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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/R1695    most recent 90839.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Boini, K. M. Articles by Lang, F. PubMed PubMed Citation Articles by Boini, K. M. Articles by Lang, F.

ENDOCRINE PHYSIOLOGY AND METABOLISM

Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

¹Departments of Physiology I and ²Internal Medicine, Division of Diabetology, Endocrinology, Angiology, Nephrology, and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany; ³Department of Gastroenterology, Hepatology, and Infectiology, University of Düsseldorf, Düsseldorf, Germany; ⁴Departments of Medicine and Pharmacology, University of California San Diego, San Diego, California; ⁵Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development/National Institutes of Health, Bethesda, Maryland

Submitted 14 October 2008 ; accepted in final form 31 March 2009

The pore-forming K⁺-channel -subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K⁺ uptake and glucose metabolism. Insulin (100 nM)-induced K⁺ uptake was determined in isolated perfused livers from KCNQ1-deficient mice (kcnq1^–/–) and their wild-type littermates (kcnq1^+/+). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled ³H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K⁺ uptake was significantly more sustained in isolated perfused livers from kcnq1^–/– mice than from kcnq1^+/+mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1^–/– than in kcnq1^+/+ mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1^–/– than in kcnq1^+/+mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1^–/– than in kcnq1^+/+mice. Uptake of ³H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1^–/– than in kcnq1^+/+mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K⁺ uptake by insulin and thereby influences K⁺-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism.

K⁺ channels; blood glucose; kidney; liver; skeletal muscle