The pathophysiology of type 2 diabetes
Jean GIRARDInstitut Cochin
Paris
Genetic factors
Insulin-resistanceAcquired
factors
Hyperinsulinemia
ß-cell deficiency
CompensationNormal glucose tolerance
Gluco-lipotoxicity
Acquired factors
Type 2 diabetes
Insulin-resistanceGlucose production
Insulin secretion
Genetic factors
Causes of hyperglycemia in type 2 diabetes
MuscleGlucose
Liver
Pancreas
InsulinGlucagon
5
0
10
50
0
100
hours
0 1 2 3
90
80
70
60
100
The euglycemic clamp
Plasma glucose (md/dl)
Exogenous glucose (mg/min/kg)
Plasma insulin (mU/ml)
Insulin resistance in type 2 diabetes
Hepatic glucose production
Peripheral glucose utilisation
Plasma insulin (µU/ml)
T2D
T2DControl
Control
0 50 100 0 100 200
Glucose uptake(mg/min/kg)
Glycogen synthesisGlycolysis
Oxidation
3
2
0
1
Control Type 2 diabetes
Insulin-stimulated glucose uptake and glycogen synthesis are reduced in Type 2 diabetes
Non-oxidative glucose metabolisme in skeletal muscle
Glucose
Glucose
Glucose-6-P
GlycogenPyruvate
Glucose transport
Hexokinase II
Glycogen synthaseGlycolysis
Effect of insulin on glucose transport in skeletal muscleof type 2 diabetes
3-O-methylglucose transport(mmol/h/ml cell water)
2.5
2.0
1.5
1.0
0.5
0
Type 2 diabetes
Control
0 100 1000200 400
Insulin (U/ml)
Control
Type 2 diabetes
10
5
15
0
0 20 40 60 80 100 120 Minutes
Glycogen synthesis in skeletal muscles during a hyperglycemic hyperinsulinemic clamp
Glycogen concentrationin gastrocnemius (mmol/kg)
20
Skeletal muscles are responsible for the decreased whole body insulin-stimulated glucose uptake
Glucose transport is the rate-limiting step of insulin-stimulated glucose metabolism
in skeletal muscle
Insulin-stimulated skeletal muscle glycogen metabolism is reduced in type 2 diabetes
Conclusions
Insulin
Binding AutophosphorylationTyrosine kinase activity
Tyr Tyr
ATP
Tyr-P
IRS IRS-Tyr-P
Metabolic effects
Extracellular
Intracellular
Tyr-PP-TyrP-Tyr
Glucose transportGlycogen synthesis
Inhibition of glucose production
IRS-1P-Tyr
Tyr-P Tyr-P Tyr-P
Tyr-P
Insuline
Tyr-P
p85
PDK-1
p110
Protéine kinase CProtéine kinase B
PI 3 kinase
Metabolic effects
Tyr-P
IRS-1 tyrosine phosphorylation in human skeletal muscle
Control Type 2 diabetes
Clamp
Basal8
4
0
% of basal values
IRS-1 associated PI 3 kinase in human skeletal muscle
Control Type 2 diabetes
Clamp
Basal500
250
0
% of basal values
Defects in insulin-signaling pathways in Type 2 diabetes
The insulin receptor number is reduced by 20%, but this is compensated by hyperinsulinemia
The tyrosine phosphorylation of IRS-1 and the activation of PI 3 kinase are decreased in Type 2 diabetes
Increased activity of tyrosine phosphatases ?
Serine phosphorylation of IRSs ?
