sodium-glucose cotransporter

**Mechanism** - SGLTs are secondary active (symport) transporters. The basolateral Na+/K+-ATPase keeps intracellular Na+ low. Na+ then moves down its gradient into the cell and brings glucose with it against its concentration gradient. - Glucose leaves the cell on the basolateral side by facilitated diffusion through GLUT2 (and GLUT1).

**Isoforms** - SGLT2: low-affinity, high-capacity. It sits in the early proximal tubule (S1/S2), carries 1 Na+ per glucose, and reabsorbs ~90% of filtered glucose. - SGLT1: high-affinity, low-capacity. It sits in the late proximal tubule (S3) and the small intestinal brush border, carries 2 Na+ per glucose, and absorbs glucose and galactose. It does not transport fructose, which uses GLUT5. - Normally all filtered glucose is reabsorbed. The renal threshold is ~180-200 mg/dL (plasma), and the transport maximum (Tm) is ~375 mg/min. Above this, glucosuria occurs.

**Clinical significance** - *SGLT2 inhibitors* (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin): - They block proximal glucose reabsorption, causing glucosuria, osmotic diuresis, and modest weight loss and BP reduction. - They are used in T2DM. They also have proven benefit in HFrEF and HFpEF, in CKD (slowing progression, including in nondiabetic patients), and in reducing cardiovascular events in ASCVD. - Their glucose-lowering effect is glucose-dependent and falls as GFR falls, so hypoglycemia risk is low as monotherapy. - Adverse effects: - Genital mycotic infections (most common) and UTIs. - Euglycemic DKA, especially in T1DM, with prolonged fasting, or perioperatively. Hold before surgery. - Volume depletion and orthostatic hypotension, especially with loop diuretics. - Fournier gangrene (rare). - Canagliflozin: lower-limb amputation signal. - *Familial renal glucosuria*: loss-of-function mutation in SLC5A2 (SGLT2). It causes benign isolated glucosuria with normal serum glucose. - *Glucose-galactose malabsorption*: autosomal recessive SGLT1 (SLC5A1) defect. It causes severe osmotic watery diarrhea in neonates after feeding with glucose, galactose, or lactose. It resolves with a fructose-based formula. The oral glucose tolerance test is abnormal, and there is no glucosuria in the usual sense. - *Oral rehydration therapy*: SGLT1 couples Na+ and glucose uptake, which drives water absorption in the gut. This is why glucose-containing ORS works in secretory diarrhea such as cholera. - Compare Fanconi syndrome, which causes generalized proximal tubule dysfunction (glucosuria with normal serum glucose, plus aminoaciduria, phosphaturia, and proximal RTA).

**High-yield associations** - Glucosuria with normal serum glucose → SGLT2 mutation or Fanconi syndrome. - SGLT2 inhibitor + ill or fasting patient with anion gap acidosis and near-normal glucose → euglycemic DKA. - SGLT2 inhibitors lower BP and preload, and reduce HF hospitalizations. - Expect urine dipstick glucose to be positive on SGLT2 inhibitors (the expected pharmacologic effect). - Related transporters: GLUT2 (liver, pancreatic beta cell, basolateral kidney/intestine), GLUT4 (insulin-dependent, in muscle and fat), GLUT5 (fructose).