Type 2 diabetes Derek LeRoith. Insulin Resistance: A Core Defect of The Metabolic Syndrome Insulin...
-
Upload
edwin-felix-mcdowell -
Category
Documents
-
view
239 -
download
0
Transcript of Type 2 diabetes Derek LeRoith. Insulin Resistance: A Core Defect of The Metabolic Syndrome Insulin...
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
Cell Compensation:
Christopher J. Nolan
1. Expansion of cell mass
2. Enhanced insulin biosynthesis
3. Increased responsiveness
of nutrient-secretion coupling
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)
Christopher J. Nolan
Cells dysfunctionIGT and early T2D
T2D: initiation rolesGluolipotoxicityLipotoxicityOxidative stress/ROSDysregulated TG/FFA cyclingAltered AMPK/Mal-CoA Cell exhaustionER stress
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 BrownleeAldose Reductase and The Polyol Pathway
Decreased levels of GSH Increased oxidative stress