Back to Browse Journals » Pharmacogenomics and Personalized Medicine » Volume 3

The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes

Authors Veronica Lang, Peter E Light

Published Date November 2010 Volume 2010:3 Pages 145—161


Published 24 November 2010

Veronica Lang, Peter E Light
Department of Pharmacology and Alberta Diabetes Institute, Faculty of Medicine and Dentistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada

Abstract: Neonatal diabetes mellitus (NDM) is a monogenic disorder caused by mutations in genes involved in regulation of insulin secretion from pancreatic β-cells. Mutations in the KCNJ11 and ABCC8 genes, encoding the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel Kir6.2 and SUR1 subunits, respectively, are found in ~50% of NDM patients. In the pancreatic β-cell, KATP channel activity couples glucose metabolism to insulin secretion via cellular excitability and mutations in either KCNJ11 or ABCC8 genes alter KATP channel activity, leading to faulty insulin secretion. Inactivation mutations decrease KATP channel activity and stimulate excessive insulin secretion, leading to hyperinsulinism of infancy. In direct contrast, activation mutations increase KATP channel activity, resulting in impaired insulin secretion, NDM, and in severe cases, developmental delay and epilepsy. Many NDM patients with KCNJ11 and ABCC8 mutations can be successfully treated with sulfonylureas (SUs) that inhibit the KATP channel, thus replacing the need for daily insulin injections. There is also strong evidence indicating that SU therapy ameliorates some of the neurological defects observed in patients with more severe forms of NDM. This review focuses on the molecular and cellular mechanisms of mutations in the KATP channel that underlie NDM. SU pharmacogenomics is also discussed with respect to evaluating whether patients with certain KATP channel activation mutations can be successfully switched to SU therapy.

Keywords: neonatal diabetes, KCNJ11, ABCC8, ATP-sensitive potassium channels

Download Article [PDF] View Full Text [HTML] 

Creative Commons License This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution - Non Commercial (unported, v3.0) License. The full terms of the License are available at Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at:

Readers of this article also read:

Tubeimoside-1 induces glioma apoptosis through regulation of Bax/Bcl-2 and the ROS/Cytochrome C/Caspase-3 pathway

Jia G, Wang Q, Wang R, Deng D, Xue L, Shao N, Zhang Y, Xia X, Zhi F, Yang Y

OncoTargets and Therapy 2015, 8:303-311

Published Date: 30 January 2015

Surgical outcomes in phacoemulsification after application of a risk stratification system

Tsinopoulos IT, Lamprogiannis LP, Tsaousis KT, Mataftsi A, Symeonidis C, Chalvatzis NT, Dimitrakos SA

Clinical Ophthalmology 2013, 7:895-899

Published Date: 16 May 2013

Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability

Luo H, Jiang B, Li B, Li Z, Jiang BH, Chen YC

International Journal of Nanomedicine 2012, 7:3951-3959

Published Date: 24 July 2012

The essential oils component p-cymene induces proton leak through Fo-ATP synthase and uncoupling of mitochondrial respiration

Custódio JBA, Ribeiro MV, Silva FSG, Machado M, Sousa MC

Journal of Experimental Pharmacology 2011, 3:69-76

Published Date: 25 August 2011

The future role of personalized medicine in the treatment of glioblastoma multiforme

Jing Li, Chunhui Di, Austin K Mattox, et al

Pharmacogenomics and Personalized Medicine 2010, 3:111-127

Published Date: 19 August 2010

Silver/poly (lactic acid) nanocomposites: preparation, characterization, and antibacterial activity

Kamyar Shameli, Mansor Bin Ahmad, Wan Md Zin Wan Yunus, et al

International Journal of Nanomedicine 2010, 5:573-579

Published Date: 6 August 2010

Influence of socioeconomic lifestyle factors and genetic polymorphism on type 2 diabetes occurrences among Tunisian Arab and Berber groups of Djerba Island

Thouraya Baroudi Ouederni, Ahmed Fadiel, Nejla Stambouli, et al

Pharmacogenomics and Personalized Medicine 2009, 2:49-57

Published Date: 21 August 2009

Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer

Evelina Miele, Gian Paolo Spinelli, Ermanno Miele, Federica Tomao, Silverio Tomao

International Journal of Nanomedicine 2009, 4:99-105

Published Date: 27 April 2009