ATP-sensitive potassium channelopathies: focus on insulin secretion

Abstract

ATP-sensitive potassium (K ATP ) channels, so named because they are inhibited by intracellular ATP, play key physiological roles in many tissues. In pancreatic β cells, these channels regulate glucose-dependent insulin secretion and serve as the target for sulfonylurea drugs used to treat type 2 diabetes. This review focuses on insulin secretory disorders, such as congenital hyperinsulinemia and neonatal diabetes, that result from mutations in K ATP channel genes. It also considers the extent to which defective regulation of K ATP channel activity contributes to the etiology of type 2 diabetes. General properties of ATP-sensitive potassium channelsPhysiological roles ATP-sensitive potassium (K ATP ) channels couple cell metabolism to electrical activity of the plasma membrane by regulating membrane K + fluxes (1). A reduction in metabolism opens K ATP channels, producing K + efflux, membrane hyperpolarization, and suppression of electrical activity. Conversely, increased metabolism closes K ATP channels. The consequent membrane depolarization stimulates electrical activity and may thereby trigger cellular responses such as the release of hormones and neurotransmitters, or muscle contraction.Studies on isolated cells and tissues, and more recently on genetically modified mice and patients with mutations in K ATP channel genes, have demonstrated that K ATP channels play a multitude of physiological roles (1). They contribute to glucose homeostasis by regulating insulin secretion from pancreatic β cells (2-7), glucagon secretion from pancreatic α cells (8), somatostatin secretion from D cells (9), and GLP-1 secretion from L cells (10). In ventromedial hypothalamic neurons they mediate the counter-regulatory response to glucose (11), and in arcuate nucleus neurons they may be involved in appetite regulation (12). In these glucose-sensing cells, K ATP channels respond to fluctuating changes in blood glucose concentration. In many other tissues, however, they are largely closed under resting conditions and open only in response to ischemia, hormones, or neurotransmitters. In cardiac muscle and central neurons the resulting reduction in electrical activity helps protect against cardiac stress and brain seizures (13-17). K ATP channels are involved in ischemic preconditioning in heart (18) and the regulation of vascular smooth muscle tone (opening of K ATP channels leads to relaxation) (19-21). They also modulate electrical activity and neurotransmitter release at synapses in many brain regions, including the hippocampus, substantia nigra, and hypothalamus (12,(22)(23)(24)(25)(26)(27).Given their critical role in regulating electrical excitability in many cells, it is perhaps not surprising that disruption of K ATP channel function can lead to disease. To date, mutations in K ATP channel genes have been shown to cause neonatal diabetes (7,(28)(29)(30)(31)(32)(33), hyperinsulinemia (6, 34-40), and dilated cardiomyopathy (41) in humans. Studies on genetically modified mice have also implicated impaired K ATP channel func...

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

“…Furthermore, the V252A mutation was associated with TNDM in one patient and with PNDM in others, highlighting the importance of the genetic background of the different patients and/or the role of environmental influences [34]. Differences in clinical phenotype associated with the same mutations have also been reported previously [8,9].…”

“…This adds to accumulating evidence that KCNJ11 mutations that cause neonatal diabetes do so by affecting K ATP channel ATP sensitivity, either directly or indirectly [8,9,13,14,[26][27][28][29][30].…”

“…In some patients, the diabetes is transient, although it may frequently relapse, whereas in other cases it is permanent and requires insulin treatment for life. The commonest cause of permanent neonatal diabetes (PNDM) are heterozygous activating mutations in the KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the K ATP channel in the pancreatic beta cell [7][8][9]. KCNJ11 mutations account for around 50% of cases of PNDM [7][8][9][10][11][12][13].…”

“…Mutations in K ATP channel subunits that reduce channel function lead to congenital hyperinsulinism, whereas those that enhance channel function cause diabetes [8,9]. To date, mutations in Kir6.2 associated with TNDM and PNDM have been shown to enhance K ATP channel activity by decreasing ATP inhibition at Kir6.2 [7-9, 13, 14, 26-31].…”

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

“…In contrast, Irs2 expression was not increased by either of the sulfonylureas. Sulfonylureas are known to close ATP-sensitive potassium channels regardless of glucose metabolism, and their closure results in membrane depolarisation, an influx of Ca 2+ through voltage-dependent Ca 2+ channels, and an increase in cytosolic free Ca 2+ concentration, thereby triggering insulin secretion [26]. If that is true, why did the sulfonylureas fail to increase Irs2 expression despite being able to increase the Ca 2+ influx?…”