Switching From Insulin to Sulfonylurea in Diabetes Associated With Variants in MODY Genes (SUtoChildT1D)

Switching From Insulin to Sulfonylurea in Childhood and Adult Diabetes Due to Variants in the HNF1A, HNF4A, or HNF1B Genes

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).

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.

Maturity-Onset Diabetes of the Young, Type 3, Maturity Onset Diabetes of the Young, Type 1, Childhood Diabetes Mellitus, Insulin-dependent Diabetes Mellitus

Switching insulin-treated diabetes patients with possibly disease causing mutations in HNF1A, HNF4A, or HNF1B to treatment with sulfonylurea.

Increasing doses of sulfonylurea class of drug to see whether insulin treatment can be reduced in dose or stopped.

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, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea

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

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

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

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

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)

Department of Pediatrics and Adolescents, Haukeland University Hospital, and Department of Clinical Science, Faculty of Medicine, University of Bergen

IPD that underlie the results in the planned publications. The IPD will be summary data, and with no personal identifiers.

IPD will be shared after written request and consideration to the corresponding author of the respective publication. Data will be shared with researchers in the same or similar field only. IPD will include summary data without personal identity and Describe by what access criteria IPD and any additional supporting information will be shared, including with whom, for what types of analyses, and by what mechanism. The corresponding and first authors will review requests and criteria for reviewing requests may also be provided.

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