The D-Day of ghrelin
نویسندگان
چکیده
Ghrelin has emerged as an important player in the regulation of glucose homeostasis. During caloric restriction, the presence of acyl ghrelin (the active isoform) is necessary for the defense against hypoglycemia and survival [1]. In fasted humans, ghrelin administration enhances growth hormone (GH) secretion, suppresses insulin release and promotes insulin resistance to maintain normoglycemia [2]. The exact mechanism for the insulinostatic effect of ghrelin is not known. Ghrelin is secreted primarily by gastric endocrine cells, although a novel endocrine cell type ( 3cells) in the pancreatic islet [3] also produces ghrelin raising the possibility of intra-islet regulation. Ghrelin has been shown to activate its receptor, the GH secretagogue receptor (GHSR) 1a, on b cells to inhibit glucose-stimulated insulin secretion (GSIS) through a Gai2 signaling pathway [4] and acts directly on a cells to stimulate glucagon secretion by elevating intracellular calcium and promoting ERK phosphorylation [5]. Another major inhibitor of insulin secretion from b cells is somatostatin (SST) through the SST receptor subtype-5 (SSTR5). Park and colleagues reported collaborative actions between ghrelin and SST via their receptors in INS-1 b cells to modulate GSIS during lowand high-energy balance states [6]. The close proximity of islet cells makes it difficult to distinguish between direct and indirect effects of hormones on b cells. However, the recent advances in molecular genetic techniques and next-generation sequencing allows for unbiased evaluation of gene expression in individual cells and provides a unique opportunity to intercept cross talk between pancreatic islet cells. In this issue of Molecular Metabolism, DiBruccio et al. [7] report a novel insulinostatic mechanism of ghrelin by acting directly on d cells to promote SST release. Little is known about the factors that regulate d cell function despite these being the third most prevalent islet cell type. DiGruccio and colleagues generated a triple transgenic reporter mouse that enabled FACS purification of a, b and d cells from the same islets. Comprehensive transcriptomes for each of the three islet cell types was performed. Static and perifusion assays were performed in both mouse and human islets to measure SST secretion from d cells. Using RNA sequencing, fluorescent in situ hybridization (FISH), and qPCR analyses, they found that the Ghsr gene was abundantly and selectively expressed in d cells. Stimulation of mouse and human islets with ghrelin produced a robust increase in glucose-stimulated SST secretion, and stimulation of calcium responses in d cells in intact mouse
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