1 ± 51.7 vs. 283.9 ± 44.0 µg/min·L). In study B, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT induced a late GH increase in both NS (150–240 min area under the curve, 249.6 ± 45.2 µg/min·L) and OB (103.2 ± 31.4 µg/min·L). Moreover, OGTT enhanced the GHRH-induced GH rise in NS as well as in OB [1433.0 ± 202.0 vs. 967.9 ± 116.3 µg/min·L (P < 0.03) and 763.8 ± 131.0 vs. 278.1 ± 52.3 µg/min·L (P < 0.01), respectively]. The GH responses to OGTT alone and combined with GHRH in OB were lower (P < 0.03) than those in NS. Our data show that in human obesity, the oral glucose load loses its precocious inhibitory effect on the GHRH-induced GH rise but maintains its late stimulatory effect on somatotrope secretion. These findings suggest that the inhibitory and stimulatory effects of glucose load on GH secretion are unlikely to be due to biphasic modulation of hypothalamic somatostatin release, which seems selectively refractory to stimulation by hyperglycemia in obesity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE CONTROL of GH secretion is mainly exerted by the hypothalamus via GHRH and somatostatin, although also several neurotransmitters, hormones and metabolic fuels play important roles (1, 2). Among metabolic fuels, it is well known that glucose has a biphasic effect on somatotrope secretion (3, 4, 5). In fact, in normal subjects the glucose load has a precocious inhibitory effect and a late stimulatory effect on both basal and GHRH-stimulated GH secretion (6, 7, 8, 9, 10). The mechanism underlying the acute inhibitory effect is probably mediated by an increase in hypothalamic somatostatin release (11, 12), whereas that mediating the stimulatory influence is still unclear. Interestingly, the absence of a glucose-induced inhibitory effect has been demonstrated in several conditions of exaggerated GH secretion, such as acromegaly, diabetes mellitus type 1, hyperthyroidism, anorexia nervosa, and catabolic states as well as in newborns (13, 14, 15, 16, 17, 18, 19). In all of these conditions, the stimulatory effect was maintained, giving rise to the concept of the so-called paradoxical stimulatory effect.

Noteworthy, the inhibitory influence of glucose on GH secretion has been lacking even in obesity, a well known GH hyposecretory state (20, 21, 22, 23, 24, 25). In fact, neither hyperglycemic clamp nor oral glucose load is able to modify both basal and GHRH- as well as arginine-stimulated GH secretion in obese patients (24, 25). Actually, both GHRH- and arginine-stimulated GH secretion in obesity is normally inhibited by pirenzepine, a muscarinic antagonist, as well as by exogenous somatostatin administration (25). Thus, the refractoriness to the inhibitory effect of glucose load on GH secretion in obesity is selective.

On the other hand, nothing is known about the stimulatory effect of glucose in obesity. Thus, the aim of the present study was to verify whether the late stimulatory effect of glucose load on both basal and GHRH-induced GH secretion is preserved in patients with simple obesity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Fifteen women with simple obesity (OB; age, 33.9 \ 2.6 yr; body mass index, 36.4 \ 1.5 kg/m2; waist/hip ratio, 0.9 \ 0.1) and 12 normal women (NS; 26.5 \ 1.0 yr; 21.4 \ 0.3 kg/m2) were studied. All subjects gave their informed consent to participate in the study, which had been approved by our local ethical committee.

OB and NS women were divided into two groups. Subjects in group A (six OB and six NS) underwent the following two tests: GHRH (GHRH-29, GEREF, Serono, Milan, Italy; 1 µg/kg, iv, at 0 min) alone and preceded by an oral glucose load (OGTT; 100 g at -45 min). Subjects in group B (nine OB and six NS) underwent the following three tests: OGTT (at 0 min) and GHRH (at 150 min) preceded by saline and OGTT, respectively.

All tests were performed in the morning after an overnight fast, in random order, at least 3 days apart. Both NS and OB women were tested in their early follicular phase. Tests were begun between 0830–0900 h, 30 min after an indwelling catheter had been inserted into a cubital vein of the forearm, kept patent by a slow infusion of isotonic saline. Blood samples for GH and glucose measurements were taken every 15 min from -60 to 90 min during tests in group A and from 0–240 min during tests in group B.

