ATP-sensitive K + channels and disease: from molecule to malady
Abstract
This essay is based on a lecture given to the American Physiological Society in honor of Walter B. Cannon, an advocate of homeostasis. It focuses on the role of the ATP-sensitive potassium K(+) (K(ATP)) channel in glucose homeostasis and, in particular, on its role in insulin secretion from pancreatic beta-cells. The beta-cell K(ATP) channel comprises pore-forming Kir6.2 and regulatory SUR1 subunits, and mutations in either type of subunit can result in too little or too much insulin release. Here, I review the latest information on the relationship between K(ATP) channel structure and function, and consider how mutations in the K(ATP) channel genes lead to neonatal diabetes or congenital hyperinsulinism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the intact cell, KATP channel activity is determined by the balance between the stimulatory and inhibitory effects of nucleotides.
“In the intact cell, KATP channel activity is determined by the balance between the stimulatory and inhibitory effects of nucleotides (25).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [25]
Gain-of-function mutations in either Kir6.2 or SUR1 result in neonatal diabetes, which usually presents within the first six months of life and is associated with a low birth weight.
“Gain-of-function mutations in either Kir6.2 or SUR1 result in neonatal diabetes (ND), which usually presents within the first six months of life and is associated with a low birth weight (25, 29, 32, 43, 215, 255).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [25]
Cites
A genome-wide association study identifies novel risk loci for type 2 diabetes
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., et al. (2007) · Nature · doi:10.1038/nature05616 · Cited by 2,993 · see citing works
Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., et al. (2007) · Science · doi:10.1126/science.1142364 · Cited by 2,194 · see citing works
Intracellular ATP directly blocks K+ channels in pancreatic B-cells
Cook, D. L., & Hales, N. (1984) · Nature · doi:10.1038/311271a0 · Cited by 1,208 · cited 3× · see citing works
“A similar KATP channel had also just been described by Dan Cook and Nick Hales in inside-out patches excised from pancreatic -cells (10).”
BackgroundMethodGloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032922 · Cited by 1,137 · see citing works
Self-citationGloyn, A. L., Weedon, M. N., Owen, K. R., Turner, M. J., Knight, B. A., Hitman, G., Walker, M., Levy, J. C., Sampson, M., Halford, S., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.2.568 · Cited by 754 · see citing works
Detimary, P., Dejonghe, S., Ling, Z., Pipeleers, D., Schuit, F., & Henquin, J.-C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.33905 · Cited by 159 · cited 1× · see citing works
“to 4 mM when glucose is increased from 0 to 10 mM (11, 84).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Self-citationThe enteric nervous system: normal functions and enteric neuropathies
Furness, J. (2008) · Neurogastroenterology and Motility · doi:10.1111/j.1365-2982.2008.01094.x · Cited by 188 · see citing works
McTaggart, J. S., Clark, R. H., & Ashcroft, F. M. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.191767 · Cited by 168 · see citing works
“The role of the KATP channel in stimulus–secretion coupling in pancreatic β-cells is well established (Ashcroft et al. 1984; Ashcroft, 2007).”
Self-citationSUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator
Aittoniemi, J., Fotinou, C., Craig, T. J., de Wet, H., Proks, P., & Ashcroft, F. (2009) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2008.0142 · Cited by 155 · see citing works
“This loop is thought to contribute to sulphonylurea binding (Ashfield et al. 1999) and therefore presumably lies in close proximity to both TMD0 and the N-terminus of Kir6.”
Self-citationDuda, J., Pötschke, C., & Liss, B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13572 · Cited by 149 · see citing works
“…as their open probability is regulated by ATP- and ADP levels, as well as by a variety of other metabolic signals, such as insulin, leptin, ghrelin, longchain fatty acids (acyl-CoA), PIP2, pH, hydrogen peroxide, ROS/RNS, and nitric oxide (as reviewed in (Ashcroft 2007; Dragicevic et al. 2015)).”
