Physical Exercise-Induced Hyperinsulinemic Hypoglycemia Is an Autosomal-Dominant Trait Characterized by Abnormal Pyruvate-Induced Insulin Release
- Timo Otonkoski12,
- Nina Kaminen3,
- Jarkko Ustinov1,
- Risto Lapatto2,
- Thomas Meissner4,
- Ertan Mayatepek4,
- Juha Kere35 and
- Ilkka Sipilä2
- 1Program for Developmental and Reproductive Biology, Biomedicum, Helsinki, and the Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
- 2Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
- 3Department of Medical Genetics, University of Helsinki, Helsinki, Finland
- 4Department of General Pediatrics, University Children’s Hospital, Düsseldorf, Germany
- 5Department of Biosciences at Novum and Clinical Research Center, Karolinska Institute, Stockholm, Sweden
We have identified patients in whom strenuous physical exercise leads to hypoglycemia caused by inappropriate insulin release (exercise-induced hyperinsulinism [EIHI]). The aim of the present study was to test the hypothesis that the increased levels of lactate and/or pyruvate during anaerobic exercise would trigger the aberrant insulin secretion in these patients. A total of 12 patients (8 women and 4 men from two families) were diagnosed with EIHI, based on hypoglycemia and a more than threefold increase in plasma insulin induced by a 10-min bicycle exercise test. The mode of inheritance was autosomal dominant in these families. The acute response of insulin release to a bolus of intravenous pyruvate (13.9 mmol/1.73 m2) was studied in the patients and eight healthy control subjects. Insulin secretion did not respond to the pyruvate bolus in healthy control subjects. However, all EIHI patients responded to pyruvate, displaying a brisk increase in plasma insulin. The 1 + 3-min peak response was 5.6-fold in the patients and 0.9-fold in the control subjects (P < 0.001). To test the hypothesis that the pathogenesis of EIHI would involve monocarboxylate transport or metabolism in the β-cell, we sequenced the genes encoding the known monocarboxylate transporter proteins and tested the transport of pyruvate into patient fibroblasts. The results revealed normal coding sequences and pyruvate transport. In conclusion, EIHI represents a new autosomal-dominant hyperinsulinemia syndrome that may be more common than has been realized. The pyruvate test provides a simple, safe, and specific diagnostic test for this condition.
Address correspondence and reprint requests to Timo Otonkoski, MD, Biomedicum Helsinki, Room C503b, PO Box 63, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland. E-mail:.
Received for publication 15 April 2002 and accepted in revised form 14 October 2002.
CHI, congenital hyperinsulinism; EIHI, exercise-induced hyperinsulinism; KRB, Krebs-Ringer bicarbonate buffer; MCT, monocarboxylate transporter.