Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice

Single ventricular myocytes were prepared from control db/+ and insulin-resistant diabetic db/db male mice at 6 and 12 weeks of age. Peak and sustained outward potassium currents were measured using whole-cell voltage clamp methods. At 6 weeks currents were fully developed in control and diabetic mice, with no differences in the density of either current. By 12 weeks both currents were significantly attenuated in the diabetic mice, but could be augmented by in vitro incubation with the angiotensin-converting enzyme (ACE) inhibitor quinapril (1 mum, 5-9 h). In cells from female db/db mice (12 weeks of age), K+ currents were not attenuated and no effects of quinapril were observed. To investigate whether lack of insulin action accounts for these gender differences, cells were also isolated from cardiomyocte-specific insulin receptor knockout (CIRKO) mice. Both K+ currents were significantly attenuated in cells from male and female CIRKO mice, and action potentials were significantly prolonged. Incubation with quinapril did not augment K+ currents. Our results demonstrate that type 2 diabetes is associated with gender-selective attenuation of K+ currents in cardiomyocytes, which may underlie gender differences in the development of some cardiac arrhythmias. The mechanism for attenuation of K+ currents in cells from male mice is due, at least in part, to an autocrine effect resulting from activation of a cardiac renin-angiotensin system. Insulin is not involved in these gender differences, since the absence of insulin action in CIRKO mice diminishes K+ currents in cells from both males and females.