BackgroundDragicevic, E., Schiemann, J. M., & Liss, B. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.10.037 · Cited by 137 · see citing works
“…in SN DA neurons might provide another novel neuroprotective strategy for PD. Pharmacological K-ATP channel blockers (like glibenclamide) are – similar to LTCC blockers – already well-established and widely used drugs to treat type 2 diabetes (T2D) (Ashcroft, 2007; Ashcroft and Rorsman, 2013).”
InfluentialAnti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM
Martin, G. M., Kandasamy, B., DiMaio, F., Yoshioka, C., & Shyng, S. (2017) · eLife · doi:10.7554/elife.31054 · Cited by 129 · see citing works
“2 and SUR1 are gated by intracellular ATP and ADP, with ATP inhibiting channel activity while Mg2+-complexed ATP and ADP stimulating channel activity (Aguilar-Bryan and Bryan, 1999; Ashcroft, 2007).”
BackgroundHyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells
Brereton, M. F., Rohm, M., Shimomura, K., Holland, C., Tornovsky-Babeay, S., Dadon, D., Iberl, M., Chibalina, M. V., Lee, S., Glaser, B., et al. (2016) · Nature Communications · doi:10.1038/ncomms13496 · Cited by 124 · see citing works
Self-citationNew insights into KATP channel gene mutations and neonatal diabetes mellitus
Pipatpolkai, T., Usher, S., Stansfeld, P. J., & Ashcroft, F. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0351-y · Cited by 122 · see citing works
Self-citationHuman KATP channelopathies: diseases of metabolic homeostasis
Olson, T. M., & Terzic, A. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0771-y · Cited by 112 · see citing works
“Failure to respond to stress load, in the context of a genetic defect and malfunction in sensor proteins, results in maladaptation and poor outcome highlighting the centrality of processes responsible for the maintenance of ecogenetic homeostasis in disease avoidance and species preservation [11, 83, 134].”
BackgroundClark, R., McTaggart, J., Webster, R., Männikkö, R., Iberl, M., Sim, X., Rorsman, P., Glitsch, M., Beeson, D., & Ashcroft, F. (2010) · Science · doi:10.1126/science.1186146 · Cited by 102 · see citing works
Self-citationWnt Signaling in Pancreatic Islets
Liu, Z., & Habener, J. F. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-3271-3_17 · Cited by 92 · see citing works
Shortcomings of current models of glucose‐induced insulin secretion
Henquin, J., Nenquin, M., Ravier, M., & Szollosi, A. (2009) · Diabetes, obesity and metabolism · doi:10.1111/j.1463-1326.2009.01109.x · Cited by 88
Is Type 2 Diabetes a Glycogen Storage Disease of Pancreatic β Cells?
Ashcroft, F. M., Rohm, M., Clark, A., & Brereton, M. F. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.014 · Cited by 84 · see citing works
Self-citationYang, G.-D., Tang, G., Zhang, L., Wu, L.-Y., & Wang, R. (2011) · American Journal of Pathology · doi:10.1016/j.ajpath.2011.04.028 · Cited by 83 · see citing works
“KATP channel activation also influences cell viability, and suppression of KATP channel activity protects murine pancreatic cells against oxidative stress.(34,35) In the present study, we found that STZ treatment significantly increased pancreatic H2S production in wildtype mice but not in CSE KO mice (Figure 4A), sug…”
BackgroundGupta, P., Bala, M., Gupta, S. K., Dua, A., Dabur, R., Injeti, E. R., & Mittal, A. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.09.029 · Cited by 90 · see citing works
Ion channels and regulation of insulin secretion in human β-cells: a computational systems analysis
Fridlyand, L. E., Jacobson, D. A., & Philipson, L. H. (2013) · Islets · doi:10.4161/isl.24166 · Cited by 78 · see citing works
Molecular structure of an open human KATP channel
Zhao, C., & MacKinnon, R. (2021) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2112267118 · Cited by 72 · see citing works
Modeling KATP channel gating and its regulation
Proks, P., & Ashcroft, F. M. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.10.002 · Cited by 65 · see citing works
Self-citationGlucose elicits cephalic-phase insulin release in mice by activating KATP channels in taste cells.
