*Mouse models of SGLT2 deficiency*

surface of cells within the S3 segment of the proximal tubule, where it contributes to renal

SGLT1 is a high-affinity, low-capacity transporter with a Km of 0.5 mM for the substrate αMDG in *Xenopus laevis* oocytes. Substrate transport of glucose is coupled to symport of two sodium ions. The protein is highly glycosylated which leads to an apparent molecular weight of 75

Mutations in the SGLT1 gene cause glucose-galactose malabsorption (GGM). GGM was first described in 1962 [7] as a severe life-threatening diarrhea in new-born children, that is fatal within weeks unless lactose, glucose, and galactose are removed from the diet. The diarrhea returns immediately upon reintroduction of the respective sugars into the diet. GGM was predicted to be caused by defective intestinal sodium-coupled glucose transport, a hypothesis that was confirmed following the cloning of human SGLT1 and the identification of homozy‐

GGM is a rare autosomal recessive disease caused by missense, nonsense, frame-shift, and splice-site mutations within the SGLT1 gene. Missense mutations-even single amino acid changes-have been demonstrated to cause missorting of the protein in cells, suggesting that slight conformational changes in the protein can interfere with proper folding and/or delivery and integration of SGLT1 into the plasma membrane and thereby affecting its function. More

SGLT2 was cloned from human kidney cDNA in 1992 and was found to encode for a 672 amino acid protein with 59% similarity to SGLT1. SGLT2 is almost exclusively expressed in the kidney and localizes to the apical domain of epithelial cells that line the S1/S2 segments of the proximal convoluted renal tubule. It has been characterized as a kidney-specific transporter controlling the initial step of renal glucose reabsorption, working in concert with SGLT1, which appears responsible for clearance of residual glucose in the more distal S3 segment of the proximal tubular system (Figure 3A). In contrast to SGLT1, which transports glucose and galactose, SGLT2 represents a low-affinity, high-capacity sodium-glucose symporter with a Km for glucose of 6 mM and a sodium-to-glucose coupling ratio of 1:1 while having no affinity for

than 80 patients with GGM have been screened for mutations in the SGLT1 gene [1].

*Human Physiology-Familial Renal Glucosuria (FRG) is caused by non-functional SGLT2*

Glucosuria in the absence of both generalized proximal tubular dysfunction and hyperglyce‐ mia is known as De-Toni-Debré-Fanconi syndrome. This is recognized as an inherited disorder

*Humans with deficiency for SGLT1 display glucose and galactose malabsorption*

gous carriers for the D28N mutation encoding a non-functional protein [8].

glucose reabsorption (Figure 3A).

*2.4.1. SGLT1 physiology*

**2.5. SGLT2 (***SLC5A2)*

galactose.

*2.5.1. SGLT2 physiology*

and designated as familial renal glucosuria (FRG).

kDa.

12 Glucose Homeostasis

The metabolic consequences of SGLT2 deficiency in mice have been investigated in a model of diet-induced obesity and associated insulin resistance and a genetic model of T2DM, the db/db mouse strain [10]. Deletion of SGLT2 leads to increased urine output and a tremendous increase in glucosuria that is associated with compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice are protected from diet-induced hyperglycemia and glucose intolerance and have reduced plasma insulin concentrations. In the diabetic db/db mouse, deficiency of SGLT2 prevents fasting hyperglycemia and is associated with normalized plasma insulin levels and preserved pancreatic β-cell function. These data confirm the concept of glucotoxicity which was established by studying the anti-diabetic effects of blocking renal glucose reabsorption in diabetic rats by pharmacological means of SGLT inhibition using phlorizin [11].
