Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

Diabetes Care. 2015 Nov;38(11):2033-41. doi: 10.2337/dc15-0837. Epub 2015 Oct 5.

Abstract

Objective: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin.

Research design and methods: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing.

Results: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin.

Conclusions: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

Trial registration: ClinicalTrials.gov NCT00610038.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Brain / pathology
  • Child
  • Child, Preschool
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / physiopathology
  • Drug Substitution*
  • Female
  • Glyburide / administration & dosage
  • Glyburide / therapeutic use*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / therapeutic use*
  • Infant
  • Infant, Newborn
  • Insulin / administration & dosage
  • Insulin / therapeutic use
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Neurologic Manifestations
  • Neuropsychological Tests
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Psychomotor Performance
  • Sulfonylurea Receptors / genetics

Substances

  • ABCC8 protein, human
  • Hypoglycemic Agents
  • Insulin
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Sulfonylurea Receptors
  • Glyburide

Supplementary concepts

  • Diabetes Mellitus, Permanent Neonatal, With Neurologic Features

Associated data

  • ClinicalTrials.gov/NCT00610038