Factors responsible for the decrease in insulin signaling in Type 2 diabetes
Defect
Insulin receptor number
Tyrosine kinase activity
Glucose transport
Factors responsible
Increased plasma insulin
Serine Phosphorylation of IRS
Hyperglycemia, decreased Glut4 translocation
InsulinHyperglycemia
IRS-1Tyr-P
Tyr-P Tyr-PTyr-P
Ser-P
Tyr-P
Glucose transport
Protein Kinase C
Decreased association with PI 3 Kinase
The hexosamine pathway
Glycolysis
Glucose
Glucose-6-P
Fructose-6-P
Glutamine:fructose-6-Pamidotransferase
Glucosamine-6-P
Pyruvate
N-acetyl-glucosamine-6-P
UDP-N-acetyl-glucosamine
Glutamine Glutamate
Glucose
Pyruvate
N-acétyl-Glucosamine-6-P
UDP-N-Acétyl-glucosamine
G-6-P
Glycoprotéines
Glucosamine-6-PF-6-P
GFA
Glucose
GlycogèneG-1-P
Possible role of metabolites of the hexosamine pathwayin insulin resistance due to chronic hyperglycemia
GFA = Glutamine:fructose-6-P amidotransferase
10 100 1000
G-6-P (M)
100
50
0
Glycogen synthase activity% of total
Insulin
Insulin + glucosamine
The O-GlcNac glycosylation of glycogen synthase results in reduced activation in response to insulin
Insulin resistance in type 2 diabetes
Adipose tissue lipolysis
Plasma insulin (µU/ml)
T2D
Control
0 100
100
0
30
Type 2 diabetics have high plasma FFA all along the day
Plasma FFA(mol/l)
Type 2 diabetes
Control
Hours
8 10 12 14 16 18 20
800
0
200
400
600
Fatty acid-induced insulin resistance :Randle’s hypothesis 1963
FFA
Fatty acyl-CoA
Acetyl-CoANADH
Mitochondria
Citrate
Glucose
G-6-P
Pyruvate
Glucose
PFK
HK
PDH
Potential steps controlling muscle glucose metabolism in response to FFA
Glucose Glucose G-6-P Glycogen
Glucose transport Hexokinase Glycogen synthase
Metabolite levels during the clamp
Control ControlFFA FFA
Arbitraryunits
100
0
50
Control FFA
Fatty acid-induced insulin resistance : Shulman 1999
FFA
Fatty acyl-CoA
Protein kinase C
IRS-SerP
PI 3 Kinase
Glucose transport
Insulin
Adipose tissue of type 2 diabetics
Insulin resistance
RésistineTNF IL-6AdiponectineVisfatine
Insulin sensitivity
Insulin TNF
IRS-1Tyr-P
Tyr-P Tyr-P Tyr-P
Ser-P
Tyr-P
Biological effects
Sphingomyelinase
Ceramides
Protein Kinase CPTPase
Decreased association with PI 3 Kinase
TNF, IL-6
IRS-Ser P
PI 3 Kinase
Glucose transportMetabolic effects
Insulin
Cytokine-induced insulinoresistance
IKKß
JNK = Jun kinase
JNK
SOCS
IKKß = Inhibitor of kappa B kinase ß SOCS =Suppressor of cytokine signaling
IRS-Ser P
PI 3 Kinase
Effets métaboliquesde l’insuline
Insuline
L’insulinorésistance induite par les cytokines
IKKß
IKKß = Inhibitor of kappa B kinase ß
Salicilate TNF, IL-6
Postabsorptive glucose concentration is related to hepatic glucose production in type 2 diabetes
Hepatic glucose production(mg/min/h)
Postabsorptive glucose concentration (mg/min/h)
100 200 300 4000
4
3
2
1
0
Gluconeogenesis is responsible for increased hepatic Glucose production in type 2 diabetes
Hepatic glucose production(mg/min/kg)
4
3
2
1
0
ControlType 2 diabetes
Gluconeogenesis
Glycogenolysis
Factors responsible for increased hepatic glucose production in Type 2 diabetes
1- Liver insulin resistance
2- Increased plasma glucagon levels
3- Increased plasma FFA levels
Insulin resistance in type 2 diabetes
Hepatic glucose production(mg/min/kg)
Plasma insulin (µU/ml)
T2D
Control
0 100
4
0
50
2
Plasma glucagon(pg/ml) Type 2 diabetes
Control
200
0
50
100
150
Hours
8 10 12 14 16 18 20
Type 2 diabetics have high plasma glucagon despite hyperglycemia
•Increased mass of A cells
•Increased ratio A cells/B cells
•Hyperglucagonemia despite hyperglycemia
•Increased secretion in response to amino-acids
•Secretion of glucagon is less inhibited in response to glucose
•The impairement of glucagon secretion precedes the appearance of type 2 diabetes
Glucagon in type 2 diabetes
•Insulin resistance of A cells ?No: The impairement of A cells is not corrected by appropriate insulin-therapy
• Chronic hyperglycemia desensitizes A cell ?Possible : glucagon secretion is corrected by
normalization of glycemia in response to phlorizine
•Mechanisms responsible for glucose « blindness » of A cells ?