A serum GH assay was performed in duplicate at each time point using an immunoradiometric assay method (GH-HCTK, Sorin, Saluggia, Italy). All samples from an individual subject were analyzed together. The sensitivity of the assay was 0.15 µg/L. The inter- and intraassay coefficients of variation were between 4.9–6.5% and between 1.5–2.9%, respectively. Basal serum insulin-like growth factor I (IGF-I) levels were assayed by RIA (Nichols Institute, San Juan Capistrano, CA) after acid-ethanol extraction. The inter- and intraassay coefficients of variations were 5.2–8.4% and 2.4–3.0%, respectively. Plasma glucose levels were measured by the glucose oxidase colorimetric method (GLUCOFIX, Menarini Diagnostics, Firenze, Italy).

The GH secretory responses were expressed either as absolute values (micrograms per L) or as areas under the curve (AUC; micrograms per min/L) calculated by trapezoidal integration. Undetectable GH levels were entered into AUC calculations as 0. Glucose (milligrams per dL) and IGF-I (micrograms per L) levels were expressed as absolute values.

Statistical evaluation of the data was carried out using nonparametric ANOVA (Kruskall-Wallis test) and signed Wilcoxon’s test where appropriate. Results are reported as the mean \ SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal GH levels in OB (0.8 \ 0.2 µg/L) were lower (P < 0.05) than those in NS (2.9 \ 1.2 µg/L), whereas IGF-I levels in OB and NS were similar (198.2 \ 18.6 and 225.6 \ 12.4 µg/L).

Group A

GHRH administration elicited a clear increase in GH levels in both NS (peak vs. basal, 10.4 \ 1.8 vs. 0.9 \ 0.1 µg/L; P < 0.01) and OB (6.0 \ 1.4 vs. 0.6 \ 0.3 µg/L; P < 0.05); however, the GH response in the latter group (AUC, 283.9 \ 44.0 µg/min·L) was significantly lower (P < 0.01) than that in the former (696.3 \ 110.8 µg/min·L; Fig. 1Go).



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  		Figure 1. Mean (±SEM) GH curves and AUCs after GHRH (at 0 min) administered alone and preceded by an oral glucose load (at -45 min) in NS and OB.

 
An oral glucose load blunted the GHRH-induced GH response in NS (318.9 \ 39.1 µg/min·L; P < 0.05), but failed to modify it in OB (289.1 \ 51.7 µg/min·L; Fig. 1Go).

No significant difference was found between the plasma glucose increase in OB and NS after OGTT.

Group B

An oral glucose load significantly inhibited basal GH levels in NS (nadir at 75 min vs. basal, 0.1 \ 0.0 vs. 2.0 \ 2.2 µg/L; P < 0.05), but not in OB (0.2 \ 0.3 vs. 0.5 \ 0.2 µg/L; Fig. 2Go).



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  		Figure 2. Mean (±SEM) GH curves after oral glucose (OGTT) administered alone (at 0 min) in NS and OB.

 
On the other hand, OGTT induced a late GH rise in OB (peak vs. basal, 2.5 \ 1.0 vs. 0.5 \ 0.2 µg/L; P < 0.03) as well as in NS (4.0 \ 1.2 vs. 2.0 \ 2.2 µg/L; P < 0.05). However, the GH increase in OB (150–240 min AUC, 103.2 \ 31.4 µg/min·L) was lower (P < 0.03) than that in NS (249.6 \ 45.2 µg/min·L). There was no difference between the Tmax (time maximum) in NS and OB after OGTT (Fig. 2Go).

GHRH administration induced a clear GH response in both NS (967.9 \ 116.3 µg/min·L; P < 0.03) and OB (278.1 \ 52.3 µg/min·L; P < 0.01); the GH response in NS was again higher (P < 0.01) than that in OB (Fig. 3Go).



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  		Figure 3. Mean (±SEM) GH curves and AUCs after oral glucose (at 0 min), GHRH (at 150 min), and OGTT plus GHRH in NS and OB.

 
After glucose administration, the GHRH-induced GH response was enhanced in both NS (1433.0 \ 202.0 µg/min·L; P < 0.03 vs. GHRH alone) and OB (763.8 \ 131.0 µg/min·L; P < 0.01). Again, the GH response in OB persisted at a lower level (P < 0.01) than that in NS (Fig. 3Go).

There was no difference in the Tmax (time maximum) after GHRH alone or combined with OGTT between NS and OB.

The OGTT-induced increase in plasma glucose levels was similar in both groups.

