**2.7. SGLT4 (***SLC5A9***)**

provide excellent safety and potential add-on effects such as weight loss, lipid lowering or

The kidney has an important role in controlling blood glucose levels by mediating glucose reabsorption into the bloodstream. In patients with T2DM increased renal absorptive capacity has been observed, indicating that blocking the process of glucose reuptake by the kidney might be an attractive new strategy for treatment of T2DM. However, glucosuria has histori‐ cally been perceived as a manifestation of the disease, which appears to make this therapeutic

The phenotype of subjects identified with FRG, as well as studies performed with phlorizin, indicated that correcting hyperglycemia via specific inhibition of SGLT2 might provide a new

Phlorizin, a potent SGLT inhibitor, proved to be an important tool for investigating the mechanism and consequences of blocking renal sugar reabsorption. Its use established the concept of glucotoxicity: blocking of renal glucose reabsorption with phlorizin in diabetic rats

Disadvantages of phlorizin include the non-selective inhibition of SGLT2, poor bioavailability, short half-life and potential for side effects caused e.g by blocking GLUT via its major metab‐ olite phloretin. These disadvantages that are inherited to the molecular phlorizin led into research for new compounds in order to achieve proof of concept for selective SGLT2 inhibition

Although non-selective for SGLT2, T-1095 was the first orally available phlorizin derivative that was metabolically stable. When administered to diabetic animals, T-1095 corrected hyperglycemia and reduced hyperinsulinemia, and hypertriglyceridemia [12]. These findings

In the following years, the selective SGLT2 inhibitors sergliflozin and remogliflozin progressed to clinical trials. While many selective SGLT2 inhibitors went into clinical testing, development of O-glycosidic SGLT2 inhibitors was halted, presumably due to their unfavorable pharma‐ kokinetic profile. In contrast, a number of C-glycosidic compounds which differ from Oglycosides in structure and stability are in clinical development [12] or have achieved approval and represent an innovative insulin-independent treatment option for controlling blood

The human SGLT3 cDNA was cloned from colon carcinoma and was found to encode a 659 amino acid protein with 70% identity to human SGLT1. SGLT3 mRNA is detected in the intestine, testes, uterus, lung, brain and thyroid, while the protein is predominantly found in intestine and skeletal muscle. Immunohistochemical analysis of the intestine identified cholinergic neurons in submucosal and myenteric plexuses as the site of SGLT3 expression. In skeletal muscle, SGLT3 co-localized with the nicotinic acetylcholine receptor indicating

indicated that SGLT2 inhibition might be a viable approach to treatment of T2DM.

reductions in blood pressure.

14 Glucose Homeostasis

for the treatment of T2DM.

glucose in Type 2 diabetic patients [13].

expression at the neuromuscular junction.

**2.6. SGLT3 (***SLC5A4***)**

concept seem rather counter-intuitive.

option for a safe and effective treatment of T2DM.

normalized insulin levels and restored insulin sensitivity [11].

SGLT4 was cloned from human small intestinal cDNA libraries. The mRNA encoding SGLT4 is almost exclusively found in the small intestine and kidney. SGLT4 exhibits Na+-dependent AMG transport with a Km of 2.6 mM. Inhibition studies of AMG mediated transport indicated that SGLT4 appears to transport naturally occurring sugars with a rank order of mannose, glucose, fructose, and galactose. Transport studies using radiolabeled mannose indicated that SGLT4 might be physiologically relevant for intestinal absorption as well as renal reabsorption of mannose [18].
