Impaired Vascular BK Channel Function in Type 2 Diabetes Mellitus

Diabetes mellitus has become a global epidemic. According to the World Health Organization estimate, about 285 millions people worldwide, corresponding to 6.4% of the world’s population, have diabetes in 2010. By 2030, this figure will be more than doubled (http://www.worlddiabetesday.org/media/press-materials/diabetes-data). Diabetes mellitus is a major cause of morbidity and mortality and is associated with increased risks of cardiovascular diseases, stroke, nephropathy, neuropathy, retinopathy and other microvascular complications. Type 2 diabetes mellitus is characterized by obesity, glucose intolerance, insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia and hypertension, and accounts for 90% of the total cases of diabetes mellitus. Although the clinical course of type 2 diabetes is usually less aggressive compared to its type 1 counterpart, the end results are equally devastating even with intensive glycemic control. The causes of diabetic vascular dysfunction are multifactorial, and involve endothelialdependent and -independent mechanisms. The role of endothelial-dependent vascular dysfunction in diabetes is well-known, and it is related to increased activity/bioavailability of vasoconstrictors such as reactive oxygen species (ROS), reactive nitrogen species (RNS), endothelin-1 (ET-1), angiotensin II (Ang II) and thromoxane A2 (TXA2), and reduced activity/bioavailability of endothelium-derived relaxing factors (EDRFs) such as nitric oxide (NO), carbon monoxide (CO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factors (EDHFs) (Avogaro et al., 2006; De Vriese et al., 2000; Xu & Zou, 2009). The role of endothelial-independent vascular dysfunction in diabetes mellitus, however, has received less attention, and it is by no means less important, because vascular smooth muscle physiology is profoundly modulated by diabetes mellitus. A major ionic mechanism that facilitates vascular smooth muscle relaxation is the activation of the large conductance Ca2+-activated K+ (BK) channels. Because of their large conductance and high density in vascular smooth muscle cells, BK channels are a key determinant of vascular tone, regulating tissue perfusion in response to changes in membrane potential and intracellular Ca2+ homeostasis (Ledoux et al., 2006). Substantial experimental and clinical evidence exists indicating that vascular BK channel function is impaired in type 2 diabetes (Feng et al., 2008; Liu et al., 2008). Multiple mechanisms are known to produce BK channel dysfunction in diabetes mellitus. In this article, we will describe the cellular and molecular mechanisms that underlie vascular BK channel dysfunction in type 2 diabetes. We will also provide a detailed treatise on the altered BK channel gating associated with type 2 diabetes.