Part 8

Rationale for SGLT2 InhibitorsRationale for SGLT2 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

FastingFastingPlasma GlucosePlasma Glucose

Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes

10 mmol/L10 mmol/L

Islet -cell

Impaired Insulin Impaired Insulin SecretionSecretionImpaired Insulin Impaired Insulin SecretionSecretion

Insulin Insulin ResistanceResistance

Increased Increased HGPHGP

GlucosuriaGlucosuria

FastingFastingPlasma GlucosePlasma Glucose

Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes

10 mmol/L10 mmol/L

Islet -cell

Impaired Insulin Impaired Insulin SecretionSecretionImpaired Insulin Impaired Insulin SecretionSecretion

Insulin Insulin ResistanceResistance

Increased Increased HGPHGP

5 mmol/L5 mmol/L

GlucosuriaGlucosuria

SGLT1SGLT1

(180 L/day) (900 mg/L)=162 g/day(180 L/day) (900 mg/L)=162 g/day

10%10%

GlucoseGlucose

No GlucoseNo Glucose

S1S1

S3S3

Renal Handling of GlucoseRenal Handling of Glucose

SGLT2

90%

Sodium-Glucose CotransportersSodium-Glucose Cotransporters

SGLT1 SGLT2

SiteSite Intestine, kidney Kidney

Sugar specificitySugar specificity Glucose or galactose Glucose

Glucose affinityGlucose affinityHigh

Km=0.4 mM

Low

Km=2 mM

Glucose transport Glucose transport capacitycapacity

Low High

RoleRole

Dietary absorption of glucose and galactose

Renal glucose reabsorption

Renal glucose reabsorption

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.

S1 Proximal Tubule

NaNa++

K+

AT

Pase

Glucose

GLUT2

Glucose

SGLT2

BloodBloodLumenLumen

Na+

SGLT2 Mediates GlucoseSGLT2 Mediates GlucoseReabsorption in the KidneyReabsorption in the Kidney

Plasma Glucose Concentration (mmol/L)

155

Glucose Reabsorptionand Excretion

Splay

Excre

tion

TmG

10

Actual Threshold

Reabso

rptio

n

Theoretical threshold

Renal Glucose HandlingRenal Glucose Handling

Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

Effect of Phlorizin on Insulin Sensitivity Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Designin Diabetic Rats: Study Design

Rat Rat GroupGroup

Pancreatectomy / Pancreatectomy / Diabetic StatusDiabetic Status PhlorizinPhlorizin Meal Tolerance TestMeal Tolerance Test

I (n=14)Sham

Control– +

II (n=19)90%

Diabetes– +

III (n=10)

90%

Diabetes+ +

IV (n=4)90%

Diabetes+ / –

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

Fas

tin

g G

luco

se (

mm

ol/

L)

Diabetes +/-

Phlorizin

Diabetes +

Phlorizin

Diabetes

Control

*

Fed

Glu

cose

(m

mo

l/L

)

Diabetes +/-

Phlorizin

Diabetes +

Phlorizin

Diabetes

Control

*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.

Effect of Phlorizin on Fed and Fasting Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic RatsPlasma Glucose in Diabetic Rats

†

†

0

5

10

15

20

0

2

4

6

8

Glucose Uptake

(mg/kg ∙ min)

*P<0.001 vs control and phlorizin.

Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

Insulin-Mediated Glucose Uptake in DiabeticInsulin-Mediated Glucose Uptake in DiabeticRats Following Phlorizin TreatmentRats Following Phlorizin Treatment

Diabetes+/- Phlorizin

Diabetes+ Phlorizin

DiabetesControl20

25

30

35

40

**

Mechanism of Action of Mechanism of Action of SGLT2 InhibitorsSGLT2 Inhibitors

Inhibition of SGLT2 Reversal of glucotoxicity

Insulin sensitivity in muscle• ↑ GLUT4 translocation• ↑ Insulin signaling• Other

Insulin sensitivity in liver• ↓ Glucose- 6-phosphatase

Gluconeogenesis• Decreased Cori cycle• ↓ PEP carboxykinase

-Cell function

Effect of Phlorizin on Effect of Phlorizin on -Cell Function -Cell Function in Diabetic Rats: Study Designin Diabetic Rats: Study Design

Rat GroupRat Group Pancreactomy / Diabetic StatusPancreactomy / Diabetic Status PhlorizinPhlorizin

ISham

Control–

II90%

Diabetes–

III90%

Diabetes0.4 g/kg/day

• Sprague-Dawley male rats weighing 80-100 g

• Phlorizin treatment period: 3 weeks

• Arginine clamp (2 mM); hyperglycemic clamp (≥5.5 mmol/L)

Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

First PhaseFirst Phase Second PhaseSecond Phase

Control ControlDiabetes+ Phlorizin

Diabetes+ Phlorizin

Diabetes Diabetes

6

0

4

*

*2

Plasma Insulin(ng/mL ∙ min / g

Pancreas)

Plasma Insulin Response to GlucosePlasma Insulin Response to Glucose

*P<0.001 vs control.

Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

Starke A, et al. Proc Natl Acad Sci. 1985;82:1544-1546.

Glucagon (pg/mL)

Glucose Infusion Rate (mg/kg • min)

Diabetic +Phlorizin

Diabetic

-400

-200

0241612862

Plasma Glucagon Concentration in DiabeticPlasma Glucagon Concentration in DiabeticDogs Before and After PhlorizinDogs Before and After Phlorizin