The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis

Disclosures

Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Structure & Kinetics of SGLTs

Molecular structure of SGLTs has been mainly studied on SGLT1, which is the first member of SGLTs family.[23] Additionally, SGLT2 is 59% identical to SGLT1 and is expected to share the same architecture.[28] Its secondary structure consists of 14-transmembrane helices (TM1–TM13) with both the NH2 and COOH termini facing the extracellular side of the plasma membrane (Figure 2).[34]

Figure 2.

Secondary structure model of human SGLT1. According to this model, SGLT1 transporter consist of 14 transmembrane helices (TM-1–TM-13) with both the NH and COOH termini facing the extracellular side of the plasma membrane. Adapted from [34].

Kinetics of Na+/glucose co-transporters[six-stage kinetic model (Stages C1–C6), which was originally proposed by Parent et al.[35]) and the relevant mechanical model (firstly proposed by Schultz[36]) are exhibited meticulously by E. Wright, D. Loo and B. Hirayama in their study visualized on Figure 3.[23]

Figure 3.

A six-state model of SGLTs to integrate the kinetic and structural data based on the study of Wright E, Loo D and Hirayama B. States C1–C3 faces outward and states C4–C6 inward to cells. At C1 and C6 stages, there are no ligands attached to the transporter. At C2 and C5 states, only Na+ is bound and at C3, C4 states Na+ and sugar are simultaneously attached to SGLT. Firstly, the binding sites for Na+ and glucose are exposed to the external side of the membrane (C1) and the negatively charged carrier attract Na+ ions (one for SGLT2 and two ions for SGLT1).The attachment of Na+ increase the affinity of the transporter to glucose (C2). As soon as glucose binds to the carrier too (C3), the tertiary structure of the transporter undergoes a conformational change to present Na+ and sugar binding sides to the internal side of the membrane (C3, C4), where the ligands (Na+ and glucose) are released at the intracellular place (C4,C5). At C6 stage (inward facing ligand-free state), the transporter undergoes a reversed conformation change and presents the binding sides to the extracellular place (outward facing ligand-free state) C1. Data taken from [23].

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