Glucose Reabsorption in The Kidney

Glucose is the major fuel source to the body’s tissue and its plasma concentration is maintained within narrow limits, 4–10 mM, except in diabetes where it may rise to over 16 mM. In this chapter we review the role of the kidneys in glucose homeostasis. In particular, we discuss the molecular and genetic evidence for the importance of SGLTs and GLUTs in the proximal tubule in the complete glucose absorption from the glomerular filtrate. This leads into a review of the recent developments on a new therapy for diabetes based on SGLT2 inhibitors.

Keywords

structure and function of SGLTs, glucosuria, diabetes: SGLT2 Inhibitors

Overview of Glucose Homeostasis

Glucose is the major fuel source to the body’s tissues, and it comes in various forms in the diet: simple sugar, disaccharides, polysaccharides, and starch. It is utilized in both oxidative and non-oxidative metabolic pathways, it provides a substrate for triglyceride synthesis in adipose tissue, and it is enzymatically polymerized into glycogen for storage in muscle and the liver. Glucose is synthesized endogenously in the liver and kidneys by gluconeogenesis. Its plasma concentration is maintained within narrow limits, 4–10 mM (70–110 mg/dL), with many hormonal influences. Pathological alterations in glucose homeostasis are most often identified with diabetes.

Glucose Transporters in glucose Homeostasis

The transport of glucose across biological membranes is a critical step regulating its concentration in plasma. There are two major classes of proteins responsible for glucose transport.

Facilitated GLU cose T ransporters (GLUTs) bind to glucose and translocate it across membranes in an energy-independent fashion: they require a glucose concentration gradient to drive net transport; hence they facilitate the diffusion of glucose. The GLUTs belong to the SLC2A gene family, part of the larger Membrane Facilitators Superfamily (MFS). There are currently 14 identified GLUT genes within the human body, for example, the protein coded by the SLC2A2 gene , GLUT2, allows glucose to be reabsorbed in the kidney by facilitating diffusion across basolateral membranes, and mutations in this gene are responsible for the Fanconi-Bickel Syndrome (FBS, OMIM 227810).

S odium-dependent GL ucose T ransporters (SGLTs) bind Na ⁺ ions and glucose, transporting them across the membrane in an energy-dependent fashion: the Na ⁺ electrochemical potential gradient, maintained by the Na ⁺ /K ⁺ ATPase, drives the transport of glucose into cells. This allows non-metabolized glucose analogs to accumulate in tissues in excess of the plasma concentration and so they are crucial for the reabsorption of glucose in the kidneys and the intestinal absorption of dietary glucose. SGLTs belong to the SLC5A gene family, part of the Sodium Solute Symporter (SSS) superfamily of proteins. Although the amino acid sequences are quite different among members of the SSS family, the atomic structures reveal common features that suggest similar transport mechanisms.

As with the GLUTs, SGLT genes are expressed throughout the body. However, mRNA expression profiles offer only hints of physiological function, and establishing functional roles for SGLTs in the body’s tissues has proven to be non-trivial.

Cellular and Molecular Physiology of SGLTs

SGLT1 was the first identified and is the most extensively studied Na ⁺ /D-glucose co-transporter. It was cloned in 1987 by expression cloning, and it is responsible for the intestinal absorption of D-glucose and D-galactose from the diet. Through a combination of biophysics, immunohistochemistry, molecular genetics, and freeze fracture electron microscopy, it was established that either defective translation, post- translational trafficking, or function of SGLT1 leads to glucose-galactose malabsorption (GGM, OMIM # 182380; online, Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/OMIM ). GGM is an extremely rare, autosomal recessive disease, in which patients experience life-threatening osmotic diarrhea starting in the first few days of life. Failure to absorb sugars broken down from the lactose in mother’s milk or infant formula leads to profuse, watery diarrhea that abates only when sources of glucose or galactose are eliminated from the diet. As long as GGM is identified and appropriate dietary modifications are made, patients lead relatively normal and healthy lives. Its expression cloning and detailed characterization, in addition to the molecular details of GGM, firmly established hSGLT1 as crucial to glucose and galactose absorption in the gut. On the other hand patients with GGM have only a mild renal glycosuria (see below).

There are four other members of the SLC5A gene family that are capable of transporting glucose, SGLT2, SGLT4, SGLT5 and SGLT6. Human SGLT3, which is expressed in gut neuronal cells, depolarizes the cell upon exposure to glucose, is believed to be a glucose sensor and not a transporter. hSGLT6 is a Na ⁺ /myo-inositol co-transporter which also is a low affinity glucose transporter and it is now referred to as hSMIT2. hSGLT2 (SLC5A2) is abundantly expressed in the kidney but mRNA is also found in liver, heart, brain and muscle. This is believed to be the transporter responsible for the bulk of glucose reabsorption in kidney and mutations in the gene are associated with renal glucosuria (see below). In addition to D-mannose, hSGLT4 has also been shown to transport D-glucose, fructose, and 1,5-anhydro-D-glucitol. Its mRNA has been detected in small intestine, kidney, liver, lung and brain, where it may be important in maintaining stores of mannose for protein glycosylation. SGLT5, exclusively expressed in the human kidney cortex, is a mannose and fructose sodium cotransporter with a higher affinity and turnover than for glucose. Its cellular location and function within the cortex is as yet unknown.