Childhood Diabetes Mellitus, Insulin-dependent Diabetes Mellitus, Maturity Onset Diabetes of the Young, Type 1, Maturity-Onset Diabetes of the Young, Type 3
Conditions
Keywords
Maturity onset diabetes in the young, Childhood diabetes, Type 1 diabetes
Brief summary
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).
Detailed description
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.
Interventions
DRUGSulfonylurea
Starting treatment with sulfonylurea class of drug
Sponsors
Haukeland University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Switching insulin-treated diabetes patients with possibly disease causing mutations in HNF1A, HNF4A, or HNF1B to treatment with sulfonylurea.
Eligibility
Sex/Gender
ALL
Age
2 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
* 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)
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg per day | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Level of sulfonylurea dose in mg per kg per day | 5 years | Level of sulfonylurea dose in mg per kg body weight per day, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea |
| Prevalence of side effects of sulfonylurea | 5 years | Recording potential side effects of sulfonylurea, such as nausea, change in body weight, episodes of severe hypoglycemia, discolouration of teeth, diarrhoea, cardiovascular events, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea |
| Effect on endogenous insulin secretion assessed by intravenous glucose tolerance tests | 5 years | Maximum increment of serum insulin in nmol/L and serum c-peptide in pmol/L at intravenous glucose tolerance tests, recorded at intervals of 6-12 months after exposure to sulfonylurea compared to before initiation of sulfonylurea |
| Effect on secretion of incretin hormones, assessed by oral glucose tolerance tests | 5 years | Maximum increment of serum insulin in nmol/L, serum c-peptide in pmol/L and incretins (GIP in pmol/L and GLP-1 in pmol/L) at oral glucose tolerance tests and in comparison with intravenous gluclose tolerance tests, recorded at intervals of 6-12 months after exposure to sulfonylurea compared to before initiation of sulfonylurea |
Countries
Norway
Outcome results
None listed