Clinical Trial: Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes

Study Status: Enrolling by invitation
Recruit Status: Enrolling by invitation
Study Type: Interventional

Official Title: Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to KCNJ11 (KIR6.2) Mutations

Brief Summary: The purpose of this study is to investigate long term response of sulfonylurea and glucose control in children with diabetes due to mutations in KCNJ11 that have been switched from insulin injections to sulfonylurea tablets.

Detailed Summary:

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 (Stoffers et al., 1997) or GCK (Njølstad et al., 2001) 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 (Gloyn et al., 2004; Babenko et al., 2006). 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 (Sagen et al., 2004). The effective replacement of insulin treatment by high-dose sulfonylureas has been shown to be successful in 90% of patients with Kir6.2 mutations (Pearson et al., 2006) and 85% of patients with SUR1 mutations (Rafiq et al., 2008) resulting in improved glycemic control.

  • Sulfonylurea efficacy [ Time Frame: Within 13 years from intervention ]
    Insulin requirement with or without sulfonylurea treatment during the intervention
  • Metabolic control [ Time Frame: Within 13 years from intervention ]
    Change in HbA1c levels during the intervention


    • Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • All cause mortality [ Time Frame: Within 13 years from intervention ]
      Death of all causes
    • Incidence of hypoglycemia [ Time Frame: Within 13 years from intervention ]
      Episodes per year of severe hypoglycemia (ISPAD definitions)
    • Incidence of ketoacidosis [ Time Frame: Within 13 years from intervention ]
      Episodes per year of severe ketoacidosis (ISPAD definitions)
    • Development of diarrhea [ Time Frame: Within 13 years from intervention ]
      Chronic diarrhea with no clear cause
    • Development of discoloured teeth [ Time Frame: Within 13 years from intervention ]
      Discoloured teeth with no clear cause
    • Insulin secretory response to intravenous glucose [ Time Frame: Within 13 years from intervention ]
      Change in increment of insulin and C-peptide after a standard intravenous glucose tolerance test tested at start of intervention and retested at end of the study
    • Insulin secretory response to oral glucose [ Time Frame: Within 13 years from intervention ]
      Change in increment of insulin and C-peptide after a standard oral glucose tolerance test tested at start of intervention and retested at end of the study
    • Sulfonylurea dose [ Time Frame: Within 13 years from intervention ]
      Change in sulfonylurea dose (per kg and day, and absolute dose per day) from start of intervention and up till end of study
    • Insulin secretory response to a glucagon test [ Time Frame: Within 13 years from intervention ]
      Change in increment of C-peptide and glucose after a standard glucagon test tested at start of intervention and retested at end of the study


    Original Secondary Outcome: Same as current

    Information By: Haukeland University Hospital

    Dates:
    Date Received: December 4, 2015
    Date Started: November 2015
    Date Completion: February 2016
    Last Updated: December 7, 2015
    Last Verified: December 2015