Sodium-glucose cotransporter (SGLT) activity mediates apical sodium and glucose transport across cell membranes. Cotransport is driven by active sodium extrusion by the basolateral sodium/potassium-ATPase, thus facilitating glucose uptake against an intracellular up-hill gradient.
There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The energy for active glucose transport is provided by the sodium gradient across the cell membrane, the Na+ glucose cotransport hypothesis first proposed in 1960 by Crane. Since the cloning of SGLT1 in 1987, there have been advances in the genetics, molecular biology, biochemistry, biophysics, and structure of SGLTs. There are 12 members of the human SGLT (SLC5) gene family, including cotransporters for sugars, anions, vitamins, and short-chain fatty acids. Here we give a personal review of these advances. The SGLTs belong to a structural class of membrane proteins from unrelated gene families of antiporters and Na+ and H+ symporters. This class shares a common atomic architecture and a common transport mechanism. SGLTs also function as water and urea channels, glucose sensors, and coupled-water and urea transporters. We also discuss the physiology and pathophysiology of SGLTs, e.g., glucose galactose malabsorption and familial renal glycosuria, and briefly report on targeting of SGLTs for new therapies for diabetes.