the pathophysiology of type 2 diabetes jean girard institut cochin paris

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