Permanent Neonatal Diabetes Mellitus Clinical Trial
Official title:
Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to ABCC8 (SUR1) Mutations
The purpose of this study is to investigate long term response of sulfonylurea and glucose control in children with diabetes due to mutations in ABCC8 that have been switched from insulin injections to sulfonylurea tablets.
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.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Enrolling by invitation |
NCT03655223 -
Early Check: Expanded Screening in Newborns
|
||
| Completed |
NCT02624817 -
Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
|
Phase 4 |