Insulin-dependent Diabetes Mellitus Clinical Trial
Official title:
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.
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