Adrenocortical Overexpression of Gastric Inhibitory Polypeptide Receptor Underlies Food-Dependent Cushing's Syndrome

N’Diaye, Nina

doi:10.1210/jc.83.8.2781

Cited by 72 publications

(65 citation statements)

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“…␤-and K-cell glucose resistance in IGT multiple other tissues such as adipocytes (26), adrenal glands (27), endothelium (28), and brain (29). Originally described as a "gastric inhibitory peptide" due to its potent inhibition of gastric acid secretion, GIP has other diverse effects.…”

Section: Modified Ogtt In Blsa Subjectsmentioning

confidence: 99%

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

et al. 2004

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OBJECTIVE -The role of gut-derived incretin, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]), in compensatory ␤-cell hypersecretion during insulin-resistant states and in transition to ␤-cell failure in type 2 diabetes is unknown.RESEARCH DESIGN AND METHODS -We carried out oral glucose tolerance testing followed by blood sampling 10 times for 2 h on 68 age-and BMI-matched participants of the Baltimore Longitudinal Study on Aging (BLSA) with normal glucose tolerance (34 subjects), impaired glucose tolerance (IGT) (18 subjects with both impaired fasting and 2-h plasma glucose levels), and type 2 diabetes (16 subjects with both diabetic fasting and 2-h plasma glucose levels). We assayed plasma glucose, insulin, C-peptide, glucagon, and intact and total GIP levels and quantitated glucose and hormone responses to the oral glucose tolerance test. We also compared GIP and insulin release and sensitivity indexes between groups.RESULTS -After glucose ingestion, subjects with IGT had both hyperinsulinemia and hyperemia, while subjects with type 2 diabetes had both ␤-and GIP-cell deficiency. In the former group, there was also a significant positive correlation between the augmented plasma intact and total GIP levels and both fasting and post-oral glucose load plasma insulin levels.CONCLUSIONS -Elevated plasma GIP levels are correlated with hyperinsulinemia in the impaired glucose-tolerant state, whereas type 2 diabetes is associated with a failure to secrete adequate amounts of both GIP and insulin, indicating a common pathway of resistance to and eventually failure of glucose responsiveness in ␤-and GIP-cells. Diabetes Care 27:1692-1698, 2004I n patients with type 2 diabetes, ␤-cells within the islets of Langerhans in the pancreas fail to meet the increased need for insulin created by the insulinresistant state (1). Before ␤-cell failure occurs, however, subjects compensate for insulin resistance for many years by increasing their secretory capacity, resulting in hyperinsulinemia (2). The failure of ␤-cells to continue to hypersecrete insulin underlies the conversion to clinical diabetes. The term enteroinsular axis (3) encompasses the neuro-humoral interactions long thought to exist between the endocrine pancreas and gut cell populations. In fact, the enteroendocrine system constitutes the largest system of endocrine cells in humans, both in terms of number of cells and variety of hormones produced (4). Islets of Langerhans also lie in this system, as well as the incretinproducing cells of the gut, which synthesize and release vital mediators of foodstimulated, glucose-dependent insulin secretion, which account for up to 60% of the insulin secretory response following an oral glucose load (5). The two main, if not the only physiologically relevant, incretins are glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]) and glucagonlike peptide-1 (GLP-1) (6,7). The proGIP gene is expressed in gut K-cells, the majority of which are located i...

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Section: Modified Ogtt In Blsa Subjectsmentioning

confidence: 99%

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

et al. 2004

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“…No duplications in 19q13. 32 were identified in 4 GIP nonresponsive adenoma samples and 11 GIP nonresponsive hyperplasia samples. The smallest regions of overlap (hg19 chr19: 46,167,704-46,268,140) encompassed 5 genes, namely GIPR, SNRPD2, QPCTL, FBXO46, and SIX5.…”

Section: Resultsmentioning

confidence: 99%

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Lecoq¹,

Stratakis²,

Viengchareun³

et al. 2017

JCI Insight

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“…In one patient with GIP-dependent AIMAH, the plasma ACTH and cortisol re-sponse to CRH was still preserved, presumably because the intermittent food-dependent stimulation of cortisol had not yet completely suppressed the hypothalamic-pituitary-adrenal axis (21). Recent molecular analyses indicate that the pathological adrenal tissues of the patients with GIP-dependent Cushings syndrome highly overexpressed GIP receptors which were not mutated (17,(20)(21)(22)(23)(24)(25); a very weak expression was found in the normal human adrenals (25), but was not efficiently coupled to steroidogenesis. The overexpression of GIP receptors was found to be present even in the early stages of adrenal hyperplasia (17).…”

Section: Resultsmentioning

confidence: 99%

The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

Lacroix

N’Diaye

Mircescu

et al. 2000

Braz J Med Biol Res

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Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP)-dependent Cushings syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushings syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushings syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ß-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

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Adrenocortical Overexpression of Gastric Inhibitory Polypeptide Receptor Underlies Food-Dependent Cushing's Syndrome

Cited by 72 publications

References 0 publications

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

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