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

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

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

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

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 galactose.

## *2.5.1. SGLT2 physiology*

#### *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 and designated as familial renal glucosuria (FRG).

FRG is an autosomal recessive disorder and is diagnosed by persistent isolated glucosuria (urine excretion >1 g/day) with normal fasting plasma glucose levels and oral glucose tolerance.

Since the first SLC5A2 mutation in FRG was presented in 2002 [9], forty-four mutations have been identified including premature stops, frame shifts, and missense mutations. Although the pattern of inheritance for FRG is of co-dominance, a clear definition of genotype-phenotype correlation has not been established. Individuals with similar or even identical mutations display a broad range of severity in glucosuria, indicating that environmental, as well as genetic, factors affect urinary glucose reabsorption. Since, thus far, none of the FRG mutations has been tested for functional SGLT2 effects it is unknown how the various mutations relate to the severity of glucosuria.

FRG established the fundamental role of SGLT2 in renal glucose reabsorption. Since patients with FRG are not affected by severe clinical consequences, it is considered a benign condition, more a phenotype than a disease.
