Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation

Kiyoshi Chinen,Naoaki Sakata,Gumpei Yoshimatsu,Shohta Kodama,Masafumi Nakamura

doi:10.1038/s41598-021-00740-6

Kiyoshi Chinen, Naoaki Sakata + Show 3 more

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https://doi.org/10.1038/s41598-021-00740-6

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Journal: Scientific Reports	Publication Date: Oct 28, 2021
License type: open-access

Affiliation: Fukuoka University, Kyushu University

Abstract

Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. Trials aiming to improve the function of transplanted islets have also been challenging. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. The therapeutic effects of DLS were assessed in terms of the expression/production of endocrine genes/proteins, insulin-releasing function under glucose stimulation of mouse islets, and outcomes of syngeneic murine islet transplantation with systemic DLS administration. DLS treatment promoted insulin production and suppressed somatostatin production, suggesting that cancelation of the binding between ghrelin and GHS-R1a on β or δ cells improved insulin expression. DLS also promoted the glucose-dependent insulin-releasing function of β cells. However, the therapeutic effect of DLS in islet transplantation was fractional. In conclusion, the GHS-R1a antagonist showed preferable effects in improving the therapeutic outcomes of islet transplantation, including the promotion of insulin-releasing function.

Highlights

Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets
No difference in the released insulin volume under low-glucose stimulation was observed between the no-treatment and DLS administration groups, a dose-dependent increase in insulin volume under high-glucose stimulation was detected in the DLS group, with the volume being highest at 4.0 μg/mL of DLS (16.73 ± 2.27, 22.41 ± 2.29, 21.93 ± 2.57, and 32.44 ± 1.68 pg/islet × h in the no-treatment, DLS 0.5, 2.0, and 4.0 μg/ mL groups, respectively; p < 0.01; Supplemental Fig. 1A)
growth hormone secretagogue receptor-1a (GHS-R1a) is a seven-transmembrane G protein-coupled receptor for acylated ghrelin expressed in various sites, such as the b rain[18], islets, thyroid, and h eart[19]

Summary

Introduction

Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. Islet transplantation is a promising therapy for patients with severe diabetes mellitus (DM), especially type 1 DM with insulin deficiency This therapeutic approach enables blood glucose regulation by maintaining appropriate insulin supply from transplanted islets. To establish a novel therapy aiming to improve quality, the current study focused on the crosstalk among the islet endocrine cells for ameliorating the insulin-releasing function of β cells, on ghrelin receptors. Acylated ghrelin binds to a specific receptor named growth hormone secretagogue receptor-1a (GHS-R1a) on β cells and restricts insulin release[13] This restriction depends on direct and indirect effects via δ c ells[10,14,15]. The current study attempted to clarify whether GHS-R1a regulation improved therapeutic effects of islet transplantation

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