Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway

doi:10.1016/S0196-9781(99)00011-X

Peptides

Volume 20, Issue 5, June 1999, Pages 589-594

https://doi.org/10.1016/S0196-9781(99)00011-X Get rights and content

Abstract

Gastric inhibitory polypeptide (GIP) is a 42-amino acid peptide, belonging to the VIP-secretin-glucagon superfamily, some members of this group are able to regulate adrenocortical function. GIP-receptor mRNA has been detected in the rat adrenal cortex, but investigations on the effect of GIP on steroid-hormone secretion in this species are lacking. Hence, we have investigated the distribution of GIP binding sites in the rat adrenal gland and the effect of their activation in vivo and in vitro. Autoradiography evidenced abundant [¹²⁵I]GIP binding sites exclusively in the inner adrenocortical layers, and the computer-assisted densitometric analysis of autoradiograms demonstrated that binding was displaced by cold GIP, but not by either ACTH or the selective ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP). The intraperitoneal (IP) injection of GIP dose-dependently raised corticosterone, but not aldosterone plasma concentration: the maximal effective dose (10 nmol/rat) elicited a twofold increase. GIP did not affect aldosterone and cyclic-AMP release by dispersed zona glomerulosa cells. In contrast, GIP enhanced basal corticosterone secretion and cyclic-AMP release by dispersed inner adrenocortical cells in a concentration-dependent manner, and the maximal effective concentration (10⁻⁷ M) evoked 1.5- and 2.4-fold rises in corticosterone and cyclic-AMP production, respectively. GIP (10⁻⁷ M) did not display any additive or potentiating effect on corticosterone and cyclic-AMP responses to submaximal or maximal effective concentrations of ACTH. The corticosterone secretagogue action of 10⁻⁷ M GIP was abolished by the protein kinase A (PKA) inhibitor H-89 (10⁻⁵ M), and unaffected by CIP (10⁻⁶ M). Collectively, these findings indicate that GIP exerts a moderate but statistically significant stimulatory effect on basal glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase/PKA-dependent signaling pathway.

Introduction

Gastric inhibitory polypeptide (GIP) is a 42-amino acid residue gastrointestinal peptide belonging to the VIP-secretin-glucagon superfamily, that inhibits gastric acid secretion and stimulates pancreatic insulin release in the presence of glucose (for review, see Refs. [8], [25], [27]).

In keeping with the fact that some members of the VIP-secretin-glucagon peptide family (e.g. VIP and PACAP) are able to modulate adrenal secretory activity (reviewed in Refs. [19], [20]), several clinical studies suggested the existence of a food/GIP-dependent Cushing’s syndrome [4], [7], [10], [13], [21]. In some cases of nodular adrenal hyperplasia, the IV infusion of GIP was found to increase plasma cortisol level, and the same effect was exerted by a meal. A close direct correlation was observed between the circulating levels of cortisol and GIP, and dispersed cells obtained from hyperplastic, but not normal adrenals evidenced a higher cortisol secretory response to GIP than ACTH. In situ hybridization revealed the presence of abundant GIP-receptor gene transcripts in an adrenocortical adenoma [7], thereby suggesting that food-dependent Cushing’s syndrome may result from hyper-responsiveness of adrenal tumor cells to GIP.

In contrast with the clinical studies, experimental investigations dealing with the possible functional interrelationships between adrenals and GIP are lacking, despite the fact that GIP-receptor mRNA has been demonstrated in the rat adrenal cortex [22]. Therefore, it seemed worthwhile to study the distribution of GIP binding sites in the rat adrenal gland, and to ascertain whether this peptide is able to affect steroid-hormone secretion in vivo and in vitro.

Section snippets

Animals and reagents

Adult male Wistar rats (260 ± 30 g in b.wt.) were purchased from Charles River (Como, Italy). The animals were housed 4 per cage, kept under 12:12 h light-dark cycle (illumination onset at 8:00 a.m.) at 23°C, and maintained on a standard diet (Rat–Mouse Chow; Charles River) and tap water ad lib. The study protocol followed the local ethical committee guideline for animal studies. Human GIP, [¹²⁵I]GIP, ACTH, and corticotropin-inhibiting peptide (CIP) were purchased from Peninsula Labs (St.

Autoradiography

[¹²⁵I]GIP binding sites were exclusively present in the inner adrenocortical layers (Fig. 1 A), and were almost completely displaced by addition of an excess of cold GIP (Fig. 1B). Both ACTH (data not shown) and CIP were ineffective (Fig. 1C). Quantitative densitometric analysis of autoradiograms confirmed these qualitative descriptions: they also showed that GIP concentration-dependently [F(4,24 = 5.81, P < 0.01] displaced 10⁻⁷ M [¹²⁵I]GIP binding, IC₅₀ being 4.2 ± 0.5 × 10⁻⁸ M (Fig. 2).

