ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2109721118. doi: 10.1073/pnas.2109721118. PMID: 34732576.

Brief Summary: In a mouse model of KATP neonatal diabetes mellitus, this study examined the mechanisms of cognitive deficits and development delay observed in some patients with this form of diabetes. The cognitive deficits and development delay appeared to be independent of the diabetes per se.

Gain of function mutations in the KATP channel genes are the most common cause of neonatal diabetes mellitus (NDM) in some parts of the world (1). Some patients with NDM due to gain of function in the KATP channel genes also have epilepsy, cognitive defects and developmental delay (DEND syndrome). However, the underlying mechanisms are not clear.

These authors phenotyped mice with gain of function mutations in the KATP channels either specifically in the hippocampus or pan-neuronally and compared these mice with pancreatic KATP channel knockout mice. The pan-neuronal mice exhibited some similar cognitive features as found in DEND syndrome. The hippocampal expression of KATP gain of function was associated with cognitive but not sensorimotor deficits and associated with learning and memory defects. Hippocampal neurons from pan-neuronal and hippocampal specific KATP channel mice showed sensitivity to KATP channel openers and inhibitors. Learning and memory deficits were not improved by sulfonylurea therapy. Interestingly, mice with KATP gain of function in the pancreatic beta-cell had diabetes but no cognitive deficits.

These findings indicate that KATP-GOF (gain of function) channels in the hippocampal region play an important role in learning and memory deficits and that the cognitive deficits in DEND syndrome result from neuronal KATP-GOF expression rather than from diabetes per se. The inefficacy of sulfonylureas to improve cognitive deficits in mice agrees with the limited neurological improvements observed with treatment in human DEND.

These studies have important clinical implications, pointing to potential mechanisms underlying cognitive deficits of KATP-induced DEND syndrome and indicating the need for novel drugs to treat neurological features arising from KATP-GOF mutations while also providing a platform to study other brain abnormalities induced by ion channel dysfunction.

Reference: 1. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004 Apr 29;350(18):1838–49. doi: 10.1056/NEJMoa032922. PMID: 15115830.