Factors responsible for hyperglucagonemia in Type 2 diabetes
Consequences of chronic hyperglucagonemia on hepatic glucose production in type 2 diabetes
Increased transcription of genes coding for gluconeogenic enzymes : for exemple PEPCK
Glucose production mainly due to gluconeogenesis
Gluconeogenesis is less sensitive than glycogenolysis to the inhibition by insulin : Insulin resistance
The absence of inhibition of glucagon secretion in the postprandial state induced glucose intolerance due to the non-suppression of hepatic glucose production
0 10 20 30 40 50
0
1
2
3
4
5
6
Glucogeogenesis
Glycogenolysis
Portal insulin (mU/ml)
GlycogenolysisGluconeogenesis
(mg/min/kg)
Basal
Glycogenolysis is very sensitive whereas gluconeogenesis is insensitive to an
increase in portal insulin
0
100
200
300
-60 0 60 120 180 240 360
Minutes
400
0
1
2
3
4
Exogenous glucose appearance(mg/min/kg)
Plasma glucose (mg/dl)
Type 2 diabetes
Type 2 diabetes
ControlControl
-60 0 60 120 180 240 360
Minutes
Glucose Glucose
Glucose intolerance after oral glucose administration In type 2 diabetes
Glucose utilization
(mg/min/kg)
0
2
4
6
-60 0 60 120 180 240 360
Control
Minutes
8
Type 2 diabetes
Hepatic glucose production
(µmol/min/kg)
0
1.0
2.0
3.0
4.0
-60 0 60 120 180 240 360
Minutes
Type 2 diabetes
Control
GlucoseGlucose
Glucose intolerance after oral glucose administration is due to non-suppression of hepatic glucose production
Plasma insulin (µU/ml)
0
25
50
75
100
-60 0 60 120 180 240 360
ControlType 2 diabetes
Minutes
Plasma glucagon (pg/ml)
0
50
100
150
200
-60 0 60 120 180 240 360
Minutes
Type 2 diabetes
Control
GlucoseGlucose
Glucose intolerance after oral glucose administration is due to non-suppression of plasma glucagon and to the
absence of early insulin secretion
0
100
200
300
-60 0 60 120 180 240 360
GLP-1
Type 2 diabetes
Plasma glucose
Minutes
400
(mg/dl)
Glucose
What could be expected from an inhibition of glucagon secretion in type 2 diabetes ?
0
1.0
2.0
3.0
4.0
-60 0 60 120 180 240 360
GLP-1
Hepatic glucose production
(µmol/min/Kg)
Minutes
GlucoseGLP-1 GLP-1
Type 2 diabetes
0
100
200
300
-60 0 60 120 180 240 360
Répaglinide
Type 2 diabetes
Plasma glucose
Minutes
400
(mg/dl)
Glucose
Répaglinide
What could be expected from restoring the first phase of insulin secretion, in type 2 diabetes ?
Hepatic glucose production(µmol/min/kg)
0
1.0
2.0
3.0
4.0
-60 0 60 120 180 240 360
Minutes
Type 2 diabetes
Répaglinide
Glucose
Répaglinide
Type 2 diabetics have high plasma FFA
Plasma FFA(mol/l)
Type 2 diabetes
Control
Hours
8 10 12 14 16 18 20
800
0
200
400
600
Visceral fat and insulin resistance
% visceral fat
InsulinSensitivitymmol/min/kg)
100
20
20 504030
Hepatic fatty acid oxidation provides co-factors
essential for gluconeogenesis
Fatty acid oxidation
Pyruvate OAA PEP 3-PGA 1,3-DPG GAP Glucose
ATPGTP NADHATP
ATP Acetyl-CoA ATP NADH
Role of Free Fatty Acids in Hyperglycemia
MuscleLiver
Adipose tissue
FFA
Hyperglycemia
Gluconeogenesis Glucose utilization
Glucose-induced insulin secretion is decreasedin chronically hyperglycemic Type 2 diabetic patients
Mean plasma insulin during the OGTT (U/ml)
80 100 120 140 160 180
Fasting plasma insulin (mU/ml)
100
80
60
40
20
0
Fasting plasma glucose levels (mg/dl)
Compensation of insulin-resistance by pancreatic ß-cells
Increased insulin secretion
Increased ß-cell mass
Replication of pre-existing ß-cells, neogenesis of ß-cells
Alteration of proliferation or survival of ß-cells
Functional defect– Pulsatility– First phase– Glucose-induced insulin secretion
Pancreatic ß cells from type 2 diabetic patients
Decrease in ß-cell mass– Genetic factors (HNF1, HNF4, Kir6.2, TCF7L2, Mitochondrial genes)
– Environmental factors (Gluco-lipotoxicity, physical inactivity)
Fatty acid metabolism in pancreatic ß-cells
Fatty acids
Acyl-CoA
Fatty acids
Acyl-CoA
Glucose
Normal ß-cell ß-cell from T2D
TGTG
MitochondriaMitochondria
Glucose
Cytotoxic effects of fatty acids in ß-cell from type 2 diabetic patients
Fatty acids
Acyl-CoA
TG TG
Apoptosis
Glucose
Normal ß-cell ß-cell from T2D
MitochondriaMitochondria
Fatty acids
Acyl-CoA
NO, Ceramides, ROS
Liver
Hyperglycemia
Pancreas
Adipose tissue
FFA
Muscle
Insulin Fatty acid oxidation
Gluconeogenesis
Fatty acid oxidation
Glucose uptake
Thiazolidinediones and Sulfonylurea prevent cytotoxic effects of fatty acids on pancreatic
ß-cells of type 2 diabetic patients
ß-cell from treated T2D
TG
Apoptosis
Glucose
ß-cell from T2D
Mitochondria
Fatty acids
Acyl-CoA
NO, Ceramides, ROS
TG
Apoptosis
Glucose
Mito
Fatty acids
Acyl-CoA
NO, Ceramides, ROS
SFU
TZD