Post on 02-Jan-2016
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