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Ghrelin's role in glucose homestasis during aging

生长素释放肽在衰老过程中葡萄糖稳态中的作用

基本信息

批准号：
7439165
负责人：
YUXIANG SUN
金额：
$ 6.17万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7439165
关键词：
Address Adipose tissue Adult Affect Age Age-Months Aging B-Lymphocytes Backcrossings Beta Cell Blood Glucose Body Weight Cell Death Cell physiology Cells Data Desire for food Diabetes Mellitus Diet Elderly Epidemic Exhibits Functional disorder G-Protein-Coupled Receptors Generations Genes Glucose Glucose Intolerance Glucose tolerance test Homeostasis Human Hyperglycemia Incidence Individual Insulin Resistance Intervention Islets of Langerhans Knockout Mice Knowledge Lead Leptin Life Light Link Liver Longevity Mediating Messenger RNA Molecular Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Patients Peptides Peripheral Phenotype Play Population Prevention Proteins Quality of life Regulation Reporting Resistance Rodent Role Symptoms Testing Therapeutic Agents Tissues UCP2 protein United States age related aging brain blood glucose regulation diabetic ghrelin ghrelin receptor glucose tolerance growth hormone secretagogue receptor improved increased appetite insulin secretion insulin sensitivity islet mRNA Expression middle age mouse model novel therapeutics prevent protein expression research study response

项目摘要

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.

描述（由申请人提供）：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。识别和表征与肥胖和糖尿病有关的基因将为我们了解糖尿病机制提供必要的知识，并导致可以改善老年人生活质量的干预措施。生长素释放肽是唯一已知能刺激食欲的循环肽；从而促进肥胖。我们生成并表征了生长素释放肽无效的小鼠；出乎意料的是，成年生长素释放肽-/-小鼠并不能抵抗饮食引起的肥胖。令人惊讶地发现，生长素释放肽失活会增加响应葡萄糖挑战的胰岛素分泌，并增加外周胰岛素敏感性。生长素释放肽和瘦素在能量稳态中是相互拮抗的。瘦素缺陷小鼠 (ob/ob) 食欲亢进、肥胖且血糖过高。为了研究 ghrelin 和瘦素之间的相互作用，我们还培养了 ghrelin 缺陷的 ob/ob 小鼠。 ob/ob 小鼠中 ghrelin 的失活未能挽救肥胖的贪食表型，这表明 ob/ob 表型不是 ghrelin 不受瘦素抵抗的结果；然而，尽管体重相似，ghrelin-/-.ob/ob 小鼠的血糖却显着降低。我们的数据表明，低生长素释放肽水平可能对糖尿病患者有益。我们的初步研究表明，小鼠的生长素释放肽水平可能会随着年龄的增长而增加，因此我们假设较高的生长素释放肽水平会导致衰老过程中糖尿病的发病率升高。生长素释放肽拮抗剂可能；因此，预防和/或减少衰老过程中 2 型糖尿病的发病率。该提案的具体目标是 1) 使用我们独特的小鼠模型来识别介导 ghrelin 对衰老小鼠葡萄糖耐受不良恶化的影响的调节因子，2) 随后确定它们的表达是否受 ghrelin 调节并与年龄相关。这些研究将进一步阐明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。