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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4268-4272
Copyright © 2003 by The Endocrine Society

Effects of Ghrelin on the Insulin and Glycemic Responses to Glucose, Arginine, or Free Fatty Acids Load in Humans

F. Broglio, C. Gottero, A. Benso, F. Prodam, S. Destefanis, C. Gauna, M. Maccario, R. Deghenghi, A. J. van der Lely and E. Ghigo

Division of Endocrinology and Metabolism (F.B., C.Go., A.B., F.P., S.D., M.M., R.D., E.G.), Department of Internal Medicine, University of Turin, 10126 Torino, Italy; and Division of Endocrinology (F.B., C.Ga., A.J.v.d.L.), Department of Internal Medicine, Erasmus University of Rotterdam, 3015 Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Division of Endocrinology and Metabolism Department of Internal Medicine, University of Turin Corso Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin possesses central and peripheral endocrine actions including influence on the endocrine pancreatic function. To clarify this latter ghrelin action, in seven normal young subjects [age (mean ± SEM), 28.3 ± 3.1 yr; body mass index, 21.9 ± 0.9 kg/m2), we studied insulin and glucose levels after acute ghrelin administration (1.0 µg/kg iv) alone or combined with glucose [oral glucose tolerance test (OGTT), 100 g orally], arginine (ARG, 0.5 g/kg iv) or free fatty acid (FFA, Intralipid 10%, 250 ml). Ghrelin inhibited (P < 0.05) insulin and increased (P < 0.05) glucose levels. OGTT increased (P < 0.01) glucose and insulin levels. FFA increased (P < 0.05) glucose but did not modify insulin levels. ARG increased (P < 0.05) both insulin and glucose levels. Ghrelin did not modify both glucose and insulin responses to OGTT as well as the FFA-induced increase in glucose levels; however, ghrelin administration was followed by transient insulin decrease also during FFA. Ghrelin blunted (P < 0.05) the insulin response to ARG and enhanced (P < 0.05) the ARG-induced increase in glucose levels. In all, ghrelin induces transient decrease of spontaneous insulin secretion and selectively blunts the insulin response to ARG but not to oral glucose load. On the other hand, ghrelin raises basal glucose levels and enhances the hyperglycemic effect of ARG but not that of OGTT. These findings support the hypothesis that ghrelin exerts modulatory action of insulin secretion and glucose metabolism in humans.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN IS A 28-amino acid peptide predominantly produced by the stomach, although its expression has been demonstrated also in bowel, pancreas, kidneys, placenta, gonads, pituitary, and hypothalamus (1, 2, 3, 4). Ghrelin has been discovered as a natural ligand of the orphan GH secretagogues (GHS) receptor (GHS-R) type 1a that, in turn, had been shown specific for synthetic GHS (2, 3, 5). Like synthetic GHS, ghrelin possesses a strong GH-releasing effect in humans as well as in animal, although acylation in Serine 3 is needed for its activity (6, 7).

GHS-Rs are particularly concentrated in the hypothalamus-pituitary unit but are present also in other areas of the central nervous system as well as in peripheral, endocrine, and nonendocrine tissues including the endocrine pancreas (2, 3, 4, 8, 9). This GHS-R distribution explains the GH-releasing effect but also other endocrine and nonendocrine ghrelin actions (3, 10, 11). The latter include: 1) stimulation of lactotroph and corticotroph secretion but inhibition of gonadal axis; 2) orexant activity coupled with control of energy expenditure; and 3) control of gastric motility and acid secretion as well as of exocrine and endocrine pancreatic functions (3, 10, 11, 12).

Circulating ghrelin levels, mostly represented by its unacylated form, are increased by fasting and energy restriction but decreased by food intake, glucose, insulin, and somatostatin (13, 14, 15). In agreement with the major influence of nutrition on ghrelin secretion, circulating ghrelin levels are increased in anorexia and cachexia but reduced in obesity (14, 15, 16, 17, 18); in these conditions, ghrelin levels are restored to normal by the recovery of ideal body weight (17, 18). The ghrelin changes in response to variations in the nutritional state are opposite to those of leptin, and it has been suggested that both hormones act as signals of the metabolic balance and managing the neuroendocrine and metabolic response to starvation (11, 19).

