Incretin Regulation of Insulin Secretion in Human Neonatal Diabetes

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种基因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%。糖尿病患者发生在极年轻的年龄，“新生儿糖尿病”，很可能有潜在的单基因原因，特别是在6个月前被诊断出来。芝加哥大学新生儿糖尿病登记处现在包括200多名一岁前诊断为糖尿病的患者的临床和遗传信息。在这一群体中，糖尿病最常见的遗传原因是KCNJ11基因的激活突变，该基因编码atp敏感钾（KATP）通道的Kir6.2亚基，在胰岛素分泌中起关键作用。这组受试者代表了一个无与伦比的机会来研究对胰岛素正常分泌至关重要的特定β细胞蛋白破坏的人类模型。既往接受胰岛素治疗的kcnj11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）治疗后，表现出良好的临床血糖控制，低血糖发生率最低。在磺脲治疗的患者中，胰岛素分泌的主要刺激被认为与肠促胰岛素有关，而不是与葡萄糖代谢有关。然而，关于这些患者β细胞功能的性质及其对治疗的长期反应，仍然存在许多问题。在这个应用中，我们提出了以下目标：1)与对照组相比，充分表征KCNJ11患者对葡萄糖的胰岛素反应；2)研究GLP-1信号在KCNJ11糖尿病胰岛素分泌中的具体作用；3)评价年龄在KCNJ11型糖尿病遗传诊断中的作用以及肠促胰岛素治疗与其他形式新生儿糖尿病的比较。在18岁及以上患者的住院研究中，我们将使用口服葡萄糖耐量试验（OGTT）和匹配的静脉等血糖输注（IGI）来比较磺胺脲治疗的KCNJ11患者和匹配的对照组，然后在输注GLP-1和特异性GLP-1受体拮抗剂Exendin（9-39）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和评估关键的肠促胰岛素、胰腺和肠道激素。我们还将在所有年龄的KCNJ11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葡萄糖漂移谱。这些研究将验证以下假设：1)KCNJ11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)KCNJ11糖尿病患者口服葡萄糖调节的胰岛素分泌在很大程度上依赖于血糖升高时的GLP-1信号；3)血糖控制依赖于胰岛素转化为口服磺脲类药物的年龄，即年龄的增加

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.