title: Kcne2deletion impairs insulin secretion and causes type 2 diabetes mellitus.
abstract: Type 2 diabetes mellitus (T2DM) represents a rapidly increasing threat to global public health. T2DM arises largely from obesity, poor diet, and lack of exercise, but it also involves genetic predisposition. Here we report that the KCNE2 potassium channel transmembrane regulatory subunit is expressed in human and mouse pancreatic β cells.Kcne2deletion in mice impaired glucose tolerance as early as 5 wk of age in pups fed a Western diet, ultimately causing diabetes. In adult mice fed normal chow, skeletal muscle expression of insulin receptor β and insulin receptor substrate 1 were down-regulated 2-fold byKcne2deletion, characteristic of T2DM.Kcne2deletion also caused extensive pancreatic transcriptome changes consistent with facets of T2DM, including endoplasmic reticulum stress, inflammation, and hyperproliferation.Kcne2deletion impaired β-cell insulin secretionin vitroup to 8-fold and diminished β-cell peak outward K+current at positive membrane potentials, but also left-shifted its voltage dependence and slowed inactivation. Interestingly, we also observed an aging-dependent reduction in β-cell outward currents in bothKcne2+/+andKcne2-/-mice. Our results demonstrate that KCNE2 is required for normal β-cell electrical activity and insulin secretion, and thatKcne2deletion causes T2DM. KCNE2 may regulate multiple K+channels in β cells, including the T2DM-linked KCNQ1 potassium channel α subunit.-Lee, S. M., Baik, J., Nguyen, D., Nguyen, V., Liu, S., Hu, Z., Abbott, G. W.Kcne2deletion impairs insulin secretion and causes type 2 diabetes mellitus.
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Soo Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Baik
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Liu
authors.affiliation: Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA; abbottg@uci.edu.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D055724:Electrophysiological Phenomena; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D007328:Insulin; C489619:KCNE2 protein, human; C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium
keywords: KCNQ1; Kv1.5; Kv2.1; potassium channel