There is clear negative association between ghrelin and insulin secretion (13, 16, 20) that would reflect the inhibitory influence of insulin on ghrelin synthesis and secretion (21, 22). On the other hand, ghrelin is expressed within the endocrine pancreas, although its expression has been variably localized by immunohistochemistry in human and rat {alpha}-cells (23), or in human ß-cells (9) or even in non-{alpha} non-ß-cells in human pancreas (24). Regarding the influence of ghrelin on insulin secretion, conflicting results have been reported by studies in animals, probably depending on different study protocols. In animals, some studies reported some stimulatory influence of ghrelin on insulin secretion from isolated rat pancreatic islets (23) and in rats in vivo (25, 26). Then it has been demonstrated that ghrelin blunts insulin secretion from isolated rat pancreas, perfused in situ after stimulation with glucose, arginine (ARG), and carbachol (27). Moreover, ghrelin exerts dose-dependent inhibition of the glucose-stimulated insulin secretion in mice in vivo (28).

In agreement with these latter studies in animals, various studies in humans showed that acute administration of ghrelin, but not that of peptidyl GHS, is followed by increase in glucose levels coupled with transient decrease in insulin secretion (29, 30, 31). In all, studies performed so far indicate the existence of some functional link between ghrelin and the endocrine pancreas that is, however, still unclear.

To clarify the influence of ghrelin on the endocrine pancreas in humans, we studied the effects of acute ghrelin administration on the insulin and glucose responses to oral glucose or iv ARG or free fatty acids (FFAs) load in normal young volunteers.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Seven healthy young male volunteers [age (mean ± SEM), 28.3 ± 3.1 yr; body mass index, 21.9 ± 0.9 kg/m2] were studied. All subjects gave their written informed consent to participate in the study, which had been approved by an independent Ethical Committee.

All subjects underwent the following nine testing sessions in random order and at least 3 d apart: 1) saline (3 ml iv at 0 min as a bolus); 2) ghrelin (1.0 µg/kg iv at 0 min as a bolus); 3) oral glucose load [oral glucose tolerance test (OGTT), 100 g via oral route at 0 min]; 4) ARG (0.5 g/kg iv from 0 min to +30 min); 5) lipid-heparin (FFA, Intralipid 10% 250 ml from 0 min to +120 min); 6) OGTT + ghrelin (1.0 µg/kg iv at 0 min as a bolus); 7) OGTT + ghrelin (1.0 µg/kg iv at +45 min as a bolus); 8) ARG + ghrelin (1.0 µg/kg iv at 0 min as a bolus); and 9) FFA + ghrelin (1.0 µg/kg iv at +30 min as a bolus).

After overnight fasting, the tests were begun in the morning at 0830–0900 h, 30 min after an indwelling catheter had been placed into an antecubital vein of the forearm kept patent by slow infusion of isotonic saline.

Blood samples were taken every 15 min from -15 up to +120 min. Insulin and glucose levels were assayed at each time point in all sessions.

Glucose levels (mg/dl; 1 mg/dl = 0.05551 mmol/liter) were measured by gluco-oxidase colorimetric method (GLUCOFIX, Menarini Diagnostici, Florence, Italy).

Insulin levels (mU/liter; 1 mU/liter = 7.175 pmol/liter) were measured in duplicate by immunoradiometric assay (INSIK-5, SORIN Biomedica, Saluggia, Italy). The sensitivity of the assay was 2.5 ± 0.3 mU/liter. The inter- and intraassay coefficients of variation were 6.2–10.8% and 5.5–10.6%, respectively.

GH levels (µg/liter) were measured in duplicate by immunoradiometric assay (hGH-CTK IRMA, SORIN Biomedica). The sensitivity of the assay was 0.15 µg/liter. The inter- and intraassay coefficients of variation were 2.9–4.5% and 2.4–4.0%, respectively.

Cortisol levels (µg/liter; 1 µg/liter = 2.759 nmol/liter) were measured in duplicate by RIA (CORT-CTK 125, IRMA, SORIN Biomedica). The sensitivity of the assay was 4.0 µg/liter. The inter- and intraassay coefficients of variation ranged from 6.6–7.5% and from 3.8–6.6%, respectively.

All samples from an individual subject were analyzed together.

The hormonal responses are expressed as {Delta} vs. baseline values and areas under curves ({Delta} AUC) calculated by trapezoidal integration.

The statistical analysis was carried out using a nonparametric ANOVA (Friedman test) and then by Wilcoxon matched pairs test.

Results are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Saline administration did not significantly modify insulin [{Delta}AUC (mean ± SEM), 6.6 ± 82.1 mU/min·liter] and glucose (-73.7 ± 84.9 mg/min·dl) levels.

The acute administration of ghrelin alone was followed by significant (P < 0.05), transient reduction of insulin levels (-38.1 ± 108.6 mU/min·liter) that was preceded by significant (P < 0.05), persistent increase in blood glucose levels (288.2 ± 419.0 mg/min·dl). As expected, ghrelin administration was followed also by significant increase (P < 0.01) of GH (5424.4 ± 899.5 µg/min·liter) and cortisol levels (2530.7 ± 3610.6 µg/min·liter).

