Neonatal diabetes caused by a homozygous KCNJ11 mutation demonstrates that tiny changes in ATP sensitivity markedly affect diabetes risk

Abstract

Aims/hypothesisThe pancreatic ATP-sensitive potassium (KATP) channel plays a pivotal role in linking beta cell metabolism to insulin secretion. Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively. To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. Here, we report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation.MethodsA male patient was diagnosed with diabetes shortly after birth. At 5 months of age, genetic testing revealed he carried a homozygous KCNJ11 mutation, G324R, (Kir6.2-G324R) and he was successfully transferred to sulfonylurea therapy (0.2 mg kg−1 day−1). Neither heterozygous parent was affected. Functional properties of wild-type, heterozygous and homozygous mutant KATP channels were examined after heterologous expression in Xenopus oocytes.ResultsFunctional studies indicated that the Kir6.2-G324R mutation reduces the channel ATP sensitivity but that the difference in ATP inhibition between homozygous and heterozygous channels is remarkably small. Nevertheless, the homozygous patient developed neonatal diabetes, whereas the heterozygous parents were, and remain, unaffected. Kir6.2-G324R channels were fully shut by the sulfonylurea tolbutamide, which explains why the patient’s diabetes was well controlled by sulfonylurea therapy.Conclusions/interpretationThe data demonstrate that tiny changes in KATP channel activity can alter beta cell electrical activity and insulin secretion sufficiently to cause diabetes. They also aid our understanding of how the Kir6.2-E23K variant predisposes to type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3964-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…The Kir6.2-G324R mutation reduces the channel ATP sensitivity in beta cells; however, the difference in ATP inhibition between homozygous and heterozygous patients was remarkably small. Nevertheless, the homozygous patient developed neonatal diabetes, whereas the heterozygous parents were unaffected (Vedovato et al, 2016).…”

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

“…2). Recent reports of GoF mutations in Kir6.2 and SUR1 that underlie neonatal diabetes demonstrate that even very subtle biophysical effects can result in disease (42), suggesting that dramatic changes may not be necessary. In contrast, because SUR2B may be the more pathologically relevant splice variant, it is possible that these mutations will have a greater effect on channels containing SUR2B.…”

Reflections on the sulphonylurea story: A drug class at risk of extinction or a drug class worth reviving?

“…It is debated if Kir6.2 (E23K) causes a reduction in ATP‐inhibition . Others postulate that the polymorphism in SUR1 (A1369S), which is linked to Kir6.2 (E23K), drives lower ATP‐sensitivity . Therefore, for at least some patients with diabetes, K ATP channel dysfunction contributes to their diabetes aetiology, and these patients may have a hyperpolarized beta‐cell.…”

“…38,41 Others postulate that the polymorphism in SUR1 (A1369S), which is linked to Kir6.2 (E23K), drives lower ATP-sensitivity. 42 Therefore, for at least some patients with diabetes, K ATP channel dysfunction contributes to their diabetes aetiology, and these patients may have a hyperpolarized beta-cell. The parallels here with NDM are apparent, suggesting that an appropriate dose of SU may promote GSIS with minimal hypoglycaemia.…”