Eighth United States Army Troop Command Sergeant Audie Murphy Club Members
Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division...
Transcript of Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division...
Program Editors
Ralph Anthony DeFronzo, MD Professor of Medicine and
Chief of the Diabetes Division
University of Texas Health
Science Center
Audie L. Murphy Memorial Veterans Hospital
San Antonio, Texas, USA
Jaime A. Davidson, MD President, Worldwide Initiative
for Diabetes Education
Clinical Professor of Internal Medicine
Division of Endocrinology
University of Texas Southwestern
Medical School
Dallas, Texas, USA
Jaime A. Davidson, MD President, Worldwide Initiative
for Diabetes Education
Clinical Professor of Internal Medicine
Division of Endocrinology
University of Texas Southwestern
Medical School
Dallas, Texas, USA
Faculty
Professor Rury HolmanProfessor of Diabetic Medicine
Honorary Consultant Physician
Diabetes Trials Unit
University of Oxford
Oxford, United Kingdom
Professor Stefano Del PratoProfessor of Endocrinology and Metabolism
School of Medicine
University of Pisa
Pisa, Italy
Professor Allan VaagChief Physician
Steno Diabetes Center
Gentofte, Denmark
Educational Objectives
Upon completion of this activity, participants will be able to
• Name 5 current challenges for glycemic control in individuals with type 2 diabetes
• List the key physiologic, biochemical, and molecular events involved in the renal regulation of glucose metabolism
• Understand the effects of inhibiting glucose reuptake by the kidney in individuals with type 2 diabetes
Magnitude of the Diabetes EpidemicMagnitude of the Diabetes Epidemic
28.3 M40.5 M43.0%
16.2 M32.7 M102%
53.2 M64.164.1 M20%
67.0 M 99.4 M 48%
10.4 M18.7 M80%
46.5 M
80.3 M
73%
M=million; AFR=Africa; EMME=Eastern Mediterranean and Middle East; EUR=Europe; NA=North America; SACA=South and Central America; SEA=South-East Asia; WP=Western Pacific.
International Diabetes Federation. Diabetes Atlas. 3rd ed. Available at: http://www.eatlas.idf.org/index.asp.
World
2007=246 M2025=380 M
54%
AFR
NA
SACA
EUR
SEA
WP24.5 M44.5 M82%
EMME
2007 2025
Global Projections for theGlobal Projections for theDiabetes Epidemic: 2007-2025Diabetes Epidemic: 2007-2025
Global Increase in Obesity
Overweight, BMI ≥25 kg/m2; obese, BMI >28 kg/m2 (Asian) or >30 kg/m2.
James WP. J Intern Med. 2008;263:336-352.
USAUSA
UKUK
AustraliaAustraliaFinlandFinland
SwedenSwedenNorwayNorwayBrazilBrazilCubaCuba
JapanJapan
19701970 19751975 19801980 19851985 19901990 19951995 20002000 20052005
Pre
vale
nce
of
Ob
esit
y (%
)P
reva
len
ce o
f O
bes
ity
(%)
3535
3030
2525
2020
1515
1010
55
00
20022002 20072007 20152015
Obese 356 million 523 million 704 million
Overweight 1.4 billion 1.5 billion 2.3 billion
Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: United Statesand Diabetes: United States
*BMI ≥30 kg/m2.
Centers for Disease Control and Prevention. National diabetes fact sheet. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008;Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Ogden CL, et al. NCHS data brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007.
Obesity*Obesity* DiabetesDiabetes
US Population
(%)6.5
7.8
0
5
10 20% increase
1998 2007
17.9
34.3
0
20
40 92% increase
1998 2006
4040
2020
00
Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: Mexicoand Diabetes: Mexico
ObesityObesity DiabetesDiabetes
Mexican Population
(%)
Aguilar-Salinas CA, et al. Am J Med. 2002;113:569-574; Aguilar-Salinas CA, et al. Diabetes Care. 2003;26:2021-2026; Sánchez-Castillo CP, et al. Public Health Nutr. 2005;8:53-60.
14.9
19.4
25.129.0
0
20
40
1993 2000
Men MenWomen Women
4040
2020
00
21% increase
7
8.2
0
5
10
17% increase
1993 2000
1.8
6.9
4.1
9.0
0
5
10
1991 1999-2000
Men MenWomen Women
1010
55
00
169% increase
2.5
5.5
0
3
6
Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: Chinaand Diabetes: China
Obesity*Obesity* DiabetesDiabetes
Chinese Population
(%)
*Asian-specific obesity cut-point: BMI ≥28 kg/m2.
Gu D, et al. Diabetologia. 2003;46:1190-1198; Wildman RP, et al. Obesity (Silver Spring). 2008;16:1448-1453.
