Ghrelin's role in glucose homestasis during aging

描述(申请人提供)：葡萄糖不耐受和肥胖相关的2型糖尿病的发病率随着年龄的增长而增加。与年龄相关的糖耐量异常的机制尚不清楚，但似乎与b细胞功能受损和胰岛素敏感性降低有关。肥胖和糖尿病相关基因的识别和表征将增加我们对糖尿病发病机制的基本知识，并导致能够改善老年人生活质量的干预措施。Ghrelin是已知的唯一能刺激食欲从而促进肥胖的循环肽。我们培育并鉴定了Ghrelin缺失的小鼠；出人意料的是，成年Ghrelin/-小鼠对饮食诱导的肥胖没有保护作用。令人惊讶的是，Ghrelin失活会增加胰岛素的分泌，以响应葡萄糖的挑战，并增加外周胰岛素的敏感性。Ghrelin和Leptin是能量动态平衡的相互拮抗剂。瘦素缺陷小鼠(ob/ob)具有高吞噬、肥胖和高血糖。为了研究ghrelin和瘦素之间的相互作用，我们还培育了ghrelin缺陷的ob/ob小鼠。在ob/ob小鼠中，ghrelin的失活不能挽救肥胖的肥大表型，这表明ob/ob表型不是ghrelin不被瘦素对抗的结果；然而，尽管它们的体重相似，但在ghrelin-/-.ob/ob小鼠中，血糖显著降低。我们的数据表明，低水平的Ghrelin可能对糖尿病患者有有益的影响。我们的初步研究表明，小鼠的Ghrelin水平可能会随着年龄的增长而增加，因此我们假设Ghrelin水平越高，在衰老过程中糖尿病的发病率就越高。因此，Ghrelin拮抗剂可以预防和/或减少衰老过程中的2型糖尿病的发生。这项建议的具体目的是1)使用我们独特的小鼠模型来确定Ghrelin对老年小鼠恶化的糖耐量的影响的调节因子，以及2)随后确定它们的表达是否受Ghrelin的调节并与年龄相关。这些研究将进一步阐明糖尿病和衰老过程中葡萄糖稳态的分子机制，并有可能为预防和/或治疗衰老相关糖尿病找到新的方法。

DESCRIPTION (provided by applicant): The incidence of glucose intolerance and obesity-related Type 2 diabetes increases with age. The mechanisms of age-related glucose intolerance are not clear, but it appears to be related to both impaired b- cell function and decreased insulin sensitivity. Identification and characterization of the genes involved in obesity and diabetes will add essential knowledge to our understanding of the mechanisms of diabetes and lead to interventions that can improve the quality of life in the elderly. Ghrelin is the only circulating peptide known to stimulate appetite and; thereby, promote obesity. We generated and characterized ghrelin-null mice; unexpectedly adult ghrelin-/- mice are not protected against diet-induced obesity. It was surprising to find that ghrelin inactivation augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity. Ghrelin and leptin are mutual antagonists in energy homeostasis. Leptin-deficient mice (ob/ob) are hyperphagic, obese and hyperglycemic. To investigate the interplay between ghrelin and leptin, we also generated ghrelin-deficient ob/ob mice. The inactivation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, which indicates that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin; however, despite their similar body weights, blood glucose is markedly reduced in ghrelin-/-.ob/ob mice. Our data suggest that low ghrelin levels may have a beneficial effect for diabetes patients. Our preliminary studies show that ghrelin levels may increase with age in mice, so we hypothesize that higher ghrelin levels contribute to a higher incidence of diabetes during aging. Ghrelin antagonists may; therefore, prevent and/or reduce the Incidence of Type 2 diabetes during aging. The specific aims of this proposal are 1) to use our unique mouse models to identify the regulators which mediate ghrelin's effect on the worsened glucose intolerance in aging mice and 2) to subsequently determine if their expression is regulated by ghrelin and correlated with age. These studies will shed more light on the molecular mechanisms of diabetes and glucose homeostasis during aging, and may potentially lead to the discovery of new means for the prevention and/or treatment of aging-related diabetes.