ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Int J Mol Sci. 2019 May 27;20(10). pii: E2590. doi: 10.3390/ijms20102590. PMID:31137773.

Ion channels and transporters play essential roles in excitable cells, including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, KATPchannels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential and ultimately, insulin secretion. In addition, ion channels and transporters have roles in non-excitable tissues such as the liver and skeletal muscle. Mutations in the genes encoding the ion transporter and channel proteins lead to several diseases related to glucose physiology. For example, mutations in the genes ABCC8/KCNJ11 which encode for the pancreatic K_ATP channels lead to different forms of congenital hyperinsulinism (CHI), neonatal diabetes mellitus (NDM) and in some cases Maturity Onset Diabetes of the Young (MODY). The voltage-gated potassium channel (Kv11.2) and the Kv7.1 channel have also been linked to possible episodes of hypoglycaemia. In addition, defects in some calcium channels (Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D )) also lead to hyperinsulinaemic hypoglycaemia (HH). Genetic defects in the membrane transporter (MCT1) lead to exercise induced HH. Mutations in the glucose transporter GLUT2 as associated with Fanconi-Bickel syndrome which can present with dysglycaemia (post-prandial hyperglycaemia, fasting hypoglycaemia and neonatal diabetes mellitus). Mutations in SLC19A2 ion transporter lead to Thiamine-responsive megaloblastic anaemia (TRMA), also known as Roger’s Syndrome, an autosomal recessive disorder characterized by early-onset non-autoimmune DM, megaloblastic anaemia, and sensorineural deafness. Finally, Genome-Wide Association Studies (GWAS) have identified variants or polymorphisms in channel and ion transporter genes associated with type 2 diabetes mellitus (T2DM). For example, the non-synonymous E23K variant in theKCNJ11was the first robustly replicating signal to emerge as a link to T2DM. Thus, genetic defects in ion channels and transporters genes are associated with a large number of diseases related to glucose physiology.