This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huopio, H. Articles by Otonkoski, T. Search for Related Content PubMed PubMed Citation Articles by Huopio, H. Articles by Otonkoski, T.

Acute Insulin Response Tests for the Differential Diagnosis of Congenital Hyperinsulinism

Departments of Pediatrics (H.H., J.J., J.K., R.V.) and Medicine (R.M., P.K., M.L.), Kuopio University Hospital, FIN-70211 Kuopio; Department of Pediatrics (P.T.), Oulu University Hospital, FIN-90029 Oulu; and Transplantation Laboratory, Haartman Institute, and the Hospital for Children and Adolescents (T.O.), University of Helsinki, FIN-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Hanna Huopio, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, Fin-70211 Kuopio, Finland. E-mail: hanna.huopio{at}uku.fi.

Abstract

Mutations in genes encoding the two subunits of the ß-cell ATP-sensitive potassium channel (K_ATP) channel (SUR1 and Kir6.2) are the major cause of congenital hyperinsulinism (CHI). In this study, the K_ATP channel genes were screened in a population-based study that included all verified Finnish CHI patients (n = 43) in a 27-yr period. Seven different mutations were identified, which accounted for 60% of all cases. The functional consequences of the major missense mutations were studied in vivo by determining acute (1–3 min) plasma insulin and C-peptide responses to calcium (n = 18), glucose (n = 12), and tolbutamide (n = 11) in those CHI patients who were able to take part in these studies. C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without K_ATP channel mutations. The patients with SUR1-V187D mutation showed a reduced response to tolbutamide but unexpectedly did not show any response to calcium stimulation. A compound heterozygous patient with Kir6.2-(-54)/K67N mutations responded to calcium but also to tolbutamide. In conclusion, our results show that a positive response in the calcium test is indicative of a K_ATP channel mutation, but all mutations cannot be identified with this method. The insulin response to tolbutamide in patients with SUR1 mutations is impaired to different extents, depending on the genotype. The combination of calcium and tolbutamide tests is a useful tool for the detection of CHI patients with K_ATP channel dysfunction. Our results, however, also demonstrate the complexity of these responses and the difficulties in their interpretation.

This article has been cited by other articles:

				V. Padmanabhan, A. Veiga-Lopez, D. H. Abbott, S. E. Recabarren, and C. Herkimer Developmental Programming: Impact of Prenatal Testosterone Excess and Postnatal Weight Gain on Insulin Sensitivity Index and Transfer of Traits to Offspring of Overweight Females Endocrinology, February 1, 2010; 151(2): 595 - 605. [Abstract] [Full Text] [PDF]

				H. Hibino, A. Inanobe, K. Furutani, S. Murakami, I. Findlay, and Y. Kurachi Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles Physiol Rev, January 1, 2010; 90(1): 291 - 366. [Abstract] [Full Text] [PDF]

				S. E. Calvo, D. J. Pagliarini, and V. K. Mootha Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans PNAS, May 5, 2009; 106(18): 7507 - 7512. [Abstract] [Full Text] [PDF]

				K Mazor-Aronovitch, D Gillis, D Lobel, H J Hirsch, O Pinhas-Hamiel, D Modan-Moses, B Glaser, and H Landau Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism Eur. J. Endocrinol., October 1, 2007; 157(4): 491 - 497. [Abstract] [Full Text] [PDF]

				K. Hussain, M. Seppanen, K. Nanto-Salonen, N. S. Adzick, C. A. Stanley, P. Thornton, and H. Minn The Diagnosis of Ectopic Focal Hyperinsulinism of Infancy with [18F]-Dopa Positron Emission Tomography J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2839 - 2842. [Abstract] [Full Text] [PDF]

				E. Marthinet, A. Bloc, Y. Oka, Y. Tanizawa, B. Wehrle-Haller, V. Bancila, J.-M. Dubuis, J. Philippe, and V. M. Schwitzgebel Severe Congenital Hyperinsulinism Caused by a Mutation in the Kir6.2 Subunit of the Adenosine Triphosphate-Sensitive Potassium Channel Impairing Trafficking and Function J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5401 - 5406. [Abstract] [Full Text] [PDF]

				M. J. Henwood, A. Kelly, C. MacMullen, P. Bhatia, A. Ganguly, P. S. Thornton, and C. A. Stanley Genotype-Phenotype Correlations in Children with Congenital Hyperinsulinism Due to Recessive Mutations of the Adenosine Triphosphate-Sensitive Potassium Channel Genes J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 789 - 794. [Abstract] [Full Text] [PDF]

				C. J. Westlake, L. Payen, M. Gao, S. P. C. Cole, and R. G. Deeley Identification and Characterization of Functionally Important Elements in the Multidrug Resistance Protein 1 COOH-terminal Region J. Biol. Chem., December 17, 2004; 279(51): 53571 - 53583. [Abstract] [Full Text] [PDF]

				I. Giurgea, K. Laborde, G. Touati, C. Bellanne-Chantelot, M.-C. Nassogne, C. Sempoux, F. Jaubert, N. Khoa, V. Chigot, J. Rahier, et al. Acute Insulin Responses to Calcium and Tolbutamide Do Not Differentiate Focal from Diffuse Congenital Hyperinsulinism J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 925 - 929. [Abstract] [Full Text] [PDF]

				C. A. Stanley, P. S. Thornton, A. Ganguly, C. MacMullen, P. Underwood, P. Bhatia, L. Steinkrauss, L. Wanner, R. Kaye, E. Ruchelli, et al. Preoperative Evaluation of Infants with Focal or Diffuse Congenital Hyperinsulinism by Intravenous Acute Insulin Response Tests and Selective Pancreatic Arterial Calcium Stimulation J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 288 - 296. [Abstract] [Full Text] [PDF]

				M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY Hyperinsulinism in Infancy: From Basic Science to Clinical Disease Physiol Rev, January 1, 2004; 84(1): 239 - 275. [Abstract] [Full Text] [PDF]

				T. Otonkoski, N. Kaminen, J. Ustinov, R. Lapatto, T. Meissner, E. Mayatepek, J. Kere, and I. Sipila Physical Exercise-Induced Hyperinsulinemic Hypoglycemia Is an Autosomal-Dominant Trait Characterized by Abnormal Pyruvate-Induced Insulin Release Diabetes, January 1, 2003; 52(1): 199 - 204. [Abstract] [Full Text] [PDF]