Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
关键词
抽象
描述
Neonatal diabetes mellitus is a rare, monogenic form of diabetes occurring during the first 6-9 months of life characterized by hyperglycemia requiring exogenous insulin therapy. The estimated incidence is 1 per 12000 newborns. Although homozygous or compound heterozygous mutations in the genes IPF1 or GCK were the first genetic causes of this disease to be identified, activating mutations in the KIR6.2 and sulfonylurea receptor 1 (SUR1) subunits of the pancreatic ATP-sensitive K+ channel, coded for by the genes KCNJ11 and ABCC8, have recently been identified as the major causes of both transient and permanent neonatal diabetes. In the normal pancreatic beta-cell, metabolism results in increased cellular ATP, which binds to KIR6.2. The potassium channel subsequently closes and hence depolarizes the membrane initiating insulin release via increased calcium entry. Conversely, increased cellular ADP acts on SUR1 to open the channel and prevent insulin release. Activating mutations in these channels reduces sensitivity to the inhibitory actions of ATP and increases sensitivity to the stimulatory actions of ADP. This causes the ATP-sensitive K+ channel to remain open, even in the presence of glucose, therefore preventing insulin release. Sulfonylureas act by an ATP-independent mechanism to close these channels even when mutations are present. Sulfonylureas result in insulin release and were therefore immediately considered and showed to be a potential treatment option in neonatal diabetes caused by mutations in these channels. The effective replacement of insulin treatment by high-dose sulfonylureas has been shown to be successful in 90% of patients with Kir6.2 mutations and 85% of patients with SUR1 mutations resulting in improved glycemic control.
This dramatic effect of sulfonylurea is now standard, world-wide treatment in neonatal diabetes due to a mutation in either KCNJ11 or ABCC8. There is, however, far no information on long-term use of sulfonylurea in patients with KCNJ11 or ABCC8 mutations. The investigators have therefore initiated an international, multicenter, prospective study aiming to include some 75 patients aged from 9 years with a genetic diagnosis of diabetes due to a ABCC8 gene mutation identified by sequencing in Bergen, Norway; Exeter, U.K.; Paris, France or Rome, Italy. Most patients were referred based on membership in the International Society of Pediatric and Adolescent Diabetes. All of the patients attempted transfer from treatment with insulin to a sufficient dose of sulfonylureas. No other selection criteria were applied, and all patients were included when there was outcome data following the attempted transfer. The observation period was at least 9 years after commencing sulfonylureas in all patients. The study is conducted in accordance with the Declaration of Helsinki and informed consent has been obtained from all participating patients, with parental consent given on behalf of children.
日期
最后验证: | 01/31/2020 |
首次提交: | 12/03/2015 |
提交的预估入学人数: | 12/06/2015 |
首次发布: | 12/07/2015 |
上次提交的更新: | 02/09/2020 |
最近更新发布: | 02/11/2020 |
实际学习开始日期: | 02/14/2019 |
预计主要完成日期: | 01/31/2020 |
预计完成日期: | 01/31/2020 |
状况或疾病
干预/治疗
Drug: Drug, Sulfonylurea
相
手臂组
臂 | 干预/治疗 |
---|---|
Experimental: Drug, Sulfonylurea Sulfonylurea tablets (glibenclamide, other forms of sulfonylureas) were administered at the time of intervention (before November 1, 2006). The patients have been prospectively followed up. Sulfonylurea dose, insulin requirement, death of all causes, episodes of severe hypoglycemia, ketoacidosis, development of discoloured teeth and diarrhea have been recorded. For a small number of subjects, increment of insulin and C-peptide after either an oral or intravenous glucose load and/or response to intravenous glucagon have been tested. | Drug: Drug, Sulfonylurea See Arm description. |
资格标准
有资格学习的年龄 | 9 Years 至 9 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | Inclusion Criteria: - Permanent diabetes due to a mutation in ABCC8 (SUR1) - Patients successfully transferred from insulin to sulfonylurea - Transferred to sulfonylurea treatment before November 1, 2006 (ie 9 years off insulin) - Willing and able to provide informed consent (parents if younger than 16 years of age) Exclusion Criteria: - Permanent diabetes not due to a mutation in ABCC8 (SUR1) - Patients not successfully transferred from insulin to sulfonylurea - Transferred to sulfonylurea treatment after November 1, 2006 (ie les than 9 years off insulin) - Not willing or able to provide informed consent (parents if younger than 16 years of age) |
结果
主要结果指标
1. Sulfonylurea efficacy [Within 13 years from intervention]
2. Metabolic control [Within 13 years from intervention]
次要成果指标
1. All cause mortality [Within 13 years from intervention]
2. Incidence of hypoglycemia [Within 13 years from intervention]
3. Incidence of ketoacidosis [Within 13 years from intervention]
4. Development of diarrhea [Within 13 years from intervention]
5. Development of discoloured teeth [Within 13 years from intervention]
6. Insulin secretory response to intravenous glucose [Within 13 years from intervention]
7. Insulin secretory response to oral glucose [Within 13 years from intervention]
8. Sulfonylurea dose [Within 13 years from intervention]
9. Insulin secretory response to a glucagon test [Within 13 years from intervention]