Current understanding of KATP channels in neonatal diseases: focus on insulin secretion disorders

Abstract

ATP-sensitive potassium (K ATP ) channels are cell metabolic sensors that couple cell metabolic status to electric activity, thus regulating many cellular functions. In pancreatic beta cells, K ATP channels modulate insulin secretion in response to fluctuations in plasma glucose level, and play an important role in glucose homeostasis. Recent studies show that gain-of-function and loss-of-function mutations in K ATP channel subunits cause neonatal diabetes mellitus and congenital hyperinsulinism respectively. These findings lead to significant changes in the diagnosis and treatment for neonatal insulin secretion disorders. This review describes the physiological and pathophysiological functions of K ATP channels in glucose homeostasis, their specific roles in neonatal diabetes mellitus and congenital hyperinsulinism, as well as future perspectives of K ATP channels in neonatal diseases.

Structure of a Pancreatic ATP-Sensitive Potassium Channel

“…Calcium influx triggers insulin release from b cells (Ashcroft, 2006;Nichols, 2006). Moreover, genetic mutations of genes encoding K ATP subunits cause diseases, such as neonatal diabetes, hyperinsulinism, DEND syndrome, and Cantú syndrome (Nichols, 2006;Quan et al, 2011), manifesting that K ATP channels are important therapeutic targets. K ATP channel inhibitors, such as sulfonylureas, are widely used for treating type II diabetes, while K ATP channel activators, such as potassium channel openers, are used for treating hyperinsulinism and have shown great promise for myoprotection (Flagg et al, 2010).…”

Nucleotide inhibition of the pancreatic ATP-sensitive K+ channel explored with patch-clamp fluorometry

“…As such, mutations in KATP that affect its response to changes in cellular metabolism cause diseases of insulin secretion, e.g. neonatal diabetes and persistent hyperinsulinemic hypoglycaemia of infancy (PHHI; (Quan et al, 2011;Ashcroft et al, 2017)).…”

<p>Major miRNA Involved in Insulin Secretion and Production in Beta-Cells</p>

“…In pancreatic beta-cells, KATP channels regulate the secretion of insulin. 9 With regard to structure, KATP channels, as large hetero-octameric complexes include four regulatory sulphonylurea receptors (SURx) and four pore-forming (Kir6.x) (via cytoplasmic domains bind to ATP) subunits, which are encoded by ABCC8 and KCNJ11, respectively. 10,11 Considering the KATP channel activity, the membrane is held at a hyperpolarized level that results in voltage-gated Ca2+ channels' closure.…”