Incretin Regulation of Insulin Secretion in Human Neonatal Diabetes

肠促胰岛素对人类新生儿糖尿病胰岛素分泌的调节

• 批准号: 8279876
• 负责人: Siri Atma W. Greeley
• 金额: $ 17.33万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279876
• 关键词: 18 year old; 6q24; ATP sensitive potassium channel complex; Accounting; Adult; Age; Age-Months; Age-Years; Beta Cell; Blood Circulation; Cell physiology; Chemosensitization; Chicago; Child; Chromosomes; Clinical; Diabetes Mellitus; Diagnosis; Disease; Dose; Enrollment; Evaluation; Exhibits; Functional disorder; Future; Gene Proteins; Genes; Genetic; Genetic Medicine; Genetic screening method; Genotype; Glucagon; Glucose; Glyburide; Health; Hormones; Human; Hypoglycemia; Individual; Infusion procedures; Inpatients; Institutes; Insulin; Intravenous; Investigation; Lead; Measures; Modeling; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oral; Outcome; Pancreas; Patients; Phenotype; Play; Policies; Potassium; Proteins; Publishing; Recording of previous events; Recruitment Activity; Registries; Regulation; Relapse; Role; Signal Transduction; Stimulus; Sulfonylurea Compounds; Syndrome; Testing; Universities; absorption; age effect; base; blood glucose regulation; data registry; gastric inhibitory polypeptide receptor; genome wide association study; glucagon-like peptide; glucose metabolism; glucose monitor; glycemic control; helospectin I; improved; insight; insulin secretion; insulin sensitivity; neonatal diabetes mellitus; neonatal human; receptor; response; sex

DESCRIPTION (provided by applicant): Monogenic diabetes is a group of disorders caused by mutations in any of one of a number of genes essential for the appropriate function of the insulin producing beta-cells in the pancreas. Estimates suggest that monogenic forms of diabetes could represent as much as 2% of all diabetes cases. Patients with diabetes occurring at an extremely young age, "neonatal diabetes", are very likely to have an underlying monogenic cause, especially when diagnosed before 6 months of age. The University of Chicago Neonatal Diabetes Registry now includes clinical and genetic information on over 200 subjects with diabetes diagnosed prior to one year of age. The most common genetic cause of diabetes in this group are activating mutations in the gene KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, which plays a critical role in insulin secretion. This group of subjects represent an unparalleled opportunity to investigate a human model of disruption of specific beta cell proteins critical for normal secretion of insulin. Patients with KCNJ11-related neonatal diabetes who were previously treated with insulin exhibit clinically excellent glucose control with minimal hypoglycemia when treated with sulfonylureas (usually glyburide). The predominant stimuli for secretion of insulin in sulfonylurea-treated patients have been suggested to be related to incretins rather than the metabolism of glucose. However, many questions remain regarding the nature of beta-cell function in such patients, as well as its long-term response to treatment. In this application, we thus propose the following Aims: 1) To fully characterize the insulin response to glucose in KCNJ11 patients compared to controls; 2) To characterize the specific contribution of GLP-1 signaling on insulin secretion in KCNJ11 diabetes; 3) To evaluate effect of age at genetic diagnosis of KCNJ11 diabetes and the role of incretin therapy in comparison with other forms of neonatal diabetes. During inpatient studies on subjects 18 years of age or older, we will use oral glucose tolerance testing (OGTT) followed by matched intravenous isoglycemic glucose infusion (IGI) to compare sulfonylurea-treated KCNJ11 patients with matched controls, then repeat these studies during infusions of GLP-1 and Exendin (9-39), a specific GLP-1 receptor antagonist. These tests will provide quantitative measures of insulin secretion with direct estimates of the incretin effect and evaluation of key incretin pancreatic and gut hormones. We will also monitor glucose excursion profiles with continuous glucose monitoring in response to OGTT in patients of all ages with KCNJ11 mutations as well as other forms of neonatal diabetes. These studies will test the following hypotheses: 1) Insulin secretory response to both intravenous and oral glucose is impaired in patients with KCNJ11 diabetes, 2) Oral glucose-regulated insulin secretion in KCNJ11 diabetes depends largely on GLP-1 signaling in the presence of elevated glucose, and 3) Glycemic control is dependent on age at conversion from insulin to oral sulfonylureas, that is, later age of instituting SU therapy leads to suboptimal glycemic control, with higher sulfonylurea dose and poorer neurodevelopmental outcome, and ii) glycemic control can be improved by treatment with incretin-based therapies. We anticipate that these studies will provide insight into beta cell function only possible through investigation of these rare subjects with genetic alteration of beta cell function. Furthermore, such studies have not yet been published in subjects with neonatal diabetes. We anticipate that these studies will elucidate the role of incretins in regulating insuln secretion independent of the KATP channel. Given that most of the genes causing monogenic diabetes have been associated with Type 2 diabetes through GWAS, better understanding of the pathophysiology of genetic defects causing human beta-cell dysfunction and how patients with mutations in these genes respond to different therapies could lead to improved diagnosis and treatment for those with more common polygenic forms of diabetes. PUBLIC HEALTH RELEVANCE: The proposed studies will result in a deeper understanding of patients with human neonatal monogenic diabetes, likely to have direct future effects on the most appropriate long-term treatment for all forms of monogenic diabetes. In addition, the resulting insight into mechanisms of insulin secretion and its disruption may have ramifications for the millions of patients in the US with diabetes mellitus. Finally, the proposed studies represent a model for personalized genetic medicine, whereby iterative improvement in understanding of genotype/phenotype associations may have a dramatic impact on the treatment of individual patients, policies for genetic testing of others with similar phenotypes, and improvement of long term health outcome in these patients and those with related disorders.

