Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes

J Clin Endocrinol Metab. 2006 Jul;91(7):2782-8. doi: 10.1210/jc.2006-0201. Epub 2006 Apr 24.


Context: Birth weight is a bioassay for fetal insulin secretion because altered insulin secretion in utero alters insulin-mediated growth. Activating mutations in Kir6.2 are the major cause of neonatal diabetes and reduce insulin secretion by altering the closure of the beta-cell ATP-sensitive potassium channel in the presence of ATP.

Objective: Our objective was to examine fetal and postnatal growth in patients with activating Kir6.2 mutations and identify whether this was modified by severity of mutation or maternal diabetes.

Patients and methods: We used sd scores (SDS) for birth and postnatal growth in an international series of patients (n = 49) with Kir6.2 mutations and related this to their clinical phenotype.

Results: Birth weight was greatly reduced [-1.73 (-3.68 to 1.41), median (range) SDS], but there was postnatal catch-up because present weight was normal [-0.37 (-4.37 to 2.34) SDS]. Catch-up growth for height and weight was not seen until insulin treatment was started. Birth weight was not influenced by severity of postnatal phenotype but was increased by maternal diabetes -0.12 vs. -1.81 SDS (P = 0.037). Patients with the severe neurological developmental delay, epilepsy, and neonatal diabetes syndrome did not catch up (present weight -2.2 vs. -0.24 SDS (P = 0.003).

Conclusions: Kir6.2 mutations greatly reduce fetal insulin secretion and hence fetal growth, but this is independent of mutation severity. Increased fetal growth in response to maternal diabetes suggests that either the Kir6.2 mutated fetal beta-cell is still glucose responsive or there is a non-insulin-mediated increase in fetal growth. Postnatal catch-up requires insulin treatment but is complete, except in those with epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Birth Weight
  • Body Height
  • Body Weight
  • Diabetes Mellitus / genetics*
  • Female
  • Fetal Development / genetics*
  • Growth / genetics*
  • Humans
  • Infant, Newborn
  • Insulin / metabolism
  • Insulin / physiology
  • Insulin Secretion
  • Mutation*
  • Phenotype
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Pregnancy
  • Pregnancy in Diabetics


  • Insulin
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying