Permanent Neonatal Diabetes Caused by Glucokinase Deficiency

Inborn Error of the Glucose-Insulin Signaling Pathway

  1. Pål R. Njølstad12,
  2. Jørn V. Sagen1,
  3. Lise Bjørkhaug2,
  4. Stella Odili3,
  5. Naim Shehadeh4,
  6. Doua Bakry4,
  7. S. Umit Sarici5,
  8. Faruk Alpay5,
  9. Janne Molnes1,
  10. Anders Molven26,
  11. Oddmund Søvik1 and
  12. Franz M. Matschinsky3
  1. 1Department of Pediatrics, Haukeland University Hospital, University of Bergen, Norway
  2. 2Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, University of Bergen, Norway
  3. 3Department of Biochemistry and Biophysics, and Diabetes Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  4. 4Department of Pediatrics, Rambam Medical Center, Haifa, Israel
  5. 5Division of Newborn Medicine, Department of Pediatrics, Gülhane Military Medical Academy, Ankara, Turkey
  6. 6Department of Pathology, the Gade Institute, Haukeland University Hospital, University of Bergen, Norway
  1. Address correspondence and reprint requests to Pål R. Njølstad, MD, PhD, Department of Pediatrics, University of Bergen, N-5021 Bergen, Norway. E-mail: pal.njolstad{at}


Neonatal diabetes can be either permanent or transient. We have recently shown that permanent neonatal diabetes can result from complete deficiency of glucokinase activity. Here we report three new cases of glucokinase-related permanent neonatal diabetes. The probands had intrauterine growth retardation (birth weight <1,900 g) and insulin-treated diabetes from birth (diagnosis within the first week of life). One of the subjects was homozygous for the missense mutation Ala378Val (A378V), which is an inactivating mutation with an activity index of only 0.2% of wild-type glucokinase activity. The second subject was homozygous for a mutation in the splice donor site of exon 8 (intervening sequence 8 [IVS8] + 2T→G), which is predicted to lead to the synthesis of an inactive protein. The third subject (second cousin of subject 2) was a compound heterozygote with one allele having the splice-site mutation IVS8 + 2T→G and the other the missense mutation Gly264Ser (G264S), a mutation with an activity index of 86% of normal activity. The five subjects with permanent neonatal diabetes due to glucokinase deficiency identified to date are characterized by intrauterine growth retardation, permanent insulin-requiring diabetes from the first day of life, and hyperglycemia in both parents. Autosomal recessive inheritance and enzyme deficiency are features typical for an inborn error of metabolism, which occurred in the glucose-insulin signaling pathway in these subjects.


    • Accepted August 4, 2003.
    • Received April 7, 2003.
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