*4.2.1 Locations of SGLT2*

In humans, SGLT2 is strongly expressed in the kidney where it has been localized to the brush border membrane of the S1 and S2 segment of the proximal tubules. On the other hand, SGLT1 has been localized to the brush border membrane of the S3 segment of proximal convoluted tubules of the kidney [28–30, 48].

Proteins and mRNA of SGLT2 have also been found in alpha cells of the pancreas [31]. In addition to the kidney and pancreas, small amount of SGLT2 mRNA have been identified in the testis, liver, lung, and cerebellum [21, 28–30, 48].

## *4.2.2 Functional properties*

SGLT2 is highly selective for glucose over galactose. It has low affinity for glucose with Km = 2 mM but with high transport capacity with Tmax = 10 nmol/mg protein per minute and operates with a 1:1 stoichiometry of sodium and glucose. The apparent Michaelis-Menten Km values for glucose and sodium in human SGLT2 are 5 and 25 mM, respectively [28].

### *4.2.3 Physiological functions of SGLT2*

#### *4.2.3.1 Functions of SGLT2 in the kidney*

Details of the physiological functions of SGLT2 in the kidney have already been mentioned earlier in Section 2.3.

In T2DM, SGLT2-mediated reabsorption of glucose and sodium is increased and can be considered physiologically maladaptive as it prevents an increase in urinary glucose excretion at high blood glucose levels. The increase in proximal tubular sodium reabsorption leads to fall in the distal tubular sodium and chloride concentrations which result in glomerular hyperfiltration [49] and plays a central role in the development of diabetic nephropathy [50].

The triad of hyperglycemia, elevated GFR, and the increased proximal tubular glucose reabsorption altogether leads to increase in kidney size and volume which is combined with glomerular hypertrophy, enlarged proximal tubules, inflammation, and interstitial fibrosis. These hyperglycemia-induced alterations lead to microand macroalbuminuria which culminate into renal failure [49].
