Type 2 diabetesType 2 diabetesDerek LeRoith

Insulin Resistance: A Core Defect of The Metabolic Syndrome

InsulinResistance

Dyslipidemia Obesity

HypertensionDysfibrinolysis

Hyperglycemia

EndothelialDysfunction

MacrovascularDisease

GlucoseIntolerance

Adapted from McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718; Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.

Chris Rhodes Ph.D.PNRI, Seattle, WA.

0

10

20

Fas

tin

g G

luco

se (

mM

/L)

0

200

400

Fas

tin

g In

suli

n (

pm

ol/L

)

0

500

1000

Pla

sma

FF

A(

µm

ol/L

)

50

100

150

ß-C

ell M

ass

(%

ch

ange

)

0

2.5

5

Am

ylo

id D

ep

os

it (

% P

an

cre

ati

c A

rea

)

INCREASING AGE AND/0R DEGREE OF OBESITY(increasing peripheral insulin resistance)

Fasting Plasma Glucose

Fasting Serum Insulin

Circulating FFA

Pancreatic ß-Cell Mass

Islet Amyloid Deposit

Normal AdaptationGlucose

IntolerantType-2 Diabetes

The Pathogenesis of Obesity-linked Type-2 Diabetes[TIMM (2002) 8: 375-384]

Chris Rhodes Ph.D.PNRI, Seattle, WA.

Type-2 Diabetes - A Question of Balance

PERIPHERAL INSULIN

RESISTANCE

ß-CELL MASS

& FUNCTION

Non-Diabetic State

PERIPHERAL INSULIN

RESISTANCE

ß-CELL MASS

& FUNCTION

Diabetic State

Regulation of Islet -Cell Mass and Function

Mechanisms of cell failure in T2D Christopher J. Nolan

Mechanisms of cell compensation for insulin resistanceChristopher J. Nolan

Cell Compensation:

Christopher J. Nolan

1. Expansion of cell mass

2. Enhanced insulin biosynthesis

3. Increased responsiveness

of nutrient-secretion coupling

Christopher J. Nolan

Expansion of Cell Mass

Glucose FFA GLP-1

Enhanced Insulin Biosynthesis

Increased Responsiveness

Biphasic Insulin Secretion

Glucose Ins/IGF

Acetylcholine

Kristina M. Utzschneider

Christopher J. Nolan

Susceptible Cells

Genetic and acquired defects:Glucolipo-detoxificationMitochondrial functionAnaplerosis/cataplerosisAMPK/Mal-CoATG/FFA cyclingInsulin biosynthesisCoupling mechanismsExocytosisIntrauterine factors

I. E.T. van den Berg

Diacylglycerol Triglycerides Fatty AcidsAcylated Proteins

KATP-independentInsulin Secretion

carnitine palmitoyltransferase-1 (CPT 1)

AMPK/Malonyl-CoA Signaling Network

TG/FFA Cycling in Beta Cells

IntraUterine Growth Retardation (IUGR)

REBECCA A. SIMMONS

IUGR

Christopher J. Nolan

Cells dysfunctionIGT and early T2D

T2D: initiation rolesGluolipotoxicityLipotoxicityOxidative stress/ROSDysregulated TG/FFA cyclingAltered AMPK/Mal-CoA Cell exhaustionER stress

Lipotoxicity

Glucolipotoxicity in Beta CellsMarc Prentki

F.M. Ashcroft

Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose

metabolism and oxidative stress

Christopher J. Nolan

Cell failureOvert and late T2D

T2D: progression rolesGluolipotoxicityGlucotoxicityOxidative stress/ROSIslet inflammationProtein O-glycosylationAGEsDedifferentiationAmyloid depositionApoptosis

Michael Brownlee

Four Pathways of Hyperglycaemic Damage

Michael BrownleeAldose Reductase and The Polyol Pathway

Decreased levels of GSH Increased oxidative stress

Michael BrownleeProduction of Advanced Glycation End-

Product (AGE) Precursors

Michael Brownlee

Consequences of Hyperglycaemia-Induced Activation of Protein Kinase C (PKC)

Michael Brownlee

The Hexosamine Pathway