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）：单基因糖尿病是一组由突变引起的一组疾病，这对于胰岛中胰岛素产生β细胞的适当功能所必需的许多基因之一。估计表明，糖尿病的单基因形式可以代表所有糖尿病病例的2％。糖尿病患者在非常年轻的年龄，“新生儿糖尿病”的患者很可能会带来潜在的单基因原因，尤其是当在6个月大之前被诊断出时。芝加哥大学新生儿糖尿病登记处现在包括有关200多名糖尿病患者在一岁之前诊断出的糖尿病的临床和遗传信息。该组中糖尿病的最常见遗传原因是在基因KCNJ11中激活突变，编码ATP敏感钾（KATP）通道的KIR6.2亚基，该基因在胰岛素分泌中起着至关重要的作用。这组受试者代表了研究对正常分泌胰岛素至关重要的特定β细胞蛋白破坏人类模型的无与伦比的机会。先前接受胰岛素治疗的KCNJ11相关的新生儿糖尿病患者在用磺胺尿酸酶治疗时（通常是墨西哥乳突），表现出临床上出色的葡萄糖对照，最小的低血糖。已建议在磺酰脲治疗的患者中分泌胰岛素的主要刺激，这与肠血凝蛋白有关，而不是葡萄糖的代谢有关。但是，关于此类患者β细胞功能的性质以及其对治疗的长期反应仍然存在许多问题。因此，在此应用中，我们提出以下目的：1）与对照组相比，KCNJ11患者中胰岛素对葡萄糖的反应完全表征； 2）表征GLP-1信号传导对KCNJ11糖尿病中胰岛素分泌的特定贡献； 3）评估年龄在KCNJ11糖尿病的遗传诊断和与其他形式的新生儿糖尿病相比的作用。在对18岁或以上受试者的住院期间，我们将使用口服葡萄糖耐量测试（OGTT），然后使用匹配的静脉内异体血糖葡萄糖输注（IGI）进行比较，以比较经过相匹配的对照组的硫酸盐治疗的KCNJ11患者，然后在GLP-1和exender newerp of Glp-1和exendp-1中重复这些研究，然后重复这些研究（9-3）。这些测试将提供胰岛素分泌的定量度量，并直接估计降直直染蛋白效应和关键泌尿蛋白胰腺和肠激素的评估。我们还将通过KCNJ11突变以及其他形式的新生儿糖尿病患者的OGTT进行连续葡萄糖监测的葡萄糖偏移曲线。这些研究将检验以下假设：1）KCNJ11糖尿病患者对静脉内和口腔葡萄糖的胰岛素分泌反应受到损害磺酰脲，即后来的年龄 引起SU疗法会导致次优血糖控制，磺酰尿素剂量较高和较差的神经发育结果，ii）通过基于肠凝结蛋白的治疗方法可以改善血糖控制。我们预计这些研究将提供对β细胞的洞察力 仅通过研究这些稀有受试者的遗传改变才有可能的功能 细胞功能。此外，此类研究尚未发表在新生儿糖尿病的受试者中。我们预计，这些研究将阐明肠降血剂在调节独立于KATP通道的胰岛分泌中的作用。鉴于引起单基因糖尿病的大多数基因通过GWAS与2型糖尿病有关，因此更好地了解引起人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患者对不同疗法的反应可能会导致改善和治疗更常见的多发性多发性糖尿病的人。 公共卫生相关性：拟议的研究将使人们对人类新生儿单基因糖尿病患者有更深入的了解，这可能会对所有形式的单基因糖尿病的最适当的长期治疗产生直接影响。此外，对胰岛素分泌机制及其破坏机制的洞察力可能对美国糖尿病的数百万患者产生后果。最后，拟议的研究代表了个性化遗传医学的模型，从而迭代了解基因型/表型关联可能会对单个患者的治疗，对具有相似表型的其他人的基因测试的政策产生巨大影响，以及对这些患者和患有相关疾病的长期健康结果的基因测试。