描述（由申请人提供）：单基因糖尿病是由胰腺中产生胰岛素的β细胞的适当功能所必需的许多基因中的任何一个突变引起的一组疾病。据估计，单基因型糖尿病可能占所有糖尿病病例的2%。在极年轻的年龄发生的糖尿病患者，“新生儿糖尿病”，很可能有潜在的单基因原因，特别是在6个月大之前诊断时。芝加哥大学新生儿糖尿病登记处现在包括200多名在一岁之前诊断出糖尿病的受试者的临床和遗传信息。在这一组中，糖尿病最常见的遗传原因是基因KCNJ 11中的激活突变，该基因编码ATP敏感钾（KATP）通道的Kir6.2亚基，该亚基在胰岛素分泌中起关键作用。这组受试者代表了研究对胰岛素正常分泌至关重要的特定β细胞蛋白质破坏的人类模型的无与伦比的机会。既往接受过胰岛素治疗的KCNJ 11相关新生儿糖尿病患者在接受磺脲类药物（通常为格列本脲）治疗时，血糖控制良好，低血糖发生率极低。磺脲类药物治疗患者胰岛素分泌的主要刺激因素与肠促胰岛素有关，而与葡萄糖代谢无关。然而，关于此类患者中β细胞功能的性质以及其对治疗的长期反应仍存在许多问题。因此，在本申请中，我们提出了以下目的：1）与对照组相比，充分表征KCNJ 11患者对葡萄糖的胰岛素反应; 2）表征GLP-1信号传导对KCNJ 11糖尿病胰岛素分泌的特异性贡献; 3）评价年龄对KCNJ 11糖尿病基因诊断的影响以及肠促胰岛素治疗与其他形式的新生儿糖尿病相比的作用。在18岁或以上受试者的住院研究中，我们将使用口服葡萄糖耐量试验（OGTT），随后匹配的静脉注射异甘草酸葡萄糖（IGI），比较磺脲类药物治疗的KCNJ 11患者与匹配的对照组，然后在输注GLP-1和Exendin（9-39）（一种特异性GLP-1受体拮抗剂）期间重复这些研究。这些测试将提供胰岛素分泌的定量测量，直接估计肠促胰岛素的作用，并评价关键的肠促胰岛素、胰腺和肠道激素。我们还将在所有年龄段的KCNJ 11突变患者以及其他形式的新生儿糖尿病患者中，通过连续血糖监测来监测OGTT后的血糖波动曲线。这些研究将检验以下假设：1）KCNJ 11型糖尿病患者对静脉和口服葡萄糖的胰岛素分泌反应受损，2）KCNJ 11型糖尿病患者口服葡萄糖调节的胰岛素分泌在很大程度上取决于血糖升高时的GLP-1信号传导，3）血糖控制取决于从胰岛素转换为口服磺脲类药物时的年龄，即年龄越大， 建立SU治疗导致次优血糖控制，磺酰脲类药物剂量较高，神经发育结果较差，和ii）血糖控制可通过用基于肠促胰岛素的治疗来改善。我们预计这些研究将提供深入了解β细胞 只有通过研究这些罕见的β基因改变的受试者才可能发挥作用 细胞功能此外，此类研究尚未在新生儿糖尿病受试者中发表。我们预期这些研究将阐明肠促胰岛素在调节胰岛素分泌中的作用，而不依赖于KATP通道。鉴于大多数导致单基因糖尿病的基因通过GWAS与2型糖尿病相关，更好地了解导致人类β细胞功能障碍的遗传缺陷的病理生理学以及这些基因突变的患者如何对不同的治疗做出反应，可能会改善那些更常见的多基因糖尿病形式的诊断和治疗。 公共卫生相关性：拟议的研究将导致对人类新生儿单基因糖尿病患者的更深入了解，可能对所有形式的单基因糖尿病的最合适的长期治疗产生直接的未来影响。此外，由此产生的对胰岛素分泌机制及其中断的洞察可能对美国数百万糖尿病患者产生影响。最后，拟议的研究代表了个性化遗传医学的模型，其中对基因型/表型关联的理解的迭代改进可能会对个体患者的治疗、对具有相似表型的其他人进行基因检测的政策以及改善长期健康状况产生巨大影响这些患者和患有相关疾病的患者的结果。