UC Irvine

Coronary artery disease (CAD) is the number 1 cause of death in the U.S and globally. The traditional risk factors for CAD are hypercholesterolemia, hypertriglyceridemia, hypertension including high levels of angiotensin, diabetes, aging, and smoking. Non-traditional risk factors are chronic inflammation, hyperhomocysteinemia, high levels of C-reactive protein (CRP) and left ventricular hypertrophy (LVH). We previously found that Kcne2 deletion causes hypercholesterolemia, high levels of angiotensin, glucose intolerance and LVH. Here, we show that Kcne2 deletion promotes CAD including hypertriglyceridemia, diabetes, hyperhomocysteinemia, elevated CRP. In female western diet-fed mice, Kcne2 deletion increases plaque deposition and also causes premature ventricular complexes and sudden death. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries. NAFLD displays not only increases liver-related complications but also increases risk of developing diabetes and atherosclerosis. We discovered that Kcne2 deletion in mice causes early-onset NAFLD via iron deficiency arising from KCNE2-dependent achlorhydria, while two other KCNE2-dependent defects, cardiac dysfunction and hypothyroidism, do not contribute to early-onset NAFLD in Kcne2─/─ mice. Last, we also found that Kcne2 deletion causes Type II diabetes mellitus (T2DM) via a primary defect in insulin secretion. Kcne2 deletion in mice impairs glucose tolerance as early as 5 weeks of age in pups fed on a western diet, ultimately causing diabetes. In adult mice fed a normal diet, skeletal muscle insulin receptor β and IRS-1 expression were downregulated by Kcne2 deletion, characteristic of T2DM. Kcne2 deletion also caused extensive pancreatic transcriptome changes consistent with T2DM, which included ER stress, inflammation and hyperproliferation. Kcne2 deletion impaired isolated β-cell insulin secretion and diminished β-cell peak outward K+ current at positive membrane potentials, but also left-shifted its voltage dependence and reduced inactivation. Metabolic syndrome refers to a clustering of the following medical conditions: hypertension, insulin resistance, and hypertriglyceridemia. Metabolic syndrome is associated with the risk of developing CAD, NAFLD and T2DM. The work described herein demonstrates that Kcne2 disruption is a novel genetic predisposing factor for elements of metabolic syndrome including CAD, NAFLD and T2DM.