Blood glucose levels in the body are maintained within quite narrow limits to provide fuel for normal activities and to avoid the complications that occur in diabetes. Glucose is obtained from carbohydrates in food (55–65%) and from gluconeogenesis in the liver and kidneys. Transporters play a central role in glucose homeostasis in intestinal absorption, renal reabsorption, fluxes into and out of cells, and the regulation of blood glucose by insulin. Although there are two major classes of glucose transporters, the uniporters (GLUTs) and sodium symporters (SGLTs), the major focus has been on glucose transport into skeletal muscle and fat by GLUT4. In this lecture I will review the physiology of SGLTs and address their role in glucose homeostasis.

There are 12 members of the SGLT gene family, SLC5, and 5 of these are Na⁺-glucose symporters. In the most extensively studied, SGLT1 (SLC5A1) and SGLT2 (SLC5A2), uphill glucose transport is driven by the inward sodium gradient. Phlorizin, a plant beta-glucoside, competitively inhibits transport with inhibitor constants between 40 and 200 nM. We have recently solved the crystal structure of a bacterial SGLT (vSGLT) and this provides unique insights into the structural basis of sodium glucose coupled transport. A major surprise is that a number of unrelated symporters and antiporters share the same structure and this suggests common transport mechanisms. SGLT1 and SGLT2 transport glucose across the brush borders of the small intestine and proximal renal tubule. Mutations in SGLT1 cause a life-threatening defect in intestinal glucose absorption (Glucose-Galactose-Malabsorption) while mutations in SGLT2 produce a benign renal glucosuria (Familial Renal Glucosuria).

We are exploring the expression of SGLT genes throughout the body by measuring mRNA and protein levels in organs and tissues, and their functional activity using imaging. SGLT 1–6 genes are expressed in tissues including muscle, testis and brain. SGLT proteins are also found throughout the body including the intestine, kidney, liver, heart, testis and specific regions of the brain. This raises questions about the functional importance of SGLT expression in these cells and organs. We have developed SGLT glucose tracers for Positron Emission Tomography (PET) studies in animal models and man and confirm that the SGLTs are active in these tissues.

The pharmaceutical industry has targeted SGLT2 in the search for drugs to control blood glucose levels in diabetics. Using phlorizin as a lead compound they have developed oral drugs that inhibit the renal SGLT2. The resulting glucosuria reduces fasting and postprandial blood glucose levels. The future of such drugs depends critically on their selectivity for SGLT2 and potential side effects.