Glendinning, J., Frim, Y. G., Hochman, A., Lubitz, G. S., Basile, A., & Sclafani, A. (2017) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00433.2016 · Cited by 66 · see citing works
“Pancreatic -cells use glucokinase to link glucose influx to ATP production and KATP channels to link ATP production to membrane depolarization (3).”
Background[18F]-DOPA Positron Emission Tomography for Preoperative Localization in Congenital Hyperinsulinism
Mohnike, K., Blankenstein, O., Minn, H., Mohnike, W., Fuchtner, F., & Otonkoski, T. (2008) · Hormone Research in Paediatrics · doi:10.1159/000137655 · Cited by 65
Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1
Boini, K. M., Graf, D., Hennige, A. M., Koka, S., Kempe, D. S., Wang, K., Ackermann, T. F., Föller, M., Vallon, V., Pfeifer, K. E., et al. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90839.2008 · Cited by 62 · see citing works
The lessons of early-onset monogenic diabetes for the understanding of diabetes pathogenesis
Vaxillaire, M., Bonnefond, A., & Froguel, P. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.12.001 · Cited by 61 · see citing works
The destiny of Ca2+ released by mitochondria
Takeuchi, A., Kim, B., & Matsuoka, S. (2014) · Journal of Physiological Sciences · doi:10.1007/s12576-014-0326-7 · Cited by 56 · see citing works
Activation of the KATP channel by Mg-nucleotide interaction with SUR1
Proks, P., de Wet, H., & Ashcroft, F. M. (2010) · Journal of General Physiology · doi:10.1085/jgp.201010475 · Cited by 51 · see citing works
“…4 389–405 www.jgp.org/cgi/doi/10.1085/jgp.201010475 389 I N T R O D U C T I O N ATP-sensitive potassium (KATP) channels serve as metabolic sensors, coupling cell metabolism to plasmalemmal potassium fluxes and electrical activity in a variety of cell types (Miki and Seino, 2005; Ashcroft, 2007).”
BackgroundInfluentialSelf-citationKlupa, T., SKUPIEN, J. K., Mirkiewicz-Sieradzka, B., Gach, A., Noczyńska, A., Zubkiewicz‐Kucharska, A., Szalecki, M., Kozek, E., Nazim, J., Mlynarski, W. M., et al. (2010) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2009.0165 · Cited by 45 · see citing works
Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism
Shimomura, K., Flanagan, S., Zadek, B., Lethby, M., Zubcevic, L., Girard, C., Petz, O., Männikkö, R., Kapoor, R., Hussain, K., et al. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900018 · Cited by 41 · see citing works
“Mutations that reduce the ATP sensitivity of the KATP channel can act by impairing ATP binding or transduction, or by influencing the intrinsic (ligand-independent) gating of the channel (Ashcroft 2007; Masia et al, 2007; Proks et al, 2005b; Shimomura et al, 2006).”
BackgroundInfluentialSelf-citationDirect Activation of β-Cell KATP Channels with a Novel Xanthine Derivative
Raphemot, R., Swale, D. R., Dadi, P., Jacobson, D., Cooper, P., Wojtovich, A. P., Banerjee, S., Nichols, C., & Denton, J. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.091884 · Cited by 40 · see citing works
“of severe hypoglycemia, such as congenital hyperinsulinism and insulin-producing pancreatic tumors (Ashcroft, 2007; Nichols et al., 2007).”
BackgroundInfluentialShimomura, K., Tusa, M., Iberl, M., Brereton, M., Kaizik, S., Proks, P., Lahmann, C., Yaluri, N., Modi, S. R., Huopio, H., et al. (2013) · Diabetes · doi:10.2337/db12-1611 · Cited by 40 · see citing works
Self-citationZlatković, J., Arrell, D. K., Kane, G. C., Miki, T., Seino, S., & Terzic, A. (2009) · PROTEOMICS · doi:10.1002/pmic.200800718 · Cited by 36 · see citing works
Metabolic Causes of Epileptic Encephalopathy
Yu, J. Y., & Pearl, P. L. (2013) · Epilepsy Research and Treatment · doi:10.1155/2013/124934 · Cited by 43 · see citing works
KATP Channel Mutations and Neonatal Diabetes
Shimomura, K., & Maejima, Y. (2017) · Internal Medicine · doi:10.2169/internalmedicine.8454-16 · Cited by 36 · see citing works
“Similarly, the mutations that cause iDEND are associated with larger remaining KATP channel currents in comparison to PNDM or TNDM (41).”
