Possible New Strategies for the Treatment of Congenital Hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.

ATP binding without hydrolysis switches sulfonylurea receptor 1 (SUR1) to outward-facing conformations that activate K channels.

Neuroendocrine-type ATP-sensitive K (K) channels are metabolite sensors coupling membrane potential with metabolism, thereby linking insulin secretion to plasma glucose levels. They are octameric complexes, (SUR1/Kir6.2), comprising sulfonylurea receptor 1 (SUR1 or ABCC8) and a K-selective inward rectifier (Kir6.

ATP mediates a negative autocrine signal on stimulus-secretion coupling in mouse pancreatic β-cells.

Purpose: The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal.

Atrial Natriuretic Peptide Affects Stimulus-Secretion Coupling of Pancreatic β-Cells.

Atrial natriuretic peptide (ANP) influences glucose homeostasis and possibly acts as a link between the cardiovascular system and metabolism, especially in metabolic disorders like diabetes. The current study evaluated effects of ANP on β-cell function by the use of a β-cell-specific knockout of the ANP receptor with guanylate cyclase activity (βGC-A-KO). ANP augmented insulin secretion at the threshold glucose concentration of 6 mmol/L and decreased K single-channel activity in β-cells of control mice but not of βGC-A-KO mice.

The LXR Ligand T0901317 Acutely Inhibits Insulin Secretion by Affecting Mitochondrial Metabolism.

The role of liver X receptor (LXR) in pancreatic β-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in β-cells induces lipotoxicity, a key step in the development of β-cell dysfunction, which accompanies type 2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the micromolar range to study the significance of LXR activation.