OGTT induced obvious increase (P < 0.01) in glucose (3627.0 ± 396.1 mg/min·dl) and insulin (7242.3 ± 812.8 mU/min·liter) levels (Fig. 1Go).



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  		FIG. 1. Mean (±SEM) {Delta} insulin and glucose levels after oral glucose load (OGTT, 100 g via oral route at 0 min) alone or in coadministration with ghrelin (1.0 µg/kg iv at 0 min or +45 min as a bolus) in normal subjects.

 
Lipid-heparin infusion induced a significant (P < 0.05) progressive increase in glucose levels (1476.0 ± 528.5 mg/min·dl) without any significant change in insulin secretion (30.3 ± 100.5 mU/min·liter) (Fig. 2Go).



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  		FIG. 2. Mean (±SEM) {Delta} insulin and glucose levels after lipid-heparin (FFA, Intralipid 10% 250 ml from 0 min to +120 min) alone or in coadministration with ghrelin (1.0 µg/kg iv at +30 min as a bolus) in normal subjects.

 
As expected, ARG infusion increased (P < 0.05) both insulin (1463.7 ± 226.4 mU/min·liter) and glucose (525.0 ± 233.8 mg/min·dl) levels (Fig. 3Go).



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  		FIG. 3. Mean (±SEM) {Delta} insulin and glucose levels after ARG (0.5 g/kg iv from 0 min to +30 min) alone or in coadministration with ghrelin (1.0 µg/kg iv at 0 min as a bolus) in normal subjects.

 
The glucose and insulin responses to OGTT were unchanged by ghrelin administration, either when ghrelin was simultaneously administered with OGTT at time 0 min (glucose, 4378.8 ± 1421 mg/min·dl; insulin, 7878.0 ± 1020.5 mU/min·liter) or when ghrelin was injected 45 min after glucose ingestion (glucose, 3067.5 ± 1994.2 mg/min·dl; insulin, 8423.9 ± 1547 mU/min·liter) (Fig. 1Go).

The significant increase in glucose levels induced by lipid-heparin was not modified by ghrelin administration (2006.3 ± 472.4 mg/min·dl). Even during lipid-heparin infusion, ghrelin administration was followed by significant reduction in insulin levels (-282.5 ± 68.3 mU/min·liter; P < 0.05) (Fig. 2Go).

On the other hand, the insulin response to ARG was blunted by ghrelin administration (311.0 ± 313.4 mU/min·liter; P < 0.05). The blunting effect of ghrelin on the insulin response to ARG was coupled with a more remarkable increase in glucose levels (1078.5 ± 360.5 mg/min·dl; P < 0.05) (Fig. 3Go).

Side effects

Four of seven subjects after ghrelin administration and three of seven after the administration of ghrelin and ARG administration reported feeling hungry at the end of the testing session. Transient facial flushing was recorded in two of seven subjects after ARG administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study in humans demonstrate that the acute administration of acylated ghrelin specifically blunts the ARG-induced insulin increase while enhancing the hyperglycemic effect of the amino acid. In fact, acute ghrelin administration does not modify the insulin and glucose responses to oral glucose load. On the other hand, ghrelin shows transient inhibitory effect on insulin secretion coupled with increase in glucose levels that persists unmodified during infusion of lipids.

In addition to strong GH-releasing effect, ghrelin and synthetic GHS possess other central and peripheral actions in agreement with the widespread distribution of GHS-R in central and peripheral, endocrine and nonendocrine tissues (3, 4, 32). These actions include: 1) stimulatory effect on the hypothalamus-pituitary-adrenal axis; 2) central orexigenic effect and influence on energy balance; and 3) gastroenteropancreatic actions including impact on exocrine and endocrine pancreatic function (3, 10, 11, 12). Interestingly, it has been demonstrated that the central cholinergic system plays major role in mediating some ghrelin actions including stimulatory influence on GH secretion, appetite, and gastric motility and acid secretion (25, 33, 34); however, the endocrine response to ghrelin in humans has been found basically refractory to cholinergic agonists and antagonists (35).

Expression of both ghrelin and GHS-R within the endocrine pancreas has been demonstrated (4, 8, 9, 23, 24, 26). It had been already demonstrated that synthetic GHS have influence on insulin secretion and glucose metabolism in humans as well as in animals (23, 24, 25, 26, 29, 36, 37, 38, 39). Prolonged treatment with GHS had been followed by hyperglycemia in obese rats, and this effect was supposed to reflect GHS-induced enhancement in the activity of hypothalamo-pituitary-adrenal axis (39). Chronic treatment with MK-0677, a nonpeptidyl GHS, in normal elderly subjects as well as in GHD patients was coupled with hyperglycemia and hyperinsulinism in some subjects, but this effect was supposed to reflect increased GH secretion (36, 38). Again, chronic treatment with MK-0677 impaired glucose tolerance in obese subjects (37). On the other hand, although prolonged treatment with hexarelin, a peptidyl GHS, in elderly subjects did not modify glucose metabolism (40), acute GH releasing peptide-6 administration was associated to worsening in insulin sensitivity after fasting or pretreatment with GH antagonist in normal subjects as well as in patients with severe GH deficiency (41).

