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