Acute Insulin Response Tests for the Differential Diagnosis of Congenital Hyperinsulinism

Abstract

Mutations in genes encoding the two subunits of the beta-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.

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

“…in the remaining case (36). To our knowledge, the mechanistic link between the gene mutation and uORFs had not been previously proposed for SRY (32), IRF6 (33), or GCH1 (34).…”

“…We found 11 additional mutations ( Table 2) that were detected by resequencing in known disease-related genes in affected patients (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). These uORF-altering mutations were not present in population controls (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), and were either the sole mutation detected in the sequenced exons, or were compound heterozygous with a missense/nonsense mutation ( Table 2). The patient presentation was consistent with a recessive phenotype in 3 of the 4 compound heterozygous cases (37, 38, 42, 43), and was ambiguous …”

Identification and Characterization of Functionally Important Elements in the Multidrug Resistance Protein 1 COOH-terminal Region

“…However, examination of the known ABC crystal structures supports the possibility of interactions between residues in sheet C2 and the Walker A motif in NBD2. Furthermore, a naturally occurring Val mutation of a Leu in SUR1 (Leu 1551 ) that is analogous to Leu 1500 in MRP1, impairs MgADP activation of K ATP channels and results in congenital hyperinsulinism (56,57 (58). In addition, nonconserved COOH-terminal residues have been identified recently in SUR2A and SUR2B splice variants that contribute to differences in ADP sensitivity (59).…”

Characterisation of new KATP-channel mutations associated with congenital hyperinsulinism in the Finnish population

“…Non-functional K ATP channels result in continuous depolarization of the beta cell and persistent insulin secretion, which is not linked to the plasma glucose concentration [16]. We investigated the functional effects of four new CHI mutations found in the Finnish population [23]. Three of these mutations are in the SUR1 subunit and the fourth is in Kir6.2.…”

“…1), recently identified in the Finnish population [23]. Three of these mutations are found in the C-terminal domain of SUR1 (L1551V, A1457T and V1550D), and one is found in the N-terminus of Kir6.2 (K67N).…”