The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (ICaL) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca2+ influx. The current density of ICaL was reduced in OZR, whereas the threshold activation and the current-voltage relationship of ICaL were not significantly altered. L-type Ba2+ current (IBaL) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of IBaL in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of CavB2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of ICaL and IBaL, 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients.
Calcium-compounds; Weight-factors; Physiological-effects; Physiological-function; Heart; Diseases; Laboratory-animals; Cardiac-function; Cardiovascular-system; Cardiovascular-system-disease; Cardiovascular-system-disorders;
Author Keywords: obesity; insulin resistance; long QT; action potential; L-type calcium current; calmodulin
H.-G. Yu, Center for Cardiovascular and Respiratory Sciences, Dept. of Physiology and Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia Univ., Morgantown, WV 26056