Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

Abstract

The pore-forming K+-channel α-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.

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes

“…We also pooled the two samples to analyse the effects of SNPs on waist circumference and waist/hip ratio. We found that rs2237892 was significantly associated with waist circumference only in cases (β0−0.0026 per C allele for log 10 [waist circumference]; 95% CI −0.0045, −0.0007; p00.007) (ESM Table 3). However, the significance was not retained after further adjusting for BMI (p00.648).…”

“…It may suggest that the association between KCNQ1 and BMI was independent of beta cell function. A possibility has been raised that Kcnq1 may be a novel element affecting insulin sensitivity, because a striking increase in insulin sensitivity was found in Kcnq1 knockout mice [10]. In view of the close relationship between insulin resistance and obesity, it is tempting to speculate that the association between KCNQ1 and obesity might be mediated by insulin sensitivity.…”

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

“…This result is in apparent contradiction to the previous report that insulin sensitivity was enhanced in KCNQ1-deficient mice. 17 The chromanol 293B dosage used here is within the range utilized in previous studies to inhibit KCNQ1 effectively in vivo, 19,35 but the insufficient pharmacokinetic exposure of the animal to the inhibitor cannot be completely excluded. On the other hand, it also cannot be ruled out that some compensatory or consequential alterations might contribute to the altered insulin sensitivity upon global KCNQ1 knockout.…”

“…5,16 The glucose-stimulated incretin glucagon-like peptide 1 (GLP-1) was assumed to be a candidate linker between KCNQ1 and b-cells function, 16 but this hypothesis has not been verified so far. A study in gene-targeted mice demonstrated that the KCNQ1 knockout results in enhanced insulin sensitivity and in turn inhibits insulin release, 17 adding more attractiveness over the mechanism by which KCNQ1 exert its effects on b-cells in vivo.…”

Upregulation of KCNQ1/KCNE1 K+channels by Klotho

“…[21][22][23][24][25][26]33 In the liver, for instance, KCNQ1 governs cell volume and thus cell volume-sensitive functions including glucose uptake. 46 Beyond that KCNQ1 is important for a variety of functions including hearing, 30 3 -exit K + channel activity influences cytosolic pH, which in turn influences caspase activation 54 and glycolysis. 55 In conclusion, the present observations point to a novel effect of Klotho, i.e., the upregulation of the slowly activating heterotetrameric K + channel KCNQ1/KCNE1.…”