BackgroundInfluentialAmenable Treatable Severe Pediatric Epilepsies
Pearl, P. L. (2016) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2016.06.004 · Cited by 43 · see citing works
de Wet, H., Proks, P., Lafond, M., Aittoniemi, J., Sansom, M. S. P., Flanagan, S., Pearson, E., Hattersley, A., & Ashcroft, F. M. (2008) · EMBO Reports · doi:10.1038/embor.2008.71 · Cited by 37 · see citing works
“Activating mutations in ABCC8 or KCNJ11 cause neonatal diabetes by preventing metabolically induced channel closure (Hattersley & Ashcroft, 2005; Ashcroft, 2007).”
BackgroundResultInfluentialSelf-citationATP-Sensitive Potassium Channels in Health and Disease
Clark, R. H., & Proks, P. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-3271-3_8 · Cited by 29 · see citing works
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy
Sandal, T., Laborie, L., Brusgaard, K., Eide, S., Christesen, H. T., Søvik, O., Pr, N., & Molven, A. (2009) · Clinical Genetics · doi:10.1111/j.1399-0004.2009.01152.x · Cited by 32 · see citing works
Nam, Y., Hong, B., Rodriguez, I., Park, M., Jeong, S. Y., Lee, Y.-G., Shim, J. H., Yasmin, T., Kim, N., Koo, Y., et al. (2020) · Nutrients · doi:10.3390/nu12020324 · Cited by 34 · see citing works
Taylor, C. W., Prole, D. L., & Rahman, T. (2010) · Biochemistry · doi:10.1021/bi100823m · Cited by 39 · see citing works
Molecular and clinical features of KATP‐channel neonatal diabetes mellitus in Japan
Hashimoto, Y., Dateki, S., Hirose, M., Satomura, K., Sawada, H., Mizuno, H., Sugihara, S., Maruyama, K., Urakami, T., Sugawara, H., et al. (2017) · Pediatric Diabetes · doi:10.1111/pedi.12447 · Cited by 32 · see citing works
βIV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells
Kline, C. F., Wright, P. J., Koval, O. M., Zmuda, E., Johnson, B. L., Anderson, M. E., Hai, T., Hund, T., & Mohler, P. (2013) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1314195110 · Cited by 32
Vedovato, N., Cliff, E. R. S., Proks, P., Varadarajan, P., Flanagan, S. E., Ellard, S., Hattersley, A. T., & Ashcroft, F. M. (2016) · Diabetologia · doi:10.1007/s00125-016-3964-x · Cited by 30 · see citing works
Self-citationZhou, Q., Garin, I., Castaño, L., Argente, J., Muñoz-Calvo, M., de Nanclares, G. P., & Shyng, S. (2010) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2010-1231 · Cited by 28 · see citing works
Männikkö, R., Flanagan, S. E., Sim, X., Segal, D. G., Hussain, K., Ellard, S., Hattersley, A. T., & Ashcroft, F. M. (2011) · Diabetes · doi:10.2337/db10-1583 · Cited by 26 · see citing works
Self-citationWaixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead
Sun, H.-S., Horgen, F., Romo, D., Hull, K. G., Kiledal, S. A., Fleig, A., & Feng, Z.-P. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00512-4 · Cited by 25 · see citing works
Díaz, P., Dimasuay, K. G., Koele‐Schmidt, L., Jang, B., Barbour, L. A., Jansson, T., & Powell, T. L. (2017) · Placenta · doi:10.1016/j.placenta.2017.05.016 · Cited by 30 · see citing works
Light, P. E. (2010) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s6969 · Cited by 21 · see citing works
“The resultant decrease in potassium ion efflux depolarizes the β-cell membrane potential, leading to activation of voltage-gated calcium channels, calcium influx, and calcium-stimulated insulin granule exocytosis (Figure 1B).(21) Graded increases in plasma glucose and subsequent metabolism lead to proportional decreas…”
The KATP Channel and Neonatal Diabetes
Shimomura, K. (2009) · Endocrine Journal · doi:10.1507/endocrj.k08e-160 · Cited by 20 · see citing works