More recently, other data reinforced the hypothesis that there is a functional link between ghrelin and the endocrine pancreas. In animals, some studies reported some stimulatory influence of ghrelin on insulin secretion from isolated rat pancreatic islets (23) and in rats in vivo (25, 26). Then, it has been demonstrated that ghrelin blunts insulin secretion from isolated rat pancreas, perfused in situ after stimulation with glucose, ARG, and carbachol (27). Moreover, ghrelin exerts dose-dependent inhibition of the glucose-stimulated insulin secretion in mice in vivo (28).

In humans, the acute administration of ghrelin, but not of the peptidyl GHS hexarelin that has similar GH- and cortisol-releasing effect, induces hyperglycemia followed by transient inhibition of insulin decrease (29, 30, 31). That ghrelin transiently inhibits insulin secretion despite significant rise in glucose levels is confirmed also by the present study showing also that this effect is unchanged during exposure to FFA load.

Herein we show that ghrelin administration blunts the ARG-induced insulin increase while enhancing the hyperglycemic effect of the amino acid. This effect seems specific because no change in insulin and glucose responses to oral glucose load was found after ghrelin. The modulation of the insulin and glucose response to ARG by ghrelin agrees with a study in animal (27). On the other hand, the lack of any effect of ghrelin on the OGTT-induced insulin and glucose responses does not agree with previous animal studies (27, 28). It remains to be verified whether continuous exposure to infusion of higher ghrelin doses would affect also the gluco-insulinemic response to glucose load.

The mechanisms by which ghrelin modulates the gluco-insulinemic response to ARG remains unclear. It is unlikely that they include impact on concomitant increase in GH and cortisol levels; in fact, as anticipated, peptidyl GHS do not affect at all insulin secretion and glucose levels despite similar GH and cortisol responses. It might be speculated that the expression of ghrelin and GHS-R within the endocrine pancreas suggests direct auto/paracrine influence of ghrelin on ß-cell secretion (4, 8, 9, 23, 24, 26). Were this the case, it remains to be explained why ghrelin selectively modulates the gluco-insulinemic response to ARG only.

The modulatory effect of L-ARG on insulin secretion has been demonstrated to be mainly mediated by ß-cell uptake of the positively charged L-ARG molecule followed by depolarization of the plasma membrane (42, 43). As L-ARG is unable to potentiate the glucose-induced insulin secretion in experimental conditions of maximal depolarization by K+ (43), it would be theoretically possible that ghrelin may act via depolarization of ß-cells. In agreement with this hypothesis, it has recently reported that ghrelin inhibits K+-induced insulin secretion in murine pancreatic islets independently of glucose concentrations (28).

On the other hand, a functional relationship between ghrelin and somatostatin has been demonstrated. Somatostatin inhibits ghrelin secretion that, in turn, has been found able to enhance somatostatin release in either animals or in humans (30, 44, 45, 46). The possibility that ghrelin-induced increase in circulating somatostatin levels would have a role in the blunted insulin response to ARG remains to be verified.

Finally, the possibility that ghrelin negatively influence insulin secretion via unknown mechanisms mediated by other gastro-entero-pancreatic hormones affecting ß-cell function has also to be considered (47).

Independently of speculations about the mechanisms of action, the present study shows that ghrelin specifically modulated the gluco-insulinemic response to ARG in humans. These findings further suggest the existence of a functional link between ghrelin and the endocrine pancreas though it has to be taken into account that this pharmacological study does not definitely provide physiological information.


   Acknowledgments
 
We thank Prof. F. Camanni for his support to the study and for revising the manuscript. The skillful technical assistance of Dr. A. Bertagna, Mrs. A. Barberis, and Mrs. M. Taliano is also acknowledged.


   Footnotes
 
The present study was supported by Eureka Project (Peptido 1923), Ministero dell’Università e della Ricerca Scientifica, University of Turin and Fondazione per lo Studio delle Malattie Endocrino.

Abbreviations: ARG, Arginine; FFA, free fatty acid; GHS, GH secretagogues; GHS-R, GHS receptor; OGTT, oral glucose tolerance test.

Received December 10, 2002.

Accepted May 27, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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