Part 7

GLUT2GLUT2 AMG UptakeAMG Uptake

NGT T2DM NGT T2DM

AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute.

Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

SGLT2SGLT2

NGT T2DM0

2

6

8

0

500

1000

1500

2000

No

rmal

ized

Glu

cose

T

ran

spo

rter

Lev

els

CP

M

Increased Glucose Transporter Proteins Increased Glucose Transporter Proteins and Activity in Type 2 Diabetesand Activity in Type 2 Diabetes

P<0.05

4

P<0.05

P<0.05

The Ominous OctetThe Ominous Octet

Islet -cell

ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion

NeurotransmitterNeurotransmitterDysfunctionDysfunction

Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake

Islet -cell

IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption

IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP

DecreasedDecreasedIncretin EffectIncretin Effect

DecreasedDecreasedIncretin EffectIncretin Effect

Lower Posterior Hypothalamus

Mag

nit

ud

e o

f In

hib

ito

ryR

esp

on

se (

%)

0

4

8

Obese Lean

P<0.01

Tim

e to

Ma

x In

hib

ito

ryR

esp

on

se (

min

)

0

4

8

Obese Lean

P<0.0112

Matsuda M, et al. Diabetes. 1999;48:1801-1806.

Altered Hypothalamic Function inAltered Hypothalamic Function inResponse to Glucose Ingestion inResponse to Glucose Ingestion inObese HumansObese Humans

1. Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c

2. Will require multiple drugs in combination to correct multiple pathophysiologic defects

3. Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented

Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes

DPP-4 InhibitorsSulfonylureas/Meglitinides

Treatment of Type 2 Diabetes: A SoundTreatment of Type 2 Diabetes: A SoundApproach Based Upon Its PathophysiologyApproach Based Upon Its Pathophysiology

MetforminTZDs

TZDs

TZDs

TZDsMetformin

GLP-1 analogues

Islet -cell

ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake

IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP

DPP-4=dipeptidyl peptidase-4.DPP-4=dipeptidyl peptidase-4.

Years

88

7

6

0

9

0 3 6 9 12 15

UKPDS Group. Lancet. 1998;352:854-865.

Median HbA1c

(%)

UKPDS: Effect of Glibenclamide and UKPDS: Effect of Glibenclamide and Metformin Therapy on HbAMetformin Therapy on HbA1c1c

IDF Treatment

Goal:<6.5%

IDF Treatment

Goal:<6.5%

Conventional Glibenclamide MetforminConventional Glibenclamide Metformin

Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.

ADOPT: Effect of Glyburide, Metformin, ADOPT: Effect of Glyburide, Metformin, and Rosiglitazone on HbAand Rosiglitazone on HbA1c1c

HbA1c (%)

Years

IDF Treatment

Goal:<6.5%

IDF Treatment

Goal:<6.5%

7.6

7.2

6.8

6.4

00 1 2 3 4 5

-0.13% (P=0.002)

-0.42% (P<0.001)

Glyburide Metformin RosiglitazoneGlyburide Metformin Rosiglitazone

Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved.

WeightManagement

Type 2Diabetes

Multiple Defects in Type 2

Diabetes

Adverse Effectsof Therapy

Hyperglycemia

Unmet Needs in Diabetes CareUnmet Needs in Diabetes Care

CVD Risk(Lipid and

HypertensionControl)

SGLT2 InhibitionSGLT2 Inhibition

A Novel Treatment Strategy for Type 2 DiabetesA Novel Treatment Strategy for Type 2 Diabetes

5 mmol/L5 mmol/L

FastingFastingPlasma GlucosePlasma Glucose

MuscleMuscle

Normal Glucose HomeostasisNormal Glucose Homeostasis

FatFat

LiverLiver

PancreasPancreas

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