Craig, T. J., Shimomura, K., Holl, R. W., Flanagan, S. E., Ellard, S., & Ashcroft, F. M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0159 · Cited by 16 · see citing works
Self-citationVariable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation
D’Amato, E., Tammaro, P., Craig, T. J., Tosi, A., Giorgetti, R., Lorini, R., & Ashcroft, F. M. (2008) · Diabetic Medicine · doi:10.1111/j.1464-5491.2008.02443.x · Cited by 23 · see citing works
Self-citationGirard, C. A., Wunderlich, F. T., Shimomura, K., Collins, S., Kaizik, S., Proks, P., Abdulkader, F., Clark, A., Ball, V., Zubcevic, L., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35772 · Cited by 105 · see citing works
Self-citationZhang, Q., Dou, H., & Rorsman, P. (2020) · The Journal of Physiology · doi:10.1113/jp279775 · Cited by 30 · see citing works
“2A) or high glucose (Zhang et al. 2013; Babinsky et al. 2017).”
Fogle, K. J., Hertzler, J. I., Shon, J. H., & Palladino, M. (2016) · Journal of neurogenetics · doi:10.1080/01677063.2016.1252765 · Cited by 20 · see citing works
“KATP is found in many tissues, including pancreatic b cells where their contribution to insulin release makes them drug targets in diabetes (Ashcroft, 2007; Hibino et al., 2010) and hyperinsulinism (Dunne, Cosgrove, Shepherd, Aynsley-Green, & Lindley, 2004).”
BackgroundKCNJ11 knockout morula re-engineered by stem cell diploid aggregation
Nelson, T. J., Martinez‐Fernandez, A., & Terzic, A. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0179 · Cited by 18 · see citing works
“2 subunit of KATP channels (Aguilar-Bryan et al. 1995; Inagaki et al. 1995), are pathogenic in a syndrome that encompasses diabetes, developmental delay and epilepsy (Proks et al. 2004; Hattersley & Ashcroft 2005; Gloyn et al. 2006; Ashcroft 2007).”
BackgroundInfluentialElSheikh, A., & Shyng, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1161117 · Cited by 18 · see citing works
Channelopathies: Decoding Disease Pathogenesis
Terzic, A., & Pérez-Terzic, C. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3001433 · Cited by 18 · see citing works
Männikkö, R., Jefferies, C., Flanagan, S. E., Hattersley, A. T., Ellard, S., & Ashcroft, F. M. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp554 · Cited by 19 · see citing works
“The increase in heterozygous KATP currents recorded in the presence of MgATP is similar to that found for other neonatal diabetes mutations associated with neurological symptoms and greater than for mutations that cause neonatal diabetes alone (3).”
BackgroundResultInfluentialSelf-citationMännikkö, R., Stansfeld, P. J., Ashcroft, A. S., Hattersley, A. T., Sansom, M. S. P., Ellard, S., & Ashcroft, F. M. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.209700 · Cited by 19 · see citing works
Self-citationTaylor, C. W., Prole, D. L., & Rahman, T. (2009) · Biochemistry · doi:10.1021/bi901739t · Cited by 38 · see citing works
Modeling K,ATP-Dependent Excitability in Pancreatic Islets
Silva, J. R., Cooper, P., & Nichols, C. G. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.09.037 · Cited by 11 · see citing works
Shimomura, K., de Nanclares, G. P., Foutinou, C., Caimari, M., Castaño, L. A., & Ashcroft, F. M. (2009) · Diabetic Medicine · doi:10.1111/j.1464-5491.2009.02901.x · Cited by 17 · see citing works
Self-citationReal time imaging of intracellular hydrogen peroxide in pancreatic islets
Neal, A., Rountree, A. M., Kernan, K. A., van Yserloo, B., Zhang, H.-L., Reed, B. J., Osborne, W., Wang, W., & Sweet, I. (2016) · Biochemical Journal · doi:10.1042/bcj20160481 · Cited by 14 · see citing works
“channels has shed light on some causes of impaired insulin secretion [3, 4].”
