part 4. etiology of type 2 diabetes insulin resistance and -cell dysfunction
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Part 4
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 Acids↑ Free 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 A
UC
(pm
ol/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
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