The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp− somatotropinomas

Regazzo, Daniela; Losa, Marco; Albiger, Nora; Terreni, Maria Rosa; Vazza, Giovanni; Ceccato, Filippo; Emanuelli, Enzo; Denaro, Luca; Scaroni, Carla; Occhi, Gianluca

doi:10.1530/eje-16-0831

Cited by 43 publications

(32 citation statements)

References 47 publications

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“…Regazzo et al . have also proposed an existence of GH/IGF-1-GIP axis and our findings also concur the existence of such an axis leading to an increased GIP levels in patients of acromegaly 34 . A still higher levels of GIP in patients of acromegaly with hyperglycaemia as compared to those with euglycemia could possibly have resulted from hyperglycaemia-induced desensitization of GIP receptors on β-cells (GIP resistance), as also seen in patients with T2DM 35 .This was further substantiated by significantly lower AUC C-peptide/GIP ratio in patients of acromegaly with diabetes as compared to those with euglycaemia.…”

Section: Discussionsupporting

confidence: 90%

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and β-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly

Shekhawat

Bhansali

Dutta

et al. 2019

Sci Rep

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Impaired insulin sensitivity (IS) and β-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, β-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised β-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of β-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of β-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

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Section: Discussionsupporting

confidence: 90%

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and β-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly

Shekhawat

Bhansali

Dutta

et al. 2019

Sci Rep

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“…Furthermore, loss of this paradoxical GH response when glucose was administered intravenously supported the hypothesis of the implication of a gastrointestinal hormone [102]. In addition, GIP stimulation of GIPR-expressing somatotroph adenomas in primary culture increased GH release in 80% of these adenomas, with 60% reaching statistical significance [103]. …”

Section: Ogtt In the Diagnosis Of Acromegalymentioning

confidence: 90%

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Hage

Kamenický

Chanson³

2019

Neuroendocrinology

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The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.

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“…Several physiologic factors may alter IGF-1 concentrations. Severe obesity, malnutrition, and prolonged fasting can reduce IGF-1 levels in patients with and without acromegaly [18,19]. High GH with low IGF-1 can be observed in states of GH resistance such as systemic inflammation, chronic liver disease, cirrhosis, and anorexia nervosa [20,21].…”

Section: Insulin-like Growth Factor-1mentioning

confidence: 99%

“…Insulin induces expression of GH receptors on hepatocytes and may have an effect at the post-receptor level; hence, portal hypoinsulinemia is associated with GH resistance resulting in compensatory elevated GH [17]. In certain patients, a paradoxical increase of GH levels after glucose load was reported, most likely mediated by glucose-dependent insulinotropic polypeptide (GIP), a peptide released after oral glucose load [18]. Paradoxical GH response after OGTT may reflect the pathophysiological severity of acromegaly and may predict the effectiveness of treatment with somatostatin receptor ligand [19].…”

Section: Nadir Growth Hormone After Ogttmentioning

confidence: 99%

The Biochemical Diagnosis of Acromegaly

Akirov

Masri-Iraqi

Dotan

et al. 2021

JCM

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Background: The diagnosis of acromegaly still poses a clinical challenge, and prolonged diagnostic delay is common. The most important assays for the biochemical diagnosis and management of acromegaly are growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Objective: Discuss the role of IGF-1, basal serum GH, and nadir GH after oral glucose tolerance test (OGTT) for the diagnosis, management, and treatment of patients with acromegaly. Methods: We performed a narrative review of the published data on the biochemical diagnosis and monitoring of acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 January 2021. The reference lists of relevant studies were also reviewed. Results: Serum IGF-1 levels, basal GH values, and nadir GH after OGTT play a major role in the diagnosis, management, and treatment of patients with acromegaly. Measurement of IGF-1 levels is the key factor in the diagnosis and monitoring of acromegaly, but basal and nadir GH following OGTT are also important. However, several factors may significantly influence the concentrations of these hormones, including assay methods, physiologic and pathologic factors. In some cases, discordant GH and IGF-1 levels may be challenging and usually requires additional data and monitoring. Conclusion: New GH and IGF-1 standards are much more precise and provide more accurate tools to diagnose and monitor patients with acromegaly. However, all these biochemical tools have their limitations, and these should be taken under consideration, along with the history, clinical features and imaging studies, when assessing patients for acromegaly.

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The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp− somatotropinomas

Cited by 43 publications

References 47 publications

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and β-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and β-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

The Biochemical Diagnosis of Acromegaly

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