BackgroundNam, Y., Lê, H. T., Rodriguez, I., Kim, E. Y., Kim, K., Jeong, S. Y., Woo, S.-H., Lee, Y. R., Castañeda, R., Hong, J., et al. (2016) · Journal of Ginseng Research · doi:10.1016/j.jgr.2016.08.007 · Cited by 14
“Closure of the KATP channels leads to membrane depolarization, the opening of voltagegated Ca2þ channels, and Ca2þ inflow and increase, which result in insulin secretion [32,33].”
BackgroundA role of the sulfonylurea receptor 1 in endocytic trafficking of ATP-sensitive potassium channels
Bruederle, C. E., Gay, J. W., & Shyng, S. (2011) · Traffic : the International Journal of Intracellular Transport · doi:10.1111/j.1600-0854.2011.01227.x · Cited by 14
Gopi, S., Kavitha, B., Kanthimathi, S., Kannan, A., Kumar, R., Joshi, R., Kanodia, S., Arya, A., Pendsey, S., Pendsey, S., et al. (2020) · Pediatric Diabetes · doi:10.1111/pedi.13109 · Cited by 13
Sixty Years of Drug Discovery for Type 2 Diabetes: Where Are We Now?
Clapham, J. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9882-1_1 · Cited by 13 · see citing works
Proks, P., Puljung, M. C., Vedovato, N., Sachse, G., Mulvaney, R., & Ashcroft, F. M. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2015.0426 · Cited by 11 · see citing works
Self-citationA Novel KCNJ11 Mutation Associated with Transient Neonatal Diabetes
Gole, E., Oikonomou, S., Ellard, S., Franco, E. D., & Karavanaki, K. (2017) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.5166 · Cited by 11 · see citing works
Tetrameric structure of SUR2B revealed by electron microscopy of oriented single particles
Fotinou, C., Aittoniemi, J., Wet, H., Polidori, A., Pucci, B., Sansom, M., Vénien-Bryan, C., & Ashcroft, F. (2013) · The FEBS Journal · doi:10.1111/febs.12097 · Cited by 11 · see citing works
Self-citationMemantine has no effect on KATP channels in pancreatic β cells
Imai, R., Misaka, S., Horita, S., Yokota, S., O’hashi, R., Maejima, Y., & Shimomura, K. (2018) · BMC Research Notes · doi:10.1186/s13104-018-3715-9 · Cited by 10 · see citing works
Lybaert, P., Hoofd, C., Guldner, D., Vegh, G., Delporte, C., Meuris, S., & Lebrun, P. (2013) · Placenta · doi:10.1016/j.placenta.2013.03.006 · Cited by 10
de Wet, H., Shimomura, K., Aittoniemi, J., Ahmad, N., Lafond, M., Sansom, M., & Ashcroft, F. (2012) · Journal of Physiology · doi:10.1113/jphysiol.2012.236075 · Cited by 10 · see citing works
Self-citationRisk loci for type 2 diabetes – Quo vadis?
Weijers, R. N. M. (2009) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2009.077 · Cited by 4 · see citing works
Nam, Y., Kim, E. B., Kang, J., Kim, J. S., Jeon, Y., Shin, S.-W., Kang, T.-H., & Kwak, J. (2023) · Nutrients · doi:10.3390/nu15071798 · Cited by 9
“When K ATP channels are shut, insulin is secreted, and when they are open, insulin is inhibited [5].”