1994 2000-2001
120% increase
Increasing Problem of WeightIncreasing Problem of WeightGain and Diabetes: IndiaGain and Diabetes: India
Rural Indian Population
(%)
*BMI ≥25 kg/m2.
Ramachandran A, et al. Diabetologia. 2004;47:860-865.
Overweight*Overweight* DiabetesDiabetes
2.2
6.4
0
4
8 191% increase
1989 2003
2.0
17.1
0
10
20 750% increase
1989 2003
2020
1010
00
HyperglycemiaHyperglycemia
• Biochemical marker by which the diagnosis of diabetes is made
– Assessed with HbA1c, daily SMBG, and eAG
• Major and treatable risk factor for microvascular disease (DCCT, UKPDS 33 and 35)
• Independent and treatable risk factor for macrovascular disease (DCCT-EDIC, UKPDS 35 and 80)
• Self-perpetuating cause of diabetes
– Glucotoxicity → insulin resistance and impaired insulin secretion
eAG=estimated average glucose.SMBG=self-monitoring of blood glucose.
HbAHbA1c1c Is Correlated With Is Correlated With
Average GlucoseAverage Glucose
AG=average glucose.
Nathan DM, et al. Diabetes Care. 2008;31:1473-1478.
450
400
350
300
250
200
150
100
50
03 5 7 9 11 13 15
AG
(m
g/d
L)
HbA1c (%)
Diabetes Report Card: HbADiabetes Report Card: HbA1c1c Levels Levels
in the United Statesin the United States
Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
Patients(%)
HbA1c
(%)
<6.0
6.0-6.9
7.0-7.9
8.0-8.9
9.0-9.9>10.0
0
20
40
60
80
100
22%22%
35%35%
20%20%
11%11%
6%6%6%6%
NHANESNHANES1988-19941988-1994
Advances in Therapy, Advances in Therapy, but Falling Short of Goalsbut Falling Short of Goals
5
6
7
8
9
10
1980s1980s 1990s1990s 2000s 2000s
Hb
AH
bA
1c1c (
%)
(%
)
SU / InsulinSU / InsulinSU / InsulinSU / Insulin Metformin (1995)Metformin (1995)Metformin (1995)Metformin (1995) TZDs (1998)TZDs (1998)TZDs (1998)TZDs (1998) Incretins (2004)Incretins (2004)Incretins (2004)Incretins (2004)
Pre-DCCTPre-DCCT9.0%9.0%
7.7
NHANESNHANES1999-20001999-2000
7.8
NHANESNHANES2001-20022001-2002
7.5
NHANESNHANES2003-20042003-2004
7.2
FutureFuture6.0% ?6.0% ?
1997: ADA lowered T2DM diagnosis from
FPG ≥7.8 mmol/Lto ≥7.0 mmol/L
1997: ADA lowered T2DM diagnosis from
FPG ≥7.8 mmol/Lto ≥7.0 mmol/L
2003: ADA eliminated HbA1c “action point” of <8% from guidelines
2003: ADA eliminated HbA1c “action point” of <8% from guidelines
SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.
Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
2005: ADA added HbA1c goal of <6% for
“individual patients” to guidelines
2005: ADA added HbA1c goal of <6% for
“individual patients” to guidelines
General ADA Target: <7%
General ADA Target: <7%
1998: UKPDS results published
1998: UKPDS results published
2008: ACCORD, ADVANCE, VADT,
and UKPDS 80 published
2008: ACCORD, ADVANCE, VADT,
and UKPDS 80 published
2009: ADA added “less stringent” HbA1c goal for patients with
significant comorbidities or risk of hypoglycemia, or short life expectancy
2009: ADA added “less stringent” HbA1c goal for patients with
significant comorbidities or risk of hypoglycemia, or short life expectancy
CVD=cardiovascular disease.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)
Relationship Between Hyperglycemia and Relationship Between Hyperglycemia and Microvascular and Macrovascular ComplicationsMicrovascular and Macrovascular Complications
IGT (HbA1c=5.9%) IGT………..…7.9%
IGT (HbA1c=6.1%) T2DM………12.6%
Neuropathy (%)Neuropathy (%)
IGT………..…13%*
*Prevalence.
Diabetes Prevention Program Research Group. Diabet Med. 2007;24:137-144; Singleton JR, et al. Diabetes Care. 2001;24:1448-1453; Ziegler D, et al. Diabetes Care. 2008;31:464-469.
Diabetic Retinopathy (%)Diabetic Retinopathy (%)
Incidence of Microvascular Incidence of Microvascular Complications in IGTComplications in IGT
Diabetes Is a Cardiovascular DiseaseDiabetes Is a Cardiovascular DiseaseRisk EquivalentRisk Equivalent
DM=diabetes mellitus; MI=myocardial infarction.Haffner SM, et al. N Engl J Med. 1998;339:229-234.
