KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies

Abstract

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic β-cells, adenosine triphosphate (ATP)-sensitive K+ (KATP) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of KATP channels are the most common cause of HI (KATP-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of KATP-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the KATP channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of KATP-HI, and offer perspectives on alternative therapeutic strategies.

Dynamic duo: Kir6 and SUR in K ATP channel structure and function

“…While drugs such as sulfonylureas and glinides stabilize the interface of the KNtp and SUR-ABC core to mimic ATP-bound closed conformation and inhibit channel activity [ 20 , 57 ], K ATP openers such as NN-414 and pinacidil stabilize SUR in the NBD dimerized conformation to stimulate channel activity [ 63 , 81 ]. Numerous K ATP gene mutations cause disease by altering channel sensitivity to ATP or MgADP [ 14 , 16 , 17 ]. Improved understanding of structural mechanisms of K ATP channel regulation will guide the development of isoform-specific K ATP channel drugs to improve the treatment of human disease.…”

Congenital Hyperinsulinism Caused by Mutations in ABCC8 Gene Associated with Early-Onset Neonatal Hypoglycemia: Genetic Heterogeneity Correlated with Phenotypic Variability

“…Although pathogenic variants in ABCC8 are more frequently associated with permanent and transient neonatal diabetes, late-onset cases are described. It is proven that autosomal dominant hyperinsulinism caused by LOF ABCC8 mutations develops reduced glucose tolerance and, in some cases, diabetes mellitus [12,32,33].…”

“…Mutations with loss of heterozygosity (LOH) in pancreatic somatic cells will determine the unbalanced expression of the imprinted genes (paternal IGF2, maternal H19 and CDKN1C) from the chromosomal 11p15.5 region, which regulates cell growth, with the appearance of focal adenomatous hyperplasia [10,11]. The presence of the paternally inherited, heterozygous K ATP mutations has a predictive value for focal CHI in 94% of cases [10,12]. In the focal form of CHI, the lesions are unique.…”

Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface

“…This enables insulin secretion to follow fluctuations in glucose concentrations. The central role of K ATP channels in insulin secretion and glucose homeostasis is underscored by dysregulated insulin secretion and blood glucose in humans bearing K ATP mutations: loss-of-function mutations cause congenital hyperinsulinism characterized by persistent insulin secretion despite life-threatening hypoglycemia 8 , 9 ; conversely, gain-of-function channel mutations result in neonatal diabetes due to insufficient insulin secretion 10 .…”