BackgroundClark, R. H., Männikkö, R., Stuckey, D., Iberl, M., Clarke, K. J., & Ashcroft, F. M. (2012) · Diabetologia · doi:10.1007/s00125-011-2428-6 · Cited by 10 · see citing works
Self-citationAccounting for Near-Normal Glucose Sensitivity in Kir6.2[AAA] Transgenic Mice
Tsaneva-Atanasova, K. T., & Sherman, A. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2009.07.060
Pharmacogenomics of sulfonylureas in type 2 diabetes mellitus; a systematic review
Karkhaneh, L., Tabatabaei-Malazy, O., Bandarian, F., Mohseni, S., & Larijani, B. (2021) · Journal of Diabetes and Metabolic Disorders · doi:10.1007/s40200-021-00908-x · Cited by 7 · see citing works
KATP channel dependent heart multiome atlas
Arrell, D. K., Park, S., Yamada, S., Alekseev, A. E., Garmany, A., Jeon, R., Vučković, I., Lindor, J. Z., & Terzic, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-11323-4 · Cited by 6 · see citing works
Mouse models of β-cell KATP channel dysfunction
Brereton, M. F., & Ashcroft, F. M. (2013) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2013.02.001 · Cited by 5 · see citing works
Self-citationMethods for Characterizing Disease-Associated ATP-Sensitive Potassium Channel Mutations
Kandasamy, B., & Shyng, S. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7362-0_8 · Cited by 7 · see citing works
Lin, R., Yen, Y.-K., Lee, C., Hsieh, S., Chang, Y., Juan, Y., Long, C., Shen, K., & Wu, B. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112447 · Cited by 4 · see citing works
Sherif, E., Abdelmaksoud, A., Elbarbary, N., & Njølstad, P. (2013) · Acta Diabetologica · doi:10.1007/s00592-010-0217-1 · Cited by 4
“Insulin hypersecretion that characterizes CHI results from permanent depolarization of the b-cell membrane and thereby continuous Ca2? influx and insulin secretion [23].”
BackgroundIon Channels and Regulation of Insulin Secretion in Beta-Cells
Oluwamodupe, C., & Babalola, O. O. (2024) · Current Molecular Biology Reports · doi:10.1007/s40610-024-00162-z · Cited by 3 · see citing works
“It has been shown that pancreatic beta cells can have intra-cellular chloride concentrations greater than 35 mm [38, 47].”
Shen, K., Munhall, A. C., & Johnson, S. (2018) · Brain Research · doi:10.1016/j.brainres.2018.10.027 · Cited by 3 · see citing works
“They are probably best characterized in pancreatic beta-cells where closure of the channel by ATP causes membrane depolarization and calcium influx and thereby triggering insulin release (Ashcroft, 2007).”
BackgroundKaleva, N., Ivanov, I., Panova, M., Shabanova, T. D., & Delgyanska, D. S. (2010) · Folia Medica · doi:10.2478/v10153-010-0008-z · Cited by 3
Hussieny, B. A. A., & Alsahlawi, M. M. R. (2023) · Al-Kufa University Journal for Biology · doi:10.36320/ajb/v13.i2.11759 · Cited by 1 · see citing works
Anti-diabetic drug binding site in KATP channels revealed by Cryo-EM
Martin, G. M., Kandasamy, B., DiMaio, F., Yoshioka, C., & Shyng, S. (2017) · bioRxiv · doi:10.1101/172908 · Cited by 2
Inherited pediatric metabolic epilepsies
Pearl, P. L., & Yu, Y. (2013) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2013.758580 · Cited by 2 · see citing works
“These mutations “lock in” the KATP channel in an open state, even under hyperglycemic conditions [29,30].”
BackgroundProtein Kinases and Pancreatic Islet Function
Xavier, G. D. S. (2012) · InTech eBooks · doi:10.5772/37282 · Cited by 1 · see citing works
Advances in Cardiac ATP-Sensitive K+ Channelopathies From Molecules to Populations
Terzic, A., Alekseev, A., Yamada, S., Reyes, S., & Olson, T. M. (2011) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.110.957662 · Cited by 2 · see citing works
Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice
Sachse, G., Haythorne, E., Proks, P., Stewart, M. E., Cater, H. L., Ellard, S., Davies, B., & Ashcroft, F. M. (2020) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15529.2 · Cited by 2 · see citing works
“ATP-sensitive potassium (K ATP ) channels play a pivotal role in coupling blood glucose levels to insulin secretion (Ashcroft, 2007).”