0
10
20
30
40
50
7-Year Incidence Rate of MI
(%)
DiabeticDiabeticn=1059n=1059
P<0.001
P<0.001
3.5
18.8 20.2
45.0
DMMI
DMNo MI
No DMMI
No DM No MI
NondiabeticNondiabeticn=1373n=1373
Microvascular Disease
0
10
20
30
40
50
60
70
80
5 6 7 8 9 10 11
Mean HbA1c (%)
Stratton IM, et al. BMJ. 2000;321:405-412.
Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001)
Historic Rationale for Improving Glycemia: Historic Rationale for Improving Glycemia: Microvascular Risk ReductionMicrovascular Risk Reduction
Incidence per 1000 Person-
Years(%)
Microvascular Disease
Stratton IM, et al. BMJ. 2000;321:405-412.
Macrovascular Disease
Estimated 14% decrease in myocardial infarction riskfor each 1% decrement in HbA1c (P<0.0001)
Less Strong Association Between Less Strong Association Between Hyperglycemia and Macrovascular Hyperglycemia and Macrovascular Risk in Type 2 DiabetesRisk in Type 2 Diabetes
Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001)
0
10
20
30
40
50
60
70
80
5 6 7 8 9 10 11
Mean HbA1c (%)
Incidence per 1000 Person-
Years(%)
Optimizing Glycemia in Advanced Type 2Optimizing Glycemia in Advanced Type 2Diabetes Exerts Unclear Macrovascular BenefitDiabetes Exerts Unclear Macrovascular Benefit
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group.N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139.
EndpointHbA1c (%)
6
7
8
9
Primary EndpointMacro
↓6%
P=0.37
Macro
↓10%
P=0.16
Intensive therapy
Conventional therapy
ADVANCEADVANCEN=11,140N=11,140
ACCORACCORDD
N=10,251N=10,251
VADTVADTN=1791N=1791
Macro
↓13%
P=0.12
-13-15
-24
-9
-40
-20
0
-6
-16
-25
-12
-40
-20
0
Lasting Benefits of Early, Intensive Intervention: UKPDS “Legacy” Effect
P=0.029
P=0.040
P=0.0099
P=0.001
P=0.052
P=0.014
P=0.44
P=0.007
Any Diabetes Endpoint
Microvascular Disease
Myocardial Infarction
All-cause Mortality
Rel
ativ
e R
isk
Red
uct
ion
(%
)
Inte
rven
tio
nP
ost
-tri
al M
on
ito
rin
g
Holman RR, et al. N Engl J Med. 2008;359:1577-1589; UKPDS Study Group. Lancet. 1998;352:837-853.
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139; Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
Early vs Late Intervention in Type 2 Diabetes
TrialTrialIntensive ArmIntensive Arm
HbAHbA1c1c Reduction ReductionNo Patients / No Patients / Trial DurationTrial Duration Disease SeverityDisease Severity MacrovasculaMacrovascula
r Benefitr Benefit
ACCORD
Goal: <6.0%
Endpoint: 6.4%
↓1.4% from BL in 4 months
N=10,251
3.4 yr
CVD or 2 risk factors
10 yr from T2DM diagnosis
NoADVANCE
Goal: <6.5%
Endpoint: 6.5%
↓0.6% from BL in 12 months
N=11,140
5.0 yr
Vascular disease or 1 risk factor
8 yr from T2DM diagnosis
VADT
Goal: ↓1.5% vs standard
Endpoint: 6.9%
↓2.5% from BL in 3 months
N=1791
5.6 yr
12 yr from T2DM diagnosis
UKPDS 80
Goal: FPG <6.0 mmol/L (108 mg/dL)
Intervention endpoint: 7.0%
Follow-up: 7.7%
N=4209
17 yr
Newly diagnosed with T2DM
Yes
Steno-2: Time to Cardiovascular EventsSteno-2: Time to Cardiovascular Events
Gaede P, et al. N Engl J Med. 2008;358:580-591.
20
40
60
80
0
0 2 4 6 8 10 12
Cumulative Incidence of
Any CV Event (%)
YearsNo. at RiskConventional 80 70 60 46 38 29 25 14Intensive 80 72 65 61 56 50 47 31
P<0.001
Conventional Treatment
Intensive Treatment
InterventionIntervention Follow-upFollow-up
Steno-2: Goal AttainmentSteno-2: Goal Attainment
BP=blood pressure.
Gaede P, et al. N Engl J Med. 2008;358:580-591.
