Part 8 Rationale for SGLT 2 Inhibitors Inhibit

Part 8

Rationale for SGLT 2 Inhibitors • Inhibit glucose reabsorption in the renal proximal tubule • Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity • This therapy is simple and nonspecific • Even patients with refractory type 2 diabetes are likely to respond

Pathophysiology of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Insulin Resistance 10 mmol/L Fasting Plasma Glucose Increased HGP Glucosuria

Pathophysiology of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Insulin Resistance 10 mmol/L Increased HGP 5 mmol/L Fasting Plasma Glucose Glucosuria

Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT 2 S 1 SGLT 1 S 3 90% 10% No Glucose

Sodium-Glucose Cotransporters Site Sugar specificity Glucose affinity Glucose transport capacity Role SGLT 1 SGLT 2 Intestine, kidney Kidney Glucose or galactose Glucose High Low Km=0. 4 m. M Km=2 m. M Low High Dietary absorption of glucose and galactose Renal glucose reabsorption

SGLT 2 Mediates Glucose Reabsorption in the Kidney Lumen K+ Blood Na+ Glucose S 1 Proximal Tubule Na+ ATPase SGLT 2 GLUT 2 Glucose Major transporter of glucose in the kidney • Low affinity, high capacity for glucose • Nearly exclusively expressed in the kidney • Responsible for ~90% of renal glucose reabsorption in the proximal tubule Hediger MA, Rhoads DB. Physiol. Rev. 1994; 74: 993 -1026.

Renal Glucose Handling Tm. G Re Ex ab cr et so rp Glucose Reabsorption and Excretion io n tio n Splay Actual Threshold 5 10 Theoretical threshold 15 Plasma Glucose Concentration (mmol/L)

Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Design Rat Group I (n=14) II (n=19) III (n=10) IV (n=4) • • Pancreatectomy / Diabetic Status Sham Control 90% Diabetes Phlorizin Meal Tolerance Test – + + + +/– 10 -12 days after discontinuation of phlorizin Phlorizin treatment period: 4 -5 weeks Diet was same for all groups; body weight was similar across groups at end of study Rossetti L, et al. J Clin Invest. 1987; 79: 1510 -1515.

Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic Rats † * 20 † 6 15 4 10 2 5 0 0 +/ s te in be iz ia r D lo Ph + s te in be iz ia r D lo Ph tes be ia D l ro t on C +/ s te in be iz ia r D lo + Ph es t in be iz ia r D hlo s P e et b ia D l ro t on C *P<0. 05 vs control and phlorizin. †P<0. 001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987; 79: 1510 -1515. Fed Glucose (mmol/L) Fasting Glucose (mmol/L) 8

Insulin-Mediated Glucose Uptake in Diabetic Rats Following Phlorizin Treatment 40 35 Glucose Uptake 30 (mg/kg ∙ min) * 25 20 Control *P<0. 001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987; 79: 1510 -1515. Diabetes * Diabetes + Phlorizin +/- Phlorizin

Mechanism of Action of SGLT 2 Inhibitors Inhibition of SGLT 2 Reversal of glucotoxicity Insulin sensitivity in muscle • ↑ GLUT 4 translocation • ↑ Insulin signaling • Other Insulin sensitivity in liver • ↓ Glucose- 6 -phosphatase Gluconeogenesis • Decreased Cori cycle • ↓ PEP carboxykinase -Cell function

Effect of Phlorizin on -Cell Function in Diabetic Rats: Study Design Rat Group I II III • • • Pancreactomy / Diabetic Status Sham Control 90% Diabetes Phlorizin – – 0. 4 g/kg/day Sprague-Dawley male rats weighing 80 -100 g Phlorizin treatment period: 3 weeks Arginine clamp (2 m. M); hyperglycemic clamp (≥ 5. 5 mmol/L) Rossetti L, et al. J Clin Invest. 1987; 80: 1037 -1044.

Plasma Insulin Response to Glucose First Phase Second Phase 6 4 Plasma Insulin (ng/m. L ∙ min / g Pancreas) * 2 * 0 Control Diabetes + Phlorizin *P<0. 001 vs control. Rossetti L, et al. J Clin Invest. 1987; 80: 1037 -1044. Control Diabetes + Phlorizin

Plasma Glucagon Concentration in Diabetic Dogs Before and After Phlorizin Glucose Infusion Rate (mg/kg • min) 2 6 8 12 16 24 0 Glucagon (pg/m. L) -200 -400 Starke A, et al. Proc Natl Acad Sci. 1985; 82: 1544 -1546. Diabetic + Phlorizin