Steroid secretion

Discussion

Our autoradiographic findings show that rat ZF/R cells not only express GIP receptor mRNA [22], but also are provided with specific [¹²⁵I]GIP binding sites. In contrast, ZG cells do not possess GIP receptors, and accordingly GIP exerts a significant glucocorticoid, but not mineralcorticoid secretagogue action in the rat both in vivo and in vitro. Previous studies did not show any secretory response of dispersed human adrenocortical cells to GIP [7], and we tentatively assume that inter-species

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Gastric inhibitory polypeptide (GIP) is best known as an incretin hormone released by enteroendocrine K-cells in response to feeding and stimulates insulin release to regulate blood glucose and nutrient homeostasis. More recently GIP has been ascribed a positive role in lipid metabolism, bone strength, cardiovascular function and cognition. The present paper considers an emerging role of GIP and related gut hormones in fertility and especially polycystic ovarian syndrome (PCOS). Key evidence concerns restoration of fertility in women with gross obesity and PCOS following bariatric surgery. This is considered to reflect indirect effects mediated by alleviation of insulin resistance together with possible direct effects of surgically induced changes of GIP, GLP-1 and related peptide hormones on ovaries and the hypothalamic-pituitary-adrenal axis. Further studies are required to determine inter-relationships between the hormones and cellular mechanisms involved but these observations suggest that GIP and other gut may provide a novel therapeutic approach for PCOS and other reproductive disorders.
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This has led to the hypothesis that the antagonism of GIPR may protect against GIP-mediated glucocorticoid release post-nutrient ingestion [11]. In rodents, where Gipr is expressed in the adrenal cortex of healthy animals [41], however, supplementation of corticosterone in Gipr knock out animals subjected to a high fat diet did not affect body weight [11], perhaps suggesting that GIP’s effects on body weight are not primarily mediated via the HPA axis. In agreement with GIP’s anti-apoptotic role in pancreatic beta cells, osteoblasts, and vascular endothelial cells [42,43], GIPR signaling may also promote cellular survival and regenerative capacity in the nervous system.
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone released from the epithelium of the upper small intestine. While GIP shares common actions on the pancreatic beta cell with glucagon-like peptide-1 (GLP-1), unlike GLP-1, GIP presents a complex target for the development of diabetes and obesity therapies due to its extra-pancreatic effects on fat mass. Recent pharmacological developments, however, have provided insight into a previously unrecognized role for GIP receptor (GIPR) signaling in regulating appetite. Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP. In this review, we discuss what is currently known about where GIP may act in the central nervous system (CNS), the characteristics of its target cell populations, and the physiological effects of manipulating the activity Gipr-expressing cells in the brain.
Toxic Responses of the Adrenal Cortex
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The adrenal gland is reported to be the most common toxicological target organ within the endocrine system. It is a vital organ with universal steroidogenic capability and there are well-described cases of human drug-induced adrenocortical toxicity, typically resulting from unpredicted enzyme inhibition. Adrenal hypertrophy/adrenocortical cellular hypertrophy are common findings in toxicity studies and also often incorrectly attributed to “stress”: these findings should not be attributed to stress unless there is clear evidence that the adrenal cortex is also functional. This article reviews the endocrinology of the hypothalamo-pituitary–adrenocortical system and steroidogenesis identifying the many potential physiological and molecular targets for toxicity and also factors predisposing the adrenal to toxic insult. In vivo assessment models and strategies are reviewed including species differences and the effects of age and gender. The need for proper examination of the mechanistic cause of adrenal hypertrophy (which usually results from excess adrenocorticotrophic hormone (ACTH) secretion) is discussed in terms of comparison of the more benign excess ACTH drive due to stress with the more sinister effect of adrenocortical steroidogenic inhibition and insufficiency which results in a loss of glucocorticoids, reduced feedback inhibition, and unrestrained ACTH stimulation of the adrenal. In vitro models and the use of human cell lines in both screening and mechanism elucidation are also discussed. Examples and mechanisms of toxic responses of the adrenal cortex are given. The focus is on the adrenal cortex as a toxicological target but adrenocortical and glucocorticoid modulation of the response to toxic insult is also discussed: adrenal functional activation is one of the most vital physiological responses after infection or injury, including toxic insult, and the action of the glucocorticoids can profoundly alter the response to toxic insult. Human adrenocortical dysfunction is discussed, both from the point view of drugs that are known to cause adrenocortical toxicity (e.g., etomidate, aminoglutethimide, synthetic steroids which all have different mechanisms) and as a means of identifying the consequences of disruption of specific molecular targets important in health and disease from which mechanisms of toxicity can be inferred. Finally, environmental evidence increased the awareness and concern of endocrine disruption through estrogenic mechanisms and the evidence for adrenal toxicity and reduced survival fitness in environmentally important sentinel species such as fish and birds is also reviewed.
Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties
