Clinical Heterogeneity in Monogenic Diabetes Caused by Mutations in the Glucokinase Gene (GCK-MODY)
- Antonio L. Cuesta-Muñoz, MD, PHD1,
- Tiinamaija Tuomi, MD, PHD2,
- Nadia Cobo-Vuilleumier, MSC1,
- Hanna Koskela, PHD2,
- Stella Odili, BA3,
- Amanda Stride, MRCP4,
- Carol Buettger, BA3,
- Timo Otonkoski, MD5,
- Philippe Froguel, MD, PHD6,
- Joseph Grimsby, PHD7,
- Maria Garcia-Gimeno, PHD8 and
- Franz M. Matschinsky, MD, PHD3
- 1IMABIS Foundation and Center for the Study of Pancreatic β-Cell Diseases, Carlos Haya University Hospital, Málaga, Spain;
- 2Research Program for Molecular Medicine, Helsinki University, Department of Medicine, Helsinki University Hospital, and the Genetic Institute, Folkhalsan Research Center, Helsinki, Finland;
- 3Department of Biochemistry and Biophysics and Diabetes Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
- 4Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.;
- 5Hospital for Children and Adolescents and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland;
- 6Centre National de la Recherche Scientifique, Institute of Biology, Pasteur Institute, Lille, France;
- 7Department of Metabolic Diseases, Hoffmann-La Roche, Nutley, New Jersey;
- 8Biomedicine Institute of Valencia and of Rare Diseases, Valencia, Spain.
- Corresponding author: Antonio L. Cuesta-Muñoz, alcm{at}fundacionimabis.org.
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A.L.C.-M. and T.T. contributed equally to this article.
Abstract
OBJECTIVE To evaluate the heterogeneity in the clinical expression in a family with glucokinase mature-onset diabetes of the young (GCK-MODY).
RESEARCH DESIGN AND METHODS Members (three generations) of the same family presented either with overt neonatal hyperglycemia, marked postprandial hyperglycemia, or glucosuria. Homeostasis model assessment of insulin resistance (HOMAIR) and insulinogenic and disposition indexes were calculated. Oral glucose tolerance test (OGTT) results in the GCK mutation carriers from this family were compared with those from other subjects with GCK mutations in the same codon (GCK261), with other missense and other types of GCK mutations in different codons from the European MODY Consortium database (GCKm).
RESULTS Mutation G261R was found in the GCK gene. During the OGTT, glucose (P = 0.02) and insulin (P = 0.009) response at 2 h as well as at the 2-h glucose increment (GCK261 versus other missense GCK mutations, P = 0.003) were significantly higher in GCK261 than in GCKm carriers.
CONCLUSIONS Differing from other GCKm carriers, the glucose and insulin response to oral glucose was significantly higher in GCK261 carriers, indicating clinical heterogeneity in GCK-MODY.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received May 8, 2009.
- Accepted October 27, 2009.
- © 2010 by the American Diabetes Association.
