Pharmacological inhibition of Kv1.3 fails to modulate insulin sensitivity in diabetic mice or human insulin-sensitive tissues

• Published in: American journal of physiology: endocrinology and metabolism 2011-08, Vol.301 (2), p.E380-E390
• Main Authors: Straub, Stephen V, Perez, Sylvie M, Tan, Beijing, Coughlan, Kimberly A, Trebino, Catherine E, Cosgrove, Patricia, Buxton, Joanne M, Kreeger, John M, Jackson, V Margaret
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipose Tissue - cytology; Adipose Tissue - physiology; Animals; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Ficusin - pharmacology; Glucose - pharmacokinetics; Humans; Hyperglycemia - metabolism; Hyperglycemia - physiopathology; Insulin - physiology; Insulin Resistance - physiology; Kv1.3 Potassium Channel - antagonists & inhibitors; Kv1.3 Potassium Channel - physiology; Mice; Muscle, Skeletal - cytology; Muscle, Skeletal - physiology; Obesity - metabolism; Obesity - physiopathology; Pancreatitis-Associated Proteins; Patch-Clamp Techniques; Potassium - metabolism; Scorpion Venoms - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00076.2011

Genetic ablation of the voltage-gated potassium channel Kv1.3 improves insulin sensitivity and increases metabolic rate in mice. Inhibition of Kv1.3 in mouse adipose and skeletal muscle is reported to increase glucose uptake through increased GLUT4 translocation. Since Kv1.3 represents a novel target for the treatment of diabetes, the present study investigated whether Kv1.3 is functionally expressed in human adipose and skeletal muscle and whether specific pharmacological inhibition of the channel is capable of modulating insulin sensitivity in diabetic mouse models. Voltage-gated K(+) channel currents in human skeletal muscle cells (SkMC) were insensitive to block by the specific Kv1.3 blockers 5-(4-phenoxybutoxy)psoralen (PAP-1) and margatoxin (MgTX). Glucose uptake into SkMC and mouse 3T3-L1 adipocytes was also unaffected by treatment with PAP-1 or MgTX. Kv1.3 protein expression was not observed in human adipose or skeletal muscle from normal and type 2 diabetic donors. To investigate the effect of specific Kv1.3 inhibition on insulin sensitivity in vivo, PAP-1 was administered to hyperglycemic mice either acutely or for 5 days prior to an insulin tolerance test. No effect on insulin sensitivity was observed at free plasma PAP-1 concentrations that are specific for inhibition of Kv1.3. Insulin sensitivity was increased only when plasma concentrations of PAP-1 were sufficient to inhibit other Kv1 channels. Surprisingly, acute inhibition of Kv1.3 in the brain was found to decrease insulin sensitivity in ob/ob mice. Overall, these findings are not supportive of a role for Kv1.3 in the modulation of peripheral insulin sensitivity.