**3. Clinical effects of mutations in SGLT1 and SGLT2**

Autosomal recessive mutations in SGLT1 lead to a disorder called glucose galactose malabsorption (GGM). SGLT1 becomes nonfunctional, and infants with GGM develop severe watery diarrhea, dehydration, and metabolic acidosis that cease on diet free of glucose, galactose, and lactose [25].

In 1927, the first case of familial renal glycosuria was reported, in which a mutation in gene for SGLT2 resulted in loss of glucose in urine ranging from 1 to 150 g per 1.73 m2 body surface areas per day. Almost 50 mutations have been identified so far leading to this condition which is characterized by urinary glucose excretion in the presence of normal plasma glucose levels and an absence of signs of general renal tubular dysfunction. Patients have normal oral glucose tolerance test and usually present with osmotic symptoms without any serious complications [26, 27]. The condition is not associated with any change in intravascular volume, serum glucose levels, or renal or bladder dysfunctions. These patients do not show higher incidence of kidney disease, DM, or urinary tract infections although those affected with severe forms of the disease may demonstrate activation of renin-angiotensinaldosterone axis as indirect evidence of volume contraction [20, 26, 27].

These observations further strengthen the belief that SGLT2-I could potentially be developed as safe OAH.
