Switching From Insulin to Sulfonylurea in Childhood and Adult Diabetes Due to Variants in the HNF1A, HNF4A, or HNF1B Genes
试验速览
- 阶段
- 4 期
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg per day
研究概览
简要总结
The purpose of this study is to switch from insulin to oral sulfonylurea in patients with apparent type 1 diabetes or maturity onset diabetes in the young that are insulin treated. The molecular cause will be DNA variants in the HNF1A, HNF4A, or HNF1B genes that are of unknown significance (VUS, class 3) or known to be pathogenic (class 4 and 5).
详细描述
Maturity onset diabetes in the young (MODY) is characterised by monogenic diabetes due to beta-cell dysfunction, with typical onset of diabetes before age of 25 years. There are 14 known forms of MODY, ranging from rather common to extremely rare.
About 1% of patients in the Norwegian Childhood Diabetes registry may have disease causing MODY mutations, according to a study recently published by the investigator's group and others.
MODY associated mutations in the transcription factors HNF1A, HNF4A, and HNF1B leads to activation of the potassium channel causing depolarisation of the beta-cell membrane, which is crucial for excretion of insulin. By treating patients with HNF1A-MODY, HNF4A-MODY, and HNF1B-MODY with sulfonylurea class of drugs, these channels will close, causing depolarisation of the beta-cell membrane, and release of insulin. Hence, these patients can often stop insulin treatment when they are treated with sulfonylurea class drugs.
Due to high throughput sequencing, a number of rare variants in these genes have been discovered. In many cases, bioinformatic tools are not sufficient to correctly classify these variants. In the present study, we intend to identify rare variants in the HNF1A, HNF4A, and HNF1B genes in patients with insulin dependent diabetes identified through the Norwegian Childhood Diabetes registry or the Norwegian MODY Registry with possibly disease causing HNF1A, HNF4A, or HNF1B mutations with sulfonylurea to see if they can reduce or even stop insulin treatment, and regulate their diabetes with sulfonylurea only. All variants will be investigated by bioinformatics tools as well as functional assays (tests for DNA-binding, transcriptional activation, nuclear localisation, protein expression). Primary endpoints are efficacy of sulfonylurea treatment measured by insulin requirement or not and level of HbA1c. Secondary endpoints are tolerance of sulfonylurea and effect on insulin secretion by oral and intravenous glucose tolerance tests. Bioinformatics and functional characterisation will be compared with success to reach primary endpoints.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 95 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diabetes and DNA sequence variant of unknown significance (VUS, class 3) or pathogenic (class 4, and 5) in the HNF1A, HNF4A, or HNF1B genes
- •On insulin treatment
- •Willing and able to provide informed consent (parents if younger than 16 years of age)
排除标准
- •Known anaphylactic response to sulfonylurea
- •Diabetes and DNA sequence variant in the HNF1A, HNF4A, or HNF1B genes that are known to be non-pathogenic (class 1-2)
- •Not willing or able to provide informed consent (parents if younger than 16 years of age)
研究组 & 干预措施
Sulfonylurea treatment group
Increasing doses of sulfonylurea class of drug to see whether insulin treatment can be reduced in dose or stopped.
干预措施: Sulfonylurea (Drug)
结局指标
主要结局
Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg per day
时间窗: 5 years
Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg bodyweight per day, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
Metabolic control of diabetes measured by HbA1c in mmol/mol
时间窗: 5 years
Metabolic control of diabetes measured by HbA1c in mmol/mol, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
次要结局
- Level of sulfonylurea dose in mg per kg per day(5 years)
- Effect on endogenous insulin secretion assessed by intravenous glucose tolerance tests(5 years)
- Prevalence of side effects of sulfonylurea(5 years)
- Effect on secretion of incretin hormones, assessed by oral glucose tolerance tests(5 years)