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

• 批准号: 7187819
• 负责人: YUXIANG SUN
• 金额: $ 6.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187819
• 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

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）：葡萄糖不耐症和与肥胖相关的2型糖尿病的发生率随着年龄的增长而增加。与年龄相关的葡萄糖不耐症的机制尚不清楚，但它似乎与B-细胞功能受损和胰岛素敏感性降低有关。对肥胖和糖尿病涉及的基因的识别和表征将为我们对糖尿病机制的理解增加基本知识，并导致干预措施，从而可以改善老年人的生活质量。生长素是唯一已知刺激食欲的循环肽。因此，促进肥胖。我们生成并表征了生长素释放的小鼠；出乎意料的成年生长素蛋白 - / - 小鼠不受饮食诱导的肥胖症的保护。令人惊讶的是，发现生长素蛋白灭活会增加胰岛素分泌，以应对葡萄糖挑战并增加周围胰岛素敏感性。生长素素和瘦素是能量稳态中的共同拮抗剂。缺乏瘦素的小鼠（OB/OB）是肥大，肥胖和高血糖。为了研究生长素蛋白和瘦素之间的相互作用，我们还产生了缺陷蛋白的OB/OB小鼠。 ob/ob小鼠中生长素的失活未能营救肥胖的倍感表型，这表明ob/ob表型并不是瘦素无反抗的生长素蛋白的结果。然而，尽管体重相似，但血糖在生长素释放肽 - / - 。ob/ob小鼠中显着降低。我们的数据表明，低血肽水平可能对糖尿病患者具有有益的作用。我们的初步研究表明，生长素素水平可能随着小鼠的年龄增长而增加，因此我们假设较高的生长素素水平在衰老期间有助于较高的糖尿病发病率。生长素拮抗剂可以；因此，预防和/或减少衰老过程中2型糖尿病的发生率。该提案的具体目的是1）使用我们独特的小鼠模型来识别介导生长素素对衰老小鼠中恶化恶化的葡萄糖不耐症的影响的调节剂，而2）随后确定其表达是否受到生长素的调节并与年龄相关。这些研究将更多地了解衰老期间糖尿病和葡萄糖稳态的分子机制，并可能导致发现预防与衰老相关糖尿病的新手段。