Dezaki Katsuya
Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.
Endocr Dev. 2013;25:135-43. doi: 10.1159/000346064. Epub 2013 Apr 25.
Given its wide spectrum of biological activities such as growth hormone (GH) release, feeding stimulation, adiposity and cardiovascular actions, the discovery of ghrelin opened many new perspectives within neuroendocrine, metabolic and cardiovascular research, thus suggesting its possible clinical application. Circulating ghrelin is produced predominantly in the stomach, and its receptor GH secretagogue receptor (GHS-R) is expressed in a variety of central and peripheral tissues. Ghrelin, GHS-R and ghrelin O-acyltransferase (GOAT), the enzyme that promotes the acylation of the third serine residue of ghrelin, are all expressed in pancreatic islets, and this peptide is released into pancreatic microcirculations. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin receptor in islet β-cells are very unique, being distinct from those utilized for GH release. Pharmacological and genetic blockade of islet-derived ghrelin markedly augments glucose-induced insulin release in vitro. Ablation of ghrelin, GHS-R or GOAT enhances insulin release and prevents impaired glucose tolerance in high-fat, diet-induced and leptin-deficient obese models. Thus, manipulation of the insulinostatic function of the ghrelin-GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand. Ghrelin antagonism provides a novel strategy to treat type 2 diabetes with dysregulated insulin release.
鉴于胃饥饿素具有广泛的生物学活性，如生长激素（GH）释放、进食刺激、肥胖及心血管作用，其发现为神经内分泌、代谢及心血管研究开辟了许多新视角，从而提示了其可能的临床应用价值。循环中的胃饥饿素主要由胃产生，其受体生长激素促分泌素受体（GHS-R）在多种中枢和外周组织中表达。胃饥饿素、GHS-R以及胃饥饿素O-酰基转移酶（GOAT，促进胃饥饿素第三个丝氨酸残基酰化的酶）均在胰岛中表达，且该肽会释放到胰腺微循环中。胃饥饿素在小鼠、大鼠及人类中均抑制胰岛素释放。胰岛β细胞中胃饥饿素受体的信号转导机制非常独特，与生长激素释放所利用的机制不同。胰岛源性胃饥饿素的药理学及基因阻断显著增强体外葡萄糖诱导的胰岛素释放。在高脂饮食诱导的肥胖模型及瘦素缺乏的肥胖模型中，胃饥饿素、GHS-R或GOAT的缺失可增强胰岛素释放并预防糖耐量受损。因此，调控胃饥饿素-GHS-R系统的胰岛素稳态功能，尤其是胰岛中的该系统，可优化胰岛素释放量以满足全身需求。胃饥饿素拮抗作用为治疗胰岛素释放失调的2型糖尿病提供了一种新策略。