Mean plasma glucose levels and glucose AUC from 150–240 min in NS and OB did not significantly differ. None of the subjects had any significant postabsorptive hypoglycemia.

Side-effects

A transient facial flushing was observed after GHRH administration in three OB and four NS. OGTT produced no side-effects in either group.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates that in obesity, although the early inhibitory effect of glucose load on somatotrope secretion is lost, the late stimulatory one is maintained. In fact, as in normal subjects, a glucose load in obese patients is able to significantly increase both basal and GHRH-induced GH secretion, although to a lesser extent.

The prompt inhibitory effect of glucose load on both basal and stimulated GH secretion has been well known for many years (6, 7, 9, 13). The mechanism underlying the inhibitory effect of glucose load on somatotrope secretion is believed to be mediated by stimulation of hypothalamic somatostatin release (12, 13). In fact, in vitro, both basal and GHRH-stimulated GH release from rat anterior pituitary cells is not inhibited by different glucose concentrations (26, 27, 28). Moreover, in humans, glucose is able to inhibit even the GHRH-induced GH rise (29), and its effect is counteracted by arginine and pyridostigmine (11, 30), which probably act via inhibition of hypothalamic somatostatin release (31).

Previous data demonstrated that in obesity, OGTT loses its ability to inhibit both basal and GHRH-induced GH secretion (24, 25), which, on the other hand, is normally abolished by pirenzepine and exogenous somatostatin (25). These data pointed to selective refractoriness to the inhibitory effect of glucose on GH secretion in obesity, and our present results confirm those findings, although the lack of an inhibitory effect of glucose load on basal GH secretion should be verified using an ultrasensitive technique for GH assay (32). A peculiar inability of hyperglycemia to trigger somatostatinergic hyperactivity in obesity could explain the lack of the inhibitory effect of glucose load on GH secretion in obesity (25).

On the other hand, it is well known that glucose is endowed with a late stimulatory effect on both basal and GHRH-stimulated GH secretion (3, 4, 5, 8, 10). Interestingly, the stimulatory effect of glucose load on somatotrope secretion has been reported in childhood (10) and is present in newborns, in whom glucose does not inhibit GH secretion (19).

The stimulatory effect of glucose load on somatotrope secretion could be due to the inhibition of hypothalamic somatostatin release or to the end of somatostatinergic hyperactivity, which could trigger the firing of GHRH-secreting neurons (33, 34, 35, 36). On the other hand, even in absence of true hypoglycemia, the decay of OGTT-induced high plasma glucose levels or an {alpha}2-adrenergically mediated mechanism could mediate the stimulatory effect of OGTT (37, 38). Moreover, recent data support the hypothesis that the stimulatory effect of glucose on GH secretion could take place directly at the pituitary level (39).

Whatever the mechanism underlying the stimulatory effect of glucose, our present data demonstrate for the first time that the stimulatory effect of glucose in obesity is preserved despite the loss of its inhibitory effect. This evidence makes unlikely the hypothesis that the biphasic modulation of hypothalamic somatostatin release underlies the dual effect of glucose load on GH secretion in man. It is noteworthy that the persistence of the stimulatory, but not the inhibitory, effect of glucose load on somatotrope secretion in obesity, a well known condition of GH hyposecretion, recalls the pattern usually seen in several GH hypersecretory states (13, 14, 15, 16, 17, 18, 19). Thus, one could speculate that the stimulatory, more so than the inhibitory, effect is the constitutive effect of glucose in humans; in fact, the former is always present.

Actually, the stimulatory effect of glucose load on both basal and GHRH-induced GH secretion in obese patients is lower than that in normal subjects. This is in agreement with evidence showing the reduction of the GH response to all known secretagogues, including GH-releasing peptides (20, 21, 22, 23, 40). It should be noted that even the GH-releasing peptide-induced GH response is refractory to inhibition by glucose load in obesity (41).

In conclusion, our findings demonstrate that, similar to what was observed in GH hypersecretory states, in obesity, a GH hyposecretory state, a glucose load loses its inhibitory, but maintains its stimulatory, effect on both basal and GHRH-induced GH secretion.


   Acknowledgments
 
The authors thank Dr. R. Rossetto for her cooperation, and Mrs. M. Taliano for her skillful technical assistance.


   Footnotes
 
1 This work was supported by grants from MURST and FSMEM. Back

Received November 15, 1996.

Revised March 21, 1997.

Accepted March 31, 1997.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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