ABCMdb

PMID: 23903354

Shimomura K, Tusa M, Iberl M, Brereton MF, Kaizik S, Proks P, Lahmann C, Yaluri N, Modi S, Huopio H, Ustinov J, Otonkoski T, Laakso M, Ashcroft FM
A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1.
Diabetes. 2013 Nov;62(11):3797-806. doi: 10.2337/db12-1611. Epub 2013 Jul 31., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC8 p.Glu1506Lys A Mouse Model of Human Hyperinsulinism Produced by the E1506K Mutation in the Sulphonylurea Receptor SUR1 Kenju Shimomura,1 Maija Tusa,2 Michaela Iberl,1 Melissa F. Brereton,1 Stephan Kaizik,1 Peter Proks,1 Carolina Lahmann,1 Nagendra Yaluri,2 Shalem Modi,2 Hanna Huopio,3 Jarkko Ustinov,4 Timo Otonkoski,4,5 Markku Laakso,2 and Frances M. Ashcroft1 Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Login to comment 1 ABCC8 p.Glu1506Lys Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). Login to comment 2 ABCC8 p.Glu1506Lys We generated a mouse expressing SUR1-E1506K in place of SUR1. Login to comment 8 ABCC8 p.Glu1506Lys We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age. Login to comment 23 ABCC8 p.Glu1506Lys Members of one family, who are heterozygous carriers of the SUR1-E1506K mutation, have mild neonatal HI but are at increased risk of diabetes in middle age (9,14); 4 out of 11 had overt diabetes, and 5 of those without diabetes showed impaired glucose tolerance. Login to comment 24 ABCC8 p.Arg370Ser Similarly, a child with a heterozygous SUR1-R370S mutation causing neonatal hyperinsulinism developed diabetes at 10 years of age (15). Login to comment 26 ABCC8 p.Glu1506Lys Despite their impaired glucose tolerance, blood glucose levels were normal in heterozygous carriers of the SUR1-E1506K mutation without diabetes, and only slightly increased in those with diabetes (14). Login to comment 27 ABCC8 p.Glu1506Lys Electrophysiological studies indicate that the E1506K mutation does not impair membrane trafficking but results in channels that are no longer activated by MgATP (9,16). Login to comment 39 ABCC8 p.Glu1506Lys Why this translates into reduced insulin secretion later in life is unclear, as is why impaired insulin secretion was observed in all carriers of the E1506K mutation but diabetes in only some of them. Login to comment 47 ABCC8 p.Glu1506Lys To address these questions, we generated a mouse carrying a human HI mutation, SUR1-E1506K, which causes neonatal hypoglycemia and predisposes to diabetes late in life (9,14). Login to comment 49 ABCC8 p.Glu1506Lys RESEARCH DESIGN AND METHODS Generation of E1506K mice. Login to comment 50 ABCC8 p.Glu1506Lys Knock-in mice expressing the murine SUR1 (Abcc8) gene containing a G-to-A missense mutation corresponding to the human SUR1-E1506K mutation were produced by targeted mutagenesis. Login to comment 52 ABCC8 p.Glu1506Lys The GAA-to-AAA change, corresponding to the GAG-to-AAG mutation in human SUR1-E1506K carriers, was introduced into mouse genomic DNA spanning 8.6 kb over the Abcc8 gene exons 30-39. Login to comment 59 ABCC8 p.Glu1506Lys These mice were then back-crossed to C57Bl/6J mice to segregate the cre transgene, and Sur1wt/E1506K /neo2/2 /cre2/2 offspring were used for further breeding. Login to comment 123 ABCC8 p.Glu1506Lys Targeted mutagenesis of the murine Abcc8 gene and production of the SUR1-E1506K knock-in mice. Login to comment 125 ABCC8 p.Glu1506Lys The Abcc8w/E1506K /neo2/2 /cre2/2 offspring were used for further breeding. Login to comment 148 ABCC8 p.Glu1506Lys RESULTS Generation of SUR1-E1506K mice. Login to comment 149 ABCC8 p.Glu1506Lys Mice homozygously expressing the E1506K mutation in SUR1 were generated by targeted mutagenesis of the SUR1 (Abcc8) gene (Fig. 1A) and back-crossed for eight generations onto a C57BL/6J background. Login to comment 150 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys Genotyping demonstrated the presence of the mutant allele in heterozygous SUR1-E1506K (hetE1506K) and homozygous E1506K (homE1506K) mice (Fig. 1B). Login to comment 151 ABCC8 p.Glu1506Lys C57BL/6J mice were used as controls and to generate heterozygous E1506K mice. Login to comment 161 ABCC8 p.Glu1506Lys The E1506K mutation increased the sensitivity of the KATP channel to MgATP, half-maximal inhibition being produced by 33, 14, and 10 mmol/L in inside-out patches from WT, hetE1506K, and homE1506K b-cells, respectively (Fig. 3B and Supplementary Table 1). Login to comment 164 ABCC8 p.Glu1506Lys These data also show that, as suggested from studies of heterologously expressed channels (9), mutant SUR1-E1506K subunits do not exert a dominant-negative effect on WT subunits in vivo. Login to comment 245 ABCC8 p.Glu1506Lys Similarly, some patients heterozygous for the E1506K mutation have severely reduced insulin secretion but no overt diabetes or glucose intolerance (9,14). Login to comment 268 ABCC8 p.Glu1506Lys It is possible that the enhanced basal insulin secretion caused by the E1506K mutation, which necessitates increased insulin production to maintain the same insulin content, places an additional stress on the b-cell that eventually leads to impaired insulin synthesis and/or trafficking (31). Login to comment 270 ABCC8 p.Glu1506Lys Interestingly, in vitro studies have shown that chronic exposure to glibenclamide (which simulates the effect of the E1506K mutation) also reduces insulin content (32). Login to comment 278 ABCC8 p.Glu1506Lys Although the E1506K mutation is dominant, homE1506K mice mimic the human disease more closely than hetE1506K mice. Why this is the case is unclear but presumably reflects differences in genetic background, lifestyle, or compensatory changes. Login to comment