Ghrelin in rat pancreatic islets decreases islet blood flow

Abstract

The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

Ghrelin deletion and conditional ghrelin cell ablation increase pancreatic islet size in mice

“…One could envision a therapeutic strategy whereby neutralizing ghrelin, such as has already been achieved using an anti-ghrelin RNA spiegelmer ( 51 ), or decreasing GHSR signaling in other ways ( 52 ) could be used to increase β cell numbers within donor islets, optimize the proliferation of cultured β cell lines, and/or favor the expansion of β cells within islet organoids (pseudoislets) ( 53 , 54 ) prior to or following β cell transplantation. Decreasing GHSR signaling in patients who have undergone islet cell transplantation would, presumably, also favorably affect glycemic control in other ways, for instance, by enhancing insulin sensitivity, directly and indirectly promoting insulin secretion, and increasing islet vascularity, all of which have previously been documented ( 6 , 9 , 14 ). It remains to be seen whether islets or β cells from low-ghrelin environments would also exhibit improved survival following transplantation, as has been shown, for instance, with enlarged islets from transgenic mice that overexpress hepatocyte growth factor in β cells ( 55 ).…”

“…In other settings, ghrelin’s glucoregulatory actions probably involve more direct effects on islet hormone secretion, including increased somatostatin secretion, increased glucagon secretion, and/or decreased insulin secretion ( 6 , 13 ). Ghrelin also decreases islet blood flow, whereas GHSR antagonism does the opposite ( 14 ).…”

Ghrelin regulates the proliferation and apoptosis of high glucose‐induced islet cells through the PI3K–Akt signaling pathway

“…Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor, which plays a pivotal role in regulating appetite and energy balance, and affecting metabolism in the body (Poher et al, 2018). There are also findings suggesting that ghrelin can act on pancreatic islet cells not only through endocrine but also through paracrine pathways (Drott et al, 2019). In recent years, many studies have concentrated on the protective effect of ghrelin on islet cells.…”

Wpływ greliny i obestatyny na właściwości fizjologiczne trzustki.

“…W mniejszych ilościach została wykryta podwzgórzu, przysadce, układzie immunologicznym, trzustce, wątrobie, w jelicie cienkim, łożysku, nerkach, nadnerczach i sercu [14]. W obrazie ostatnich badań bardzo istotna wydaje się być również grelina wydzielana podczas głodu przez komórki ε w endokrynnej części trzustki [15]. Ma to niebagatelne znaczenie kontekście interakcji z komórkami β [16], na które wpływa grelina.…”