Ghrelin's role in glucose homestasis during aging

描述（由申请人提供）：葡萄糖耐受不良和肥胖相关的2型糖尿病的发病率随着年龄的增长而增加。与年龄相关的葡萄糖耐受不良的机制尚不清楚，但它似乎与b细胞功能受损和胰岛素敏感性降低有关。对肥胖和糖尿病相关基因的识别和表征将为我们对糖尿病机制的理解增加必要的知识，并导致可以改善老年人生活质量的干预措施。胃饥饿素是唯一已知能刺激食欲的循环肽；从而促进肥胖。我们生成并表征了ghrelin-null小鼠；出乎意料的是，成年饥饿素小鼠并没有受到饮食引起的肥胖的保护。令人惊讶的是，生长素失活会增加胰岛素分泌，以应对葡萄糖的挑战，并增加外周胰岛素敏感性。胃饥饿素和瘦素在能量稳态中是相互拮抗的。瘦素缺乏小鼠（ob/ob）表现为贪食、肥胖和高血糖。为了研究饥饿素和瘦素之间的相互作用，我们还制造了饥饿素缺乏的ob/ob小鼠。在ob/ob小鼠中，饥饿素的失活不能挽救肥胖的贪食表型，这表明ob/ob表型不是饥饿素未被瘦素对抗的结果；然而，尽管他们的体重相似，但ghrelin-/-组的血糖明显降低。ob / ob老鼠。我们的数据表明，低胃饥饿素水平可能对糖尿病患者有益。我们的初步研究表明，胃饥饿素水平可能随着小鼠年龄的增长而增加，因此我们假设胃饥饿素水平升高会导致衰老过程中糖尿病的发病率升高。生长素拮抗剂可能；因此，预防和/或减少老年2型糖尿病的发病率。本提案的具体目的是：1)利用我们独特的小鼠模型来确定介导ghrelin对衰老小鼠葡萄糖耐受不良恶化影响的调节因子，2)随后确定它们的表达是否受ghrelin调节并与年龄相关。这些研究将进一步揭示衰老过程中糖尿病和葡萄糖稳态的分子机制，并可能导致发现预防和/或治疗衰老相关糖尿病的新方法。

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.