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Bone remodeling is under complex regulation from nervous, hormonal and local signals, including gut hormones. Among the gut hormones, a role for the glucose-dependent insulinotropic polypeptide (GIP) has been suggested. However, the rapid degradation of GIP in the bloodstream by the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) precludes therapeutic use. To circumvent this problem, a series of N-terminally modified GIP agonists have been developed, with N-AcGIP being the most promising. The aims of the present study were to investigate the effects of N-AcGIP on bone at the micro-level using trabecular and cortical microstructural morphology, and at the tissue-level in rats. Copenhagen rats were randomly assigned into control or N-AcGIP-treated groups and received daily injection for 4 weeks. Bone microstructural morphology was assessed by microCT and dynamic histomorphometry and tissue-level properties by nanoindentation, qBEI and infra-red microscopy. Four week treatment with N-AcGIP did not alter trabecular or cortical microstructural morphology. In addition, no significant modifications of mechanical response and properties at the tissue-level were observed in trabecular bone. However, significant augmentations in maximum load (12%), hardness (14%), indentation modulus (13%) and dissipated energy (16%) were demonstrated in cortical bone. These beneficial modifications of mechanical properties at the tissue-level were associated with increased mineralization (22%) and collagen maturity (13%) of the bone matrix. Taken together, the results support a beneficial role of GIP, and particularly stable analogs such as N-AcGIP, on tissue material properties of bone.
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Glucose-dependent insulinotropic polypeptide receptors (GIPR) are expressed throughout the body. The expression of its ligand, glucose-dependent insulinotropic polypeptide (GIP) however, has only been reported in a limited numbers of organs. Although the rat submandibular salivary gland (SMG) has been found to express GIP, its biological role is still not understood. Moreover, nothing is known about the expression of GIP in other types of salivary glands, i.e. the parotid (PG) and sublingual (SLG) glands. We detected the expression of GIP mRNA in the rat PG, SMG and SLG. Immunohistochemical analyses revealed that GIP and GIPR were expressed only in the ductal area of all types of major salivary glands, and no immunostaining was found in the acini area. We also found GIP expression in the rat SMG to be age dependent, with 8-week-old rats showing 2–3-fold higher than those of 9- and 11-week-old rats, respectively. This is the first study to indicate both GIP and GIPR expression in the rat major salivary glands, as well as its variation in the rat SMG during the growth period. These findings are crucial for a better understanding of the physiological function of GIP in rat major salivary gland.
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The adrenal gland is reported to be the most common toxicological target organ within the endocrine system. It is a vital organ with universal steroidogenic capability and there are well-described cases of human drug-induced adrenocortical toxicity, typically resulting from unpredicted enzyme inhibition. This chapter reviews the endocrinology of the hypothalamo-pituitary-adrenocortical system and steroidogenesis identifying the many potential physiological and molecular targets for toxicity and also factors predisposing the adrenal to toxic insult. In vivo assessment models and strategies are reviewed including species differences and the effects of age and gender. The need for proper examination of the mechanistic cause of adrenal hypertrophy (which usually results from excess adrenocorticotrophic hormone (ACTH) secretion) is discussed in terms of comparison of the more benign excess ACTH drive due to stress with the more sinister effect of adrenocortical steroidogenic inhibition and insufficiency which results in a loss of glucocorticoids, reduced feedback inhibition, and unrestrained ACTH stimulation of the adrenal. In vitro models and the use of human cell lines in both screening and mechanism elucidation are also discussed. Examples and mechanisms of toxic responses of the adrenal cortex are given. The focus is on the adrenal cortex as a toxicological target but adrenocortical and glucocorticoid modulation of the response to toxic insult is also discussed: adrenal functional activation is one of the most vital physiological responses after infection or injury, including toxic insult, and the action of the glucocorticoids can profoundly alter the response to toxic insult. Human adrenocortical dysfunction is discussed, both from the point view of drugs that are known to cause adrenocortical toxicity (e.g., etomidate, aminoglutethimide, synthetic steroids which all have different mechanisms) and as a means of identifying the consequences of disruption of specific molecular targets important in health and disease from which mechanisms of toxicity can be inferred. Finally, environmental evidence increased the awareness and concern of endocrine disruption through estrogenic mechanisms and the evidence for adrenal toxicity and reduced survival fitness in environmentally important sentinel species such as fish and birds is also reviewed.

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Original ArticlesGastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway

Abstract

Introduction

Section snippets

Animals and reagents

Autoradiography

Steroid secretion

Discussion

J Steroid Biochem Mol Biol

Front Neuroendocrinol

Rev Med Interne

J Steroid Biochem Mol Biol

Cell Signal

Peptides

FEBS Lett

Genomics

Interleukin-1 (IL-1)β enhances corticosterone secretion by acting directly on the rat adrenal gland

Endocrinology

Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats

Hypertension

New causes of Cushing’s syndrome

N Engl J Med

Gastric inhibitory polypeptide (GIP)isolation, structure, and basic functions

Food dependent Cushing syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells

J Clin Endocrinol Metab

Original Articles
Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway