Expression and Regulation of Facilitative Glucose Transporters in Equine Insulin-Sensitive Tissue: From Physiology to Pathology

Glucose uptake is the rate-limiting step in glucose utilization in mammalians and is tightly regulated by a family of specialized proteins, called the facilitated glucose transporters (GLUTs/SLC2). GLUT4, the major isoform in insulin-responsive tissue, translocates from an intracellular pool to the cell surface and as such determines insulin-stimulated glucose uptake. However, despite intensive research over 50 years, the insulin-dependent and -independent pathways that mediate GLUT4 translocation are not fully elucidated in any species. Insulin resistance (IR) is one of the hallmarks of equine metabolic syndrome and is the most common metabolic predisposition for laminitis in horses. IR is characterized by the impaired ability of insulin to stimulate glucose disposal into insulin-sensitive tissues. Similar to other species, the functional capability of the insulin-responsive GLUTs is impaired in muscle and adipose tissue during IR in horses. However, the molecular mechanisms of altered glucose transport remain elusive in all species, and there is still much to learn about the physiological and pathophysiological functions of the GLUT family members, especially in regard to class III. Since GLUTs are key regulators of whole-body glucose homeostasis, they have received considerable attention as potential therapeutic targets to treat metabolic disorders in human and equine patients. 1. Regulation of Glucose Transport in Healthy State Glucose is of the most abundant and essential energy sources for both plants and animals, existing in various polymerized forms such as cellulose and glycogen [1]. Glucose uptake from the bloodstream into the cell is the rate-limiting step in glucose utilization primarily in insulin-sensitive tissue in all species. Striated (i.e., cardiac and skeletal) muscle is the main tissue to utilize glucose as an energy substrate, followed by adipose tissue. For instance, skeletal muscle, which makes up 40% of the body mass in mammalian species, is the primary tissue responsible for the peripheral disposal of glucose, especially during exercise [2]. In addition, the energetic demands in the heart are extreme and as a result, the heart has the highest rate of oxygen consumption per gram of any tissue in the body [3]. In order to sustain this high energy demand, the rate of glucose utilization in the heart is greater than in skeletal muscle, adipose tissue, and lung, despite the ability of the myocardium to use other substrates (i.e., fatty acids, lactate, ketone bodies, and amino acids) [4]. Therefore, glucose transport and utilization