The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner

in Journal of Endocrinology
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Nirun Hewawasam School of Life and Health Sciences, University of Roehampton, London, UK

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Debalina Sarkar School of Life and Health Sciences, University of Roehampton, London, UK

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Olivia Bolton School of Life and Health Sciences, University of Roehampton, London, UK

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Blerinda Delishaj School of Life and Health Sciences, University of Roehampton, London, UK

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Maha Almutairi School of Life and Health Sciences, University of Roehampton, London, UK

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Aileen J F King Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London, London, UK

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Ayse S Dereli Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d’Endocrinologie, Diabète et Nutrition, Brussels, Belgium

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Chloe Despontin Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d’Endocrinologie, Diabète et Nutrition, Brussels, Belgium

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Patrick Gilon Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d’Endocrinologie, Diabète et Nutrition, Brussels, Belgium

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Sue Reeves School of Life and Health Sciences, University of Roehampton, London, UK

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Michael Patterson School of Life and Health Sciences, University of Roehampton, London, UK

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Astrid C Hauge-Evans School of Life and Health Sciences, University of Roehampton, London, UK

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https://orcid.org/0000-0003-2391-4334

Correspondence should be addressed to A C Hauge-Evans: astrid.hauge-evans@roehampton.ac.uk

*(N Hewawasam and D Sarkar shared first authorship)

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LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst−/− mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

 

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