HbA1c <6.5%
Cholesterol <175 mg/dL
Triglycerides <150 mg/dL
Systolic BP<130 mm Hg
Diastolic BP<80 mm Hg
P=0.31
P=0.35 P=0.005
P=0.27
P=0.14
Pat
ien
ts (
%)
Intensive therapy Conventional therapy
P=0.06
P<0.001
P=0.005P=0.001
P=0.21
0
20
40
60
80
100
Inte
rven
tio
nF
ollo
w-u
p
0
20
40
60
80
100
Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes
Insulin Resistance and -Cell DysfunctionInsulin Resistance and -Cell Dysfunction
Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes
Primary PredisposingFactors• Genes• Adverse intrauterine
environment
Tertiary AcceleratingFactors • Glucose and lipid toxicity
Secondary PrecipitatingFactors• Obesity• Low physical activity• Age• Smoking• Sleep disturbance• Other
Metabolic syndrome Hyperglycemia
Failing -cellFunctional -cell
Heine RJ, Spijkerman AM. 2006.
Insulin resistance Insulin resistance
Type 2 Diabetes: A HeterogeneousType 2 Diabetes: A HeterogeneousDisorderDisorder
Type 2 Diabetes: Insulin Resistance Type 2 Diabetes: Insulin Resistance Plus Impaired Plus Impaired -Cell Function-Cell Function
NormalNormal-cell -cell
functionfunction
Compensatoryhyperinsulinemia
Normoglycemia(Metabolic syndrome)
AbnormalAbnormal-cell -cell
functionfunction
Relative insulin deficiency
Hyperglycemia
Type 2 diabetes
Both insulin resistance and -cell dysfunction are present at the time of diagnosis of type 2 diabetes
InsulinInsulinresistanceresistance
DM=diabetes mellitus; IGT=impaired glucose tolerance; INS=insulin; NGT=normal glucose tolerance; OB=obesity. DeFronzo RA. Diabetes. 1988;37:667-687; Jallut D, et al. Metabolism. 1990;39:1068-1075.
Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes
Insulin-MediatedGlucoseUptake(mg/m2 • min)
300
250
200
150
100
MeanPlasma Insulin
During OGTT(µU/mL)
MeanPlasma Glucose
During OGTT(mg/dL)
140
100
60
20
400
300
200
100
OB-DM
Lo INS
LeanNGT
OB-DM
Hi INS
OB-IGT
OBNGT
Etiology of Etiology of -Cell Dysfunction -Cell Dysfunction in Type 2 Diabetesin Type 2 Diabetes
Insulin Insulin ResistanceResistance
AgeAge
-Cell-CellDysfunctionDysfunction
GeneticsGenetics(TCF 7L2)(TCF 7L2)
LipotoxicityLipotoxicity↑ ↑ Free Fatty AcidsFree Fatty Acids
GlucoseGlucoseToxicityToxicity
Amyloid (Islet Amyloid (Islet Amyloid Amyloid Polypeptide)Polypeptide)DepositionDeposition
↓ ↓ IncretinIncretinEffectEffect
ββ-Cell failure occurs much-Cell failure occurs muchearlier in the natural history earlier in the natural history
of type 2 diabetes and is more of type 2 diabetes and is more severe than previously severe than previously
appreciatedappreciated
Natural History of Natural History of -Cell Dysfunction -Cell Dysfunction in Type 2 Diabetesin Type 2 Diabetes
San Antonio Metabolism andSan Antonio Metabolism andVAGES StudiesVAGES Studies
Normal glucose toleranceNormal glucose tolerance 318318Impaired glucose toleranceImpaired glucose tolerance 259259Type 2 diabetes 201
Subjects were classified asSubjects were classified as
NonobeseNonobese ifif BMI <30 kg/mBMI <30 kg/m22
ObeseObese ifif BMI ≥30 kg/mBMI ≥30 kg/m22
VAGES=Veterans Administration Genetic Epidemiology Study.
Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435; Ferrannini E, et al. J Endocrinol Metab. 2005;90:493-500; Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
Methods: OGTT and insulin clamp
SubjectsSubjects NumberNumber
NGT NGT
<16
0
<18
0
<20
0
IGT IGT IGTIGT
<16
0
<18
0
<20
0
Q1
Q1
T2DM T2DM
Q2
Q2
Q3
Q3
Q4
Q4
Q1
Q2
Q3
Q4
T2DMT2DM
0
4
8
12
Glu
cose
AU
C(m
mo
l/L
1
20 m
in)
0
4
8
12
Insu
lin
AU
C(p
mo
l/L
1
20 m
in)
Plasma Glucose and Insulin AUCPlasma Glucose and Insulin AUC
Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
∆ I / ∆ G÷IR
2-Hour Plasma Glucose (mg/dL)
Insulin Secretion / Insulin Resistance Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT(Disposition) Index During OGTT
G=glucose; I=insulin; IR=insulin resistance.
Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
30
20
10
0
40
NGT
Lean
<100
<100
<120<14
0
Obese
<180
<180
IGTIGT
<200
<160
<160
<240
<280
<360
<320
>400
<400
T2DM
6
-4
0
-2
2
4
6.54.0 4.5 5.0 5.5 6.0
Ln ∆I / ∆G÷ IR
(mL/min • kgFFM)
Ln 2-Hour Plasma Glucose (mg/dL)
r=0.91P<0.00001
T2DM
IGT
NGT
Log Normalization of the Relationship Between Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance IndexInsulin Resistance Index
Ln=log normalization.
Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
GENFIEV: Insulin Secretion as a GENFIEV: Insulin Secretion as a Function of Insulin SensitivityFunction of Insulin Sensitivity
HOMA-R=homeostasis model assessment index ratio.
Diabetes. 2006;55(suppl 2):A322.
0
0.01
0.02
0.03
0.04
<100 120 140 160 180 200 240 280 >280
Δ AUC C-peptide /
Δ AUCGlucose ÷ HOMA-R
Δ AUC C-peptide /
Δ AUCGlucose ÷ HOMA-R
2-Hour Plasma Glucose(mg/dL)
2-Hour Plasma Glucose(mg/dL)
Trend test P<0.001
0
200
400
600
800
1000
1200
3 6 9 12
NFG/NGT IFG/NGT NFG/IGT IFG/IGT
NFG/DGT IFG/DGT DFG/IGT DFG/DGT
§§
##
**
Plasma Glucose (mmol/L)
Insu
lin
Sec
reti
on
Rat
e (
pm
ol
. min
-1 . m
-2)
*P<0.01 vs NFG/NGT; §P<0.05 vs NFG/IGT and IFG/NGT; #P<0.05 vs IFG/IGT and NFG/DGT.
Diabetes. 2006;55(suppl 2):A2472.
GeNFIEV: Stimulus-response Curve (Proportional Control) of Insulin Secretion
GENFIEV: Stimulus-Response CurveGENFIEV: Stimulus-Response Curve(Proportional Control) of Insulin Secretion(Proportional Control) of Insulin Secretion
-18
-32
-8
-40
-30
-20
-10
0
Insulin Secretion and Insulin Resistance Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGTin Different Ethnic Populations With IGT
AIR=acute insulin response to glucose.
Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139.
Latino/HispanicPima Indian White
Δ A
IR (
%)
Δ A
IR (
%)
Insulinresistance ↑↑↑ ↑↑ ↑
Decrease in AIR Necessary to Convert From NGT to IGT
Decrease in AIR Necessary to Convert From NGT to IGT
Insulin Resistance and Insulin Resistance and -Cell-CellDysfunction: SummaryDysfunction: Summary
• Individuals with impaired glucose tolerance
– Are maximally or near-maximally insulin resistant
– Have lost ~80% of their -cell function
– Have an incidence of diabetic retinopathy of ~10%
Pathogenesis of DiabetesPathogenesis of Diabetes
Evolving ConceptsEvolving Concepts
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
HGP=hepatic glucose production.
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
HGP=hepatic glucose production.
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Time (minutes)
1st Phase 2nd Phase
i.v. Glucose
Diabetes
Normal glucose tolerance
-5
-10
0 5 10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
100
95
Insu
lin S
ecre
tio
n
Time (minutes)
1st Phase 2nd Phase
i.v. Glucose
Diabetes
Normal glucose tolerance
-5-10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 10095
Insu
lin
Sec
reti
on
Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
DeFronzo RA, et al. Metabolism. 1989;38:387-395.
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Ba
sal
HG
P(m
g/k
g•
min
)
FPG (mg/dL)
2.0
2.5
3.0
3.5
4.0
100 200 300
r = 0.85P<0.001
Control
T2DMB
asal
HG
P(m
g/k
g •
min
)
FPG (mg/dL)
2.0
2.5
3.0
3.5
4.0
100 200 300
r=0.85P<0.001
Control
T2DM
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
T2DM
To
tal B
od
y G
luco
se U
pta
ke (
mg
/kg
•min
)
CON
0
7
6
5
4
3
2
1
0
P<0.01
P<0.05
12
Leg
Glu
co
se U
ptak
e(m
g/kg
leg w
t per m
in)
Time (minutes)
180140
100
60
40
8
4
0
T2DM
To
tal
Bo
dy
Glu
cose
Up
take
(m
g/k
g •
min
)
CON0
7
6
5
4
3
2
1
0
P<0.01
12
Leg
Glu
cose U
ptake
(mg
/kg leg
wt p
er min
)
Time (minutes)1801401006040
8
4
0
The Disharmonious QuartetThe Disharmonious Quartet
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptake
↑ FFA↑ FFAIncreasedIncreasedLipolysisLipolysis
FFA=free fatty acids.FFA=free fatty acids.
