Loss-of-function mutations in the
KATP channel genes KCNJ11 and ABCC8 cause
neonatal hyperinsulinism in humans. Dominantly inherited mutations cause less severe disease, which may progress to
glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). We generated a mouse expressing SUR1-E1506K in place of SUR1.
KATP channel inhibition by
MgATP was enhanced in both homozygous (homE1506K) and heterozygous (hetE1506K) mutant mice, due to impaired channel activation by
MgADP. As a consequence, mutant β-cells showed less on-cell
KATP channel activity and fired action potentials in
glucose-free
solution. HomE1506K mice exhibited enhanced insulin secretion and lower fasting
blood glucose within 8 weeks of birth, but reduced insulin secretion and
impaired glucose tolerance at 6 months of age. These changes correlated with a lower
insulin content; unlike wild-type or hetE1506K mice,
insulin content did not increase with age in homE1506K mice. There was no difference in the number and size of islets or β-cells in the three types of mice, or evidence of β-cell proliferation. 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.