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, 53 (11), 2352-6

A Mutation in KCNJ11 Causing Human Hyperinsulinism (Y12X) Results in a Glucose-Intolerant Phenotype in the Mouse

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A Mutation in KCNJ11 Causing Human Hyperinsulinism (Y12X) Results in a Glucose-Intolerant Phenotype in the Mouse

A Hugill et al. Diabetologia.

Abstract

Aims/hypothesis: We identified a mouse with a point mutation (Y12STOP) in the Kcnj11 subunit of the K(ATP) channel. This point mutation is identical to that found in a patient with congenital hyperinsulinism of infancy (HI). We aimed to characterise the phenotype arising from this loss-of-function mutation and to compare it with that of other mouse models and patients with HI.

Methods: We phenotyped an N-ethyl-N-nitrosourea-induced mutation on a C3H/HeH background (Kcnj11 ( Y12STOP )) using intraperitoneal glucose tolerance testing to measure glucose and insulin plasma concentrations. Insulin secretion and response to incretins were measured on isolated islets.

Results: Homozygous male and female adult Kcnj11 ( Y12STOP ) mice exhibited impaired glucose tolerance and a defect in insulin secretion as measured in vivo and in vitro. Islets had an impaired incretin response and reduced insulin content.

Conclusions/interpretation: The phenotype of homozygous Kcnj11 ( Y12STOP ) mice is consistent with that of other Kcnj11-knockout mouse models. In contrast to the patient carrying this mutation homozygously, the mice studied did not have hyperinsulinaemia or hypoglycaemia. It has been reported that HI patients may develop diabetes and our mouse model may reflect this clinical feature. The Kcnj11 ( Y12STOP ) model may thus be useful in further studies of K(ATP) channel function in various cell types and in investigation of the development of hyperglycaemia in HI patients.

Conflict of interest statement

Duality of Interest

The authors declare that there is no duality of interest associated with this manuscript.

Figures

Figure 1
Figure 1. Impaired glucose tolerance and increased insulin sensitivity.
Glucose tolerance (a, b), insulin secretion (c, d) and insulin tolerance (e) in homozygous (hom, square line symbols), heterozygous (het, triangular line symbols) and wildtype littermate (wt, diamond line symbols) backcross three Kcnj11Y12STOP mice at 12 weeks of age. (a,c) Female mice, (b,d) Male mice. For (a),(b),(c) and (d) n=9 wt, n=16 het, n=7 hom. (e) Male 8-week mice, n= 12 wt, n=13 het, n=7 hom. Data are given as mean±SD. * = p<0.05, ** = p<0.01 and *** = p<0.001 for Student’s t-test when comparing hom to wt.
Figure 2
Figure 2. Impaired insulin secretion and incretin response in islets isolated from wildtype, heterozygous or homozygous Kcnj11Y12STOP mice.
(a) Insulin secretion, expressed as a percentage of insulin content, in response to 2mmol/l glucose, 20mmol/l glucose or 100µmol/l tolbutamide plus 7mmol/l glucose for islets isolated from wildtype (white bars), heterozygous (grey bars) or homozygous (black bars) littermates. The data are the mean of three separate experiments (i.e. 3 mice), with 5 replicates (each of 5 islets) at each concentration. (b) Insulin secretion, as a percentage of content, in response to the incretins GLP-1 (5µM GLP-1 + 20mmol/l glucose) or GIP (10µM GIP + 20mmol/l glucose). The data represent the mean±SEM of 4 independent experiments from 4 animals per genotype (with 3-8 replicates of 5 islets per animal). (c) Fold increase in insulin secretion produced by 5µM GLP-1 or 10µM GIP (expressed as the amount of insulin secretion induced by 20mmol/l glucose plus the indicated incretin, divided by that produced by 20mmol/l glucose alone). White bars, wildtype islets. Black bars, homozygous islets. (a-c), * = p<0.05, ** = p<0.01, and *** = p<0.001 for Student’s t-test comparing wildtype to homozygote, or comparing the incretin response to the 20mmol/l glucose alone response (as indicated). ns, not significant.

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