Self-citationDiabetes mellitus beim Frühgeborenen: Erstmalige Behandlung mit Sulfonylharnstoff
Holl, R. (2009) · Klinische Pädiatrie · doi:10.1055/s-0029-1192017 · Cited by 1
Targeted analysis of whole exome sequencing in Thai patients with neonatal diabetes
Plengvidhya, N., Tangjarusritaratorn, T., Teerawattanapong, N., Narkdontri, T., Innang, S., Songlilitchuwong, S., Suthon, S., & Tangjittipokin, W. (2026) · Human Genetics · doi:10.1007/s00439-025-02815-0
“These two genes are the most frequent causes of both transient and permanent NDM. Variants in KCNJ11 or ABCC8 impair the KATP chan - nel’s sensitivity to ATP, causing persistent channel opening, membrane hyperpolarization, and reduced insulin secretion (Ashcroft 2007).”
Benguet Kankanaey self-representations in local films in Benguet, Philippines
Dalocdoc, P. J. (2025) · International journal of humanities, literature & arts · doi:10.21744/ijhla.v8n1.2367
“Coined by Richard Terdiman, it characterizes the “theory and practice of symbolic resistance" (Ashcroft, 2007).”
Fagnen, C., Bannwarth, L., Oubella, I., Zuniga, D., Haouz, A., Forest, E., Scala, R., Bendahhou, S., Zorzi, R. D., Perahia, D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010335
Knebel, B., Müller-Wieland, D., & Kotzka, J. (2010) · doi:10.1055/s-0030-1247418
The right stuff: beta-cell channels, cycles, and sensors.
Halban, P. (2008) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.90692.2008
Frances Ashcroft: 2007 Walter B. Cannon Physiology in Perspective Lecture.
Benos, D. (2007) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00530.2007
“This is an example of translational research at its finest! This body of work, summarized in the accompanying article (1), demonstrates unequivocally how a full understanding of the molecular basis of ion channel dysfunction can lead to better disease management.”
BackgroundResearch Progress on the Relationship between KATP Channels and Migraine
阳思绮, 欧. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.1682811
Glucose acts as a ligand for glucokinase to trigger postprandial secretion of GLP-1
Li, C., Li, M., Yang, H.-Y., Tian, X., Zhang, C., Zhao, L., Wu, J., Zhang, C., Liu, S., Yang, X., et al. (2026) · Vita · doi:10.15302/vita.2026.07.0059 · Cited by 1 · see citing works
Infant with diabetes – a diagnostic challenge for paediatricians
Brandt-Varma, A., & Myśliwiec, M. (2020) · Pediatria Polska · doi:10.5114/polp.2020.103508
“It is known that diabetes caused by mutations in the gene KCJN11 is sensitive to sulfonylurea treatment [4, 11].”
Background
- Authors
- Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Ashcroft, Frances M.
- ORCID
- Ashcroft, Frances M.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2007-10
- Volume
- 293
- Issue
- 4
- Pages
- E880-E889
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2134991186
- Cited by
- 107
- References
- 0
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 7 · 2019: 1 · 2018: 2 · 2017: 8 · 2016: 10 · 2015: 1 · 2014: 6 · 2013: 10 · 2012: 6
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Diabetes UK
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- ATP-sensitive potassium channels, Kir6.2, SUR1, pancreatic beta cells, insulin secretion, glucose homeostasis, neonatal diabetes, congenital hyperinsulinism, ion channel mutations, channel structure and function
- MeSH terms
- Kcnj11 Channel, Adenosine Triphosphate, Animals, Diabetes Mellitus, Glucose, Homeostasis, Humans, Models, Biological, Models, Molecular, Mutation, Potassium Channels, Potassium Channels, Inwardly Rectifying, Channelopathies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