FACoA FACoA
Gluconeogenesis Glucose Utilization
Lipolysis
Plasma FFA
HGP
Role of Free Fatty Acids Role of Free Fatty Acids HyperglycemiaHyperglycemia
HGP
MuscleMuscle LiverLiver
FACoA=FFA-derived long-chain acyl-CoA esters. Boden G. Proc Assoc Am Physicians. 1999;111:241-248.
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Free Fatty Acids Impair Free Fatty Acids Impair -Cell Function-Cell Function
*Percent difference between lipid infusion and saline infusionin subjects with family history of T2DM.
Kashyap S, et al. Diabetes. 2003;52:2461-2474.
75
25
-60
-35
-80
-60
-40
-20
0
20
40
60
80
100
Δ C-peptide Concentration
(%)*
Δ C-peptide Concentration
(%)*
First PhaseFirst Phase Second PhaseSecond Phase
Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM
Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM
P<0.001 P<0.04P<0.04
The Quintessential QuintetThe Quintessential Quintet
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
DecreasedDecreasedIncretin EffectIncretin EffectDecreasedDecreasedIncretin EffectIncretin Effect
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
*P<0.05.GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Jones IR, et al. Diabetologia. 1989;32:668-677; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.
20
15
10
5
00 60 120 180 240
Time (min)
GL
P-1
(p
mo
l/L
) * * * * ** *
*
Meal P<0.01
GIP Levels AreIncreased in T2DM
GIP
(p
mo
l/L
)
Time (min)
Postprandial GLP-1 Levels Are Decreased in Patients with
IGT and T2DM
GLP-1 and GIP Responses in GLP-1 and GIP Responses in Type 2 DiabetesType 2 Diabetes
NGT IGT T2DMNGT IGT T2DM
2100 60
***
40
0
80
-30 120 180
20
60
100
GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance
Vaag AA, et al. Eur J Endocrinol. 1996;135:425-432.
AU
C1 In
su
lin
(m
U/m
L ·
min
) 12
10
8
6
4
2
0
-2
P<0.00005
P<0.005
AU
C1 G
LP
-1 (
nm
ol/
L ·
min
)
0
1
2
3
4 P<0.05
AU
C1 G
IP (
nm
ol/
L ·
min
)
0
2
4
6
8
10
12
14
16
Controls NGT IGT T2DM
-1
Controls NGT IGT T2DMControls NGT IGT T2DM
The Setaceous SextetThe Setaceous Sextet
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
Pancreatic Pancreatic -Cells and -Cells and -Cells in-Cells inNormal IndividualsNormal Individuals
Cabrera O, et al. PNAS. 2006;103:2334-2339; Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.
-Cells-Cells -Cells-Cells
Endocrine massEndocrine mass ~50% ~35%
RoleRole Produce insulin and amylin Produce glucagon
Mechanism of Mechanism of actionaction
Secrete insulin in response to blood glucose elevations
Secrete glucagon in response to blood glucose decreases
Metabolic effectMetabolic effect
Permit glucose uptake by peripheral tissues
Suppress glucagon and HGP
Stimulate HGP to meet energy needs between
meals
10
15.8
0
2
4
6
8
10
12
14
16
18
Control Type 2 Diabetes
P<0.05
Clark A, et al. Diabetes Res. 1988;9:151-159.
Area of Area of -Cells Is Increased in-Cells Is Increased inType 2 DiabetesType 2 Diabetes
-CellIslet Area
(%)
-CellIslet Area
(%)
(n=10)(n=10) (n=15)(n=15)
SRIF=somatostatin infusion.
Baron A, et al. Diabetes. 1987;36:274-283.
0
50
100
150
200
250
Plasm
a Glu
cago
n (p
g/m
L)B
asal
HG
P (
mg
/m2 •
min
)
0
40
80
120
160
P<0.001 P<0.001
T2DM+ SRIF
T2DM+ SRIF
44% 58%
NGT T2DM NGT T2DM
Basal Glucagon Levels and Basal HepaticBasal Glucagon Levels and Basal HepaticGlucose Production in Type 2 DiabetesGlucose Production in Type 2 Diabetes
0
20
40
60
80
100
120
Pla
sma
Glu
cose
(m
mol
/L)
0
2
4
6
8
10
12
14
16
Pla
sma
Insu
lin (
mU
/L)
0
100
200
300
400
500
600
Pla
sma
Glu
cago
n (m
U/L
)
0 24 48 hr
Pla
sma
FF
A (m
ol/l)
0
100
200
300
400
500
600
700
0 24 48 hr
Del Prato S, et al. J Clin Invest. 1987;79:547-556.
Hyperglucagonemia and Insulin-Hyperglucagonemia and Insulin-Mediated Glucose MetabolismMediated Glucose Metabolism
Inverse Relationship Between Insulin:Glucagon Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGTRatio and Plasma Glucose in IGT
Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese.
Mitrakou A, et al. N Engl J Med. 1992;326:22-29.
40
1286
50
60
70
80
90
100
Glu
cose
Ap
pea
ran
ce (
mm
ol/5
hr)
Peak Postprandial PlasmaGlucose Level (mmol/L)
Plasma Insulin:Glucagon Ratio
r=0.72P<0.0001
10 14 1550 10 20
r=-0.62P<0.001
Abnormal Meal-Related Insulin and Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 DiabetesGlucagon Dynamics in Type 2 Diabetes
Glucose (mg %)
Insulin (µU/mL)
Glucagon (pg/mL)
Time (min)
Type 2 diabetes (n=12)
Normal subjects (n-=11)
-60 0 60 120 180 240
360
33030027024011080
140130120110100
90
1209060300
Meal
Delayed/depressedinsulin response
Nonsuppressed glucagon
Müller WA, et al. N Engl J Med. 1970;283:109-115.
The Septicidal SeptetThe Septicidal Septet
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
Renal Glucose Reabsorption Renal Glucose Reabsorption in Type 2 Diabetesin Type 2 Diabetes
• Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule
• Renal glucose reabsorption is increased in type 2 diabetes
• Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose
Wright EM, et al. J Intern Med. 2007;261:32-43.
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%
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
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
Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition
Familial Renal GlucosuriaFamilial Renal Glucosuria
PresentationPresentation• Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day
• AsymptomaticAsymptomatic
BloodBlood• Normal glucose concentration
• No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia
Kidney / bladderKidney / bladder• No tubular dysfunction
• Normal histology and function
ComplicationsComplications
• No increased incidence of
– Chronic kidney disease
– Diabetes
– Urinary tract infection
Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;Wright EM, et al. J Intern Med. 2007;261:32-43.
Familial Renal GlucosuriaFamilial Renal Glucosuria
Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.
Plasma Glucose Concentration (mmol/L)
155
Glucose Reabsorption
10
Type A
Type B
NormalTheoretical
Observed
Analysis of SGLT2 Gene in Patients Analysis of SGLT2 Gene in Patients With Renal GlucosuriaWith Renal Glucosuria
Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.
• 23 families analyzed for mutations• In 23 families, 21 different mutations were detected
in SGLT2• Cause of glucosuria in other 2 families remains
unknown
GLUT2GLUT2 AMG UptakeAMG Uptake
NGT T2DM NGT T2DM
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
• An adaptive response to conserve glucose (ie, for energy needs) becomes maladaptive in diabetes
• Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal reabsorption of glucose
ImplicationsImplications
SGLT2 Inhibitors for the Treatment SGLT2 Inhibitors for the Treatment of Type 2 Diabetesof Type 2 Diabetes
Effect of SGLT2 Inhibition on Effect of SGLT2 Inhibition on Renal Glucose HandlingRenal Glucose Handling
Plasma Glucose Concentration (mmol/L)
155
Glucose Reabsorptionand Excretion
Splay
Excre
tion
TmG
10
Actual Threshold
Reabso
rptio
n
Theoretical threshold
FPG (mg/dL)
Baseline Day 8 Day 15
Vehicle (n=6)0.01 mg/kg (n=6)0.1 mg/kg (n=6)1 mg/kg (n=6)10 mg/kg (n=6)
0
100
200
300
400
*P<0.05; †P<0.0001 vs vehicle. ZDF=Zucker diabetic fatty.
Han S, et al. Diabetes. 2008;57:1723-1729; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P.
Effects of Dapagliflozin on Fasting Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF RatsPlasma Glucose in ZDF Rats
*
*
*
†
†* †
Hep
atic Glu
cose P
rod
uctio
n(m
g/kg
• min
)G
luco
se I
nfu
sio
n R
ate
(mg
/kg
• m
in)
0
1.0
2.0
3.0
4.0
0
2.0
4.0
6.0
8.0
CON DAPA CON DAPA
P<0.01
P<0.01
CON=controls; DAPA=dapagliflozin.
Han S, et al. Diabetes. 2008;57:1723-1729.
Effect of Dapagliflozin on Insulin-Stimulated Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Glucose Disposal and Hepatic Glucose Production in ZDF RatsProduction in ZDF Rats
Dapagliflozin-Induced GlucosuriaDapagliflozin-Induced GlucosuriaReduces HbAReduces HbA1c1c: A Dose-Ranging Trial: A Dose-Ranging Trial
Study designStudy design
• 12 week, double-blind, placebo-controlled12 week, double-blind, placebo-controlled
– Dapagliflozin: 2.5, 5, 10, 50 mg/dayDapagliflozin: 2.5, 5, 10, 50 mg/day
– Metformin XR: 1500 mg/dayMetformin XR: 1500 mg/day
– PlaceboPlacebo
PatientsPatients• 389 drug-naive T2DM patients
• HbA1c >7.0%
MeasurementsMeasurements • FPG, PPG, HbA1c
List JF, et al. Diabetes Care. 2009;32:650-657.
Baseline HbA1c (%) 7.7 8.0 8.0 7.8 7.9 7.7
All comparisons vs placebo; no statistical comparisons with metformin were made.
List JF, et al. Diabetes Care. 2008;2009;32:650-657.
P<0.01 P<0.01
P<0.01
Effect of Dapagliflozin on HbAEffect of Dapagliflozin on HbA1c1c
Δ HbA1c (%)
P<0.01 -1
-0.8
-0.6
-0.4
-0.2
0DAPA
2.5DAPA
5DAPA
10DAPA
50PBO MET MET
XRXR15001500
Dapagliflozin: Glucosuric and Dapagliflozin: Glucosuric and Metabolic EffectsMetabolic Effects
GlucosuriaGlucosuria ↑ 52-85 g/day52-85 g/day
FPGFPG ↓ 16-30 mg/dL
PPGPPG ↓ 23-29 mg/dL
Body weightBody weight ↓ 2.2-3.2 kg (↓ 2.5%-3.4%)
Urine volumeUrine volume ↑ 107-470 mL/day
List JF, et al. Diabetes Care. 2009;32:650-657.
Adverse Events With DapagliflozinAdverse Events With Dapagliflozin
PBO(n=54)
Met 1500 mg QD(n=56)
Dapa 2.5 mg QD(n=59)
Dapa 5 mg QD(n=58)
Dapa 10 mg QD(n=47)
Dapa 20 mg QD(n=59)
Dapa 50 mg QD(n=56)
Hypoglycemia, n (%)
2 (4) 5 (9) 4 (7) 6 (10) 3 (6) 4 (7) 4 (7)
UTIs, n (%) 3 (6) 5 (9) 3 (5) 5 (9) 5 (11) 7 (12) 5 (9)
Genital infection, n (%)
0 (0) 1 (2) 2 (3) 1 (2) 1 (2) 4 (7) 4 (7)
Hypotensive event, n (%)
1 (2) 2 (4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)
UTI=urinary tract infection.
List JF, et al. Diabetes Care. 2009;32:650-657.
Investigational SGLT2 InhibitorsInvestigational SGLT2 Inhibitors
AgentAgent ManufacturerManufacturer
Phase IIIPhase III DapagliflozinDapagliflozin AstraZeneca/Bristol-Myers Squibb
Phase IIPhase II AVE-2268 sanofi-aventis
BI 10773 Boehringer Ingelheim
JNJ-28431754 Johnson & Johnson
Remogliflozin
Sergliflozin
GSK/Kissei
TS-033 Taisho
YM-543 Astellas/Kotobuki Pharmaceuticals
Phase IPhase I CSG-452A Chugai/Roche
SAR-7226 sanofi-aventis
TA-7284 Mitsubishi Tanabe/Johnson & Johnson
• Highly specific for the kidney and SGLT2 transporter
• ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1
• Marked reduction in FPG, PPG, and HbA1c in all three species
• No changes in plasma or urine electrolytes
Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR.
ISIS 388626 – A Specific SGLT2ISIS 388626 – A Specific SGLT2Antisense OligonucleotideAntisense Oligonucleotide
Unanswered Questions About Unanswered Questions About SGLT2 InhibitionSGLT2 Inhibition
DurabilityDurabilityThe efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range
Safety and Safety and tolerabilitytolerability
The long-term safety of this class remains to be proven
Risk of nocturia and genitourinary infections may limit use in some patients
Renal Renal impairmentimpairment
SGLT2 inhibition may not be effective in patients with renal impairment
SGLT2 Inhibition: Meeting UnmetSGLT2 Inhibition: Meeting UnmetNeeds in Diabetes CareNeeds in Diabetes Care
WeightManagement
Type 2Diabetes
Multiple Defects in Type 2
Diabetes
Adverse Effectsof Therapy
Hyperglycemia
CVD Risk(Lipid and
HypertensionControl)
Improvements inImprovements inGlucose and WeightGlucose and Weight
Support OtherSupport OtherCVD InterventionsCVD Interventions
ComplementsAction of Other
AntidiabeticAgents
PromotesPromotesWeight LossWeight Loss
Corrects a NovelCorrects a NovelPathophysiologicPathophysiologic
DefectDefectNo HypoglycemiaNo Hypoglycemia
ImprovesImprovesGlycemicGlycemicControlControl
ConclusionsConclusions
• SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes
• Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity
– Restores normoglycemia– Improves -cell function and insulin sensitivity
ConclusionsConclusions
• Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans
• Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes
Overall ConclusionsOverall Conclusions
• Understanding of the pathophysiology of type 2 diabetes is an evolving process
• As new concepts emerge, there is potential for new treatment modalities
• Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis