Insulin resistance and Beta cell failure:

Relevance for diabetes development, prognosis and treatment decisions

Guntram Schernthaner

Medical University of Vienna, Austria

guntram.schernthaner@meduniwien.ac.at

The “classic” concept:Development of T2DM depends on interplay between insulin resistance and beta-cell dysfunction

Gerich JE. Mayo Clin Proc. 2003;78:447-56.

Insulin resistance

Insulin resistance

Abnormalbeta-cell function

Relative insulin

deficiencyT2DM

Compensatory hyperinsulinaemia

No diabetes

Genes and environment

Normalbeta-cell function

Genes and environment

Beta cell dysfunction is a critical determinant for type 2 diabetes

Kasuga et al. Clin Invest. 2006;116 :1756-1760.

Adipokines InflammationFFAs

Insulin

resistance

Obesity

Adipocytes

Vasculature

Pancreatic islets beta cell compensation beta cell failure

Insulin secretion

by beta cells

Normal Increased Decreased

Blood glucose Normal Normal or impaired

glucose tolerance

Diabetes mellitus

Causes of beta-cell dysfunction in T2DM

DeFronzo RA. Diabetes. 2009;58:773-95.

Beta-celldysfunction

Amyloid(islet amyloidpolypeptide)deposition

Insulinresistance

Genetics(e.g. TCF 7L2)

Age

↓ Incretin effect

Glucose toxicityLipotoxicity

↑ Free fatty acids

ß-cell Volume Is Reduced by 40% in Patients with IFG and Up to 60% with Type 2 Diabetes Mellitus (DM)

Data derived from Butler AE et al. Diabetes 2003;52(1):102-110.

0

0.5

1

1.5

2

2.5

3ß

-cell v

olu

me (

%)

Lean

40% reduction

p<0.05

63% reduction

p<0.001

Nondiabetic

IFG

Type 2 DM

42% reduction

p<0.05

Obese

N=124 autopsies

IFG: Impaired Fasting Glucose

-cell function decline in DM2 regardless of intervention:

the need of early intervention

UKPDS Group. Diabetes 1995;44:1249-58

0

20

40

60

80

100

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Years Since Diagnosis

Sulfonylurea

Diet

Metformin

β-C

ell F

un

cti

on

(%

)*

Progressive loss of beta-cell function

occurs prior to diagnosis

*beta-cell function measured by HOMA

Which treatment options do we have to stop

or even reverse the progression of ß-cell

dysfunction in patients with type 2 diabetes?

QUARTET: Mean changes of FPG over two years from baseline

after addition of Pioglitazone or Gliclazide to Metformin

Weeks

-3

-2,5

-2

-1,5

-1

-0,5

0

10 20 30 40 50 60 70 80 90 100 110

Changes

from

baselin

ein

fasting

pla

sm

aglu

cose

(mm

ol/l) *

Pioglitazone

Gliclazide

* p<0.003a

*

a in patients treated for a minimum of 18 months

Charbonnel B, Schernthaner G et al: Diabetologia 2005;48:1093-1104

Fasting Plasma Glucose over Time in ADOPT Study

Rosiglitazone vs. Metformin: 9,8 (P<0,001)

Rosiglitazone vs. Glyburide: 17,4 mg/dl (P<0,001)m

g/d

l

0

120

160

140

130

150

0 1 2 3 4 5

Time (years)

Glyburide

Rosiglitazone

Metformin

Kahn SE et al. N Engl J Med 2006; 355:2427–2443

RCT of 4.360 newly diagnosed patients with type 2 diabetes followed up for a median of 4.0 years

Functional defect: Deterioration of β-cell function over time

Kahn SE, et al. N Engl J Med. 2006;355:2427-43.

−6.1% per year

−2.0% per year

−3.1% per year

0

60

70

80

90

100

0 1 2 3 4 5

Rosiglitazone vs metformin; 5.8%, p = 0.003Rosiglitazone vs glyburide; −0.8%, p = 0.67

Glyburide

Rosiglitazone

Metformin

Time (years)

HO

MA

%B

Durability of Glycemic Control with Glitazones

-2

-1

0

1

50 1 2 3 4 6

Ch

an

ge

in

Hb

A1

c (

%)

TIME (years)

ROSI...Rosiglitazone

PIO......Pioglitazone

Periscope (n=178)

RECORD (n=301) Tan (n=249)

PIO

Chicago (n=232)

PIO

Hanefeld (n=250)

PIO

Rosestock (n=115)

ROSI

Charbonnel (n=317)

PIO

ADOPT (n=1,456)

Rosiglitazone

DeFronzo (Diabetes 2009; 58:773-795)

No Durability of Glycemic Control with Sulfonylureas

Ch

an

ge

in

Hb

A1

c (

%)

DeFronzo (Diabetes 2009; 58:773-795)

TIME (years)

50 1 2 3 4 106

-2

-1

0

1

Periscope (n=178)

Glyburide

Tan (n=249)

Gliclazide

Alvarsson (n=39)GLYAlvarsson (n=48)x

Charbonnel (n=317)

x

x

x

xx

Gliclazide

SU

RECORD (n=301)

SU

Chicago (n=232)

Glimpepiride

Hanefeld (n=250)Glyburide

ADOPT (n=1,456)

Glyburide

UKPDS (n=1,573)

Glyburide

EUREXA: Exenatide BID was associated with Lower

A1C Levels Over Time Compared to Glimepiride

Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański j, Sapin H, Trautmann M, Schernthaner G. Lancet 2012; 379:2270-8

ITT Efficacy Population Time on Randomized Treatment (months)

A1C

(%

)

3 18 30 42

Exenatide BID Glimepiride

0

486

480

6

440

471

12

331

371

24

230

264

36

182

197

Patient number:

Exenatide BID

Glimepiride

EXE 6.85

GLIM 6.94

P = 0.141

EXE 6.95

GLIM 7.13

P = 0.008

EXE 7.10

GLIM 7.26

P = 0.035

6.6

6.7

6.8

6.9

7.0

7.1

7.2

7.3

7.4

7.5

7.6

EUREXA: Treatment Failure (HbA1c >7.0%) in Patients

dependent from by Baseline A1C and Study Drug

Pro

po

rtio

n o

f P

ati

en

ts N

ot

Meeti

ng

Tre

atm

en

t F

ailu

re C

rite

ria

Exenatide BID (n = 235)

Exenatide BID (n = 189)

Exenatide BID (n = 66)

Glimepiride (n = 257)

Glimepiride (n = 166)

Glimepiride (n = 64)

A1C ≤7.3%

A1C >7.3-≤8.2%

A1C >8.2%

Baseline strata Randomized treatment

Time on Randomized Treatment (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48

Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański j, Sapin H, Trautmann M, Schernthaner G. Lancet 2012; 379:2270-8

After 4 years about 35% of patients

in both groups showed similar

treatment failure even when

started from low HbA1c levels

(<7.3%)

(A) fasting plasma glucose level

(B) basal hepatic glucose production (HGP)

(C) hepatic triacylglycerol content

For comparison, data for a matched

nondiabetic control group are shown as o

• Eleven people with type 2 diabetes (49.5 years, BMI

33.6±1.2 kg/m2, were studied before and after 1, 4 and 8

weeks of a (600 kcal)/day diet.

• Normalisation of both beta cell function and hepatic

insulin sensitivity in type 2 diabetes was achieved by

dietary energy restriction alone.

• This was associated with decreased pancreatic and

liver triacylglycerol stores.

• The abnormalities underlying type 2 diabetes are

reversible by reducing dietary energy intake.

Effect of an 8-week very-low-calorie diet in type 2 diabetes on

Lim et al. Diabetologia 2011;54:2506

Restoring normoglycaemia by use of a very low calorie

diet in short- and long-duration Type 2 diabetes

Short duration

Long duration

• 87% of the short-duration group and 50% of the

long-duration group achieved nondiabetic fasting

plasma glucose levels at week 8

• In people with Type 2 diabetes of > 8 years’ duration,

a therapeutic trial of a very-low-calorie diet may be

undertaken with a 50% chance of achieving non-diabetic

fasting glucose levels off all antidiabetic therapies.

Steven S & Taylor R. Diabet. Med. 2015; 32, 1149–1155

The progression of ß-cell dysfunction in

Type 2 Diabetes has many negative conseqences

• Significant increase of HbA1c due to deterioration of

fasting and postprandial glucose control

• More complex glucose lowering strategies are needed

(second line, thirdline, combination of 4 and more),

whereby evidence for the best combination is missing

• All vascular complications start to develop with

deterioration of glycemic control

Death from Cardiovascular Causes among Patients with Type 2 Diabetes

versus Controls is related to Mean Glycated Hemoglobin Level*

Tancredi M et al. N Engl J Med 2015; 373:1720-1732

* P values for the interaction term between time-updated mean glycated hemoglobin or renal disease status and time-updated age categories were less than 0.001 in all models.

In the Swedish National Diabetes Register

435,369 patients with type 2 diabetes were

followed up for 4.6 years (mean age 65.8 yrs.)

Mean HbA1c was 7.1% and the mean duration

of diabetes was 5.7 years at baseline.

2,117,483 controls had the same follow up

Historical Assessment of Insulin Resistance

Plasma Glucose

0 1 2 3

Time in hours

0

50

100

150

200

250

300

350

400

450

Pla

sm

a g

lucose in m

g/d

L

FPG>150

FPG: 110-150

Chemical DM

Normal

Plasma Insulin

0 1 2 3

Time in hours

0

20

40

60

80

100

120

140

160

Pla

sm

a insulin

in

mU

/mL

OGTT in 95 Subjects

Reaven GM, et al. Am J Med 1976;60:80

Aetiology of Insulin Resistance

Henry RR. Ann Int Med 1996;124:97-103.

Olefsky JM. In: Ellenberg and Rifkin’s Diabetes Mellitus. 5th Ed. 1997:513-552.

Olefsky JM. In: Endocrinology. 2nd Ed. 1989;1:1369-1388.

An interplay between genetics and environment

Genetics (Inherited)

Abnormal Insulin Receptor

Abnormal Insulin

Abnormal Signaling Proteins

Type 2 Diabetes:

Hyperglycaemia

Adipocytokines

Free Fatty Acids

Environment (Acquired)

Obesity

Aging

Medications

Glucose (G)

Defective insulin secretion

Carbohydrate

Resistance to the action of insulin

Insulin (I)

G

G

G G

G

G

G

G

I

I

I

I

I

I

I

Excessive fatty acid release

Reduced glucoseuptake

Excessive glucoseproduction

What is Insulin resistance? A reduced response to circulating insulin in target tissues

DeFronzo RA. Diabetes 2009; 58:773-95

Defective insulinsecretion

Defective insulin action in T2DM

DeFronzo RA, et al. J Clin Invest. 1979;63:939-46. DeFronzo RA, et al. J Clin Invest. 1985;76:149-55.

Leg

glu

co

se u

pta

ke

(m

g/

kg

leg

weig

ht/

min

)

Time (minutes)

0

p < 0.01

12

1801401006020

8

4

0

To

tal

bo

dy g

luco

se u

pta

ke

(m

g/

kg

/m

in)

T2DMNormal0

7

6

5

4

3

2

1

Normal

T2DM-30%

-45%

Conditions associated with insulin resistance

Centralobesity

Physicalactivity

Insulin

resistanceHyperinsulinemia

HDL

Platelet

hyperactivation

Blood pressure

Microalbuminuria

PPG

Impaired glucose tolerance

Diabetes mellitus

Small dense

LDL Fibrinogen

PAI-1 Triglycerides

Chronic inflammation Proinsulin

Thrombus

Inflammatory atherosclerotic process

Small dense LDL

ox-LDL

Monocyte

chemotaxis

mf

O2

Foam cell

differentiation

fatty streakComplex

(vulnerable)

plaque

Lumen of

blood vessel

Artery wall

Endothelium

ROS

Vascular smooth

muscle cells

PLAQUE

RUPTURE

CRP: C-reactive protein

MCP-1: monocyte chemoattractant protein-1

IL-6: interleukin-6

TNFα: tumour necrosis factor alpha

MMP-9: matrix metalloproteinase-9

PAI-1: plasminogen activator inhibitor-1

Inflammatory

cytokines

IL-6, TNF

Inflammatory

markers

CRP

MMP-9

MCP-1

PAI-1

0.75

0.8

0.85

0.9

0.95

1

0 5 10 15 20 25

Years

Pro

port

ion w

ithout

Majo

r C

HD

Event

Pyörälä M et al. Circulation 1998;98:398-404

P=0.001

Q1

Q2

Q3

Q4

Q5

Kaplan-Meier survival curves for remaining free of major CHD

events during 22-year follow-up by quintiles of AUC insulin

0.75

0.8

0.85

0.9

0.95

1

0 5 10 15 20 25

Years

Pro

port

ion w

ithout

CH

D E

vent

P<0.001

T1

T2

T3

Pyörälä M et al. Circulation 1998;98:398-404

0.75

0.8

0.85

0.9

0.95

1

0 5 10 15 20 25

Years

Pro

port

ion w

ithout

Str

oke

P<0.001

T1

T2

T3

Kaplan-Meier curves for remaining free of CHD and stroke during

22-year follow-up by tertiles of insulin resistance factor score

Coronary heart disease Stroke

The association between insulin resistance and risk for stroke has been examined in

4 case-control studies and 5 prospective observational cohort studies. Six of the 9

studies provide evidence that insulin resistance is associated with risk for strokeKernan & Inzucchi, Neurology 2002; 59:809-15

Insulin resistance is an independent predictor of CVD in type 2 diabetesThe Verona Diabetes Complications Study

Bonora E, et al. Diabetes Care 2002; 25:1135*P < 0.001; n = 627 Error bars = 95% CI

0.0

0.5

1.0

1.5

2.0

2.5

Insulinresistance(per unit)

Smoking (yes vs. no)

TC:HDL(per unit)

Age(per year)

Od

ds r

ati

o (

95%

) fo

r

incid

en

t C

VD

*

*

*

*

Can Insulin Resistance Be Treated?

• Weight Reductíon

• Physical Exercise

• Improved glucose control per se

• Specific glucose lowering drugs

• Bariatric Surgery

Franssila-Kallunki A, et al. Am J Clin Nutr 1992;55:356

50

40

30

20

10

Before weight loss

Glucose

disposal

(mmol/min•kg

of lean mass)

After weight

loss

0

*P<0.05

*

Weight Reduction Improves Insulin Sensitivity

Sato Y. Horm Met Res 1984;16:483

Physical Activity Reduces Insulin Resistance

Hyperinsulinaemic Euglycaemic Clamp

5

7

9

11

45%Glucose

Infusion

Rate

(mg/kg•min)

Controls Physical Training

p< 0.05

Garvey WT, et al. Diabetes 1985;34:222

Diabetes

good control

Diabetes

poor control

Normal

Glucose

disposal

(mg/min/m2)

400

300

200

100

0

Insulin Resistance may be improved with Treatment

Some forms of insulin resistance may be reversible

Insulin Sensitivity over 2 Years: Pioglitazone vs Gliclazide

0 8 16 24 32 42 52 65 78 91 104

Weeks

110

100

90

80

50

60

70

Insulin Sensitivity (HOMA-S%)

Tan MG et al: Diabetes Care 2005; 28:544-50

Gliclazide

* p < 0,001

Pioglitazone

* ** *

* ** * * * * *

β-Zell-Acivity over 2 Years: Pioglitazone vs Gliclazide

0 8 16 24 32 42 52 65 78 91 104

80

70

60

30

40

50

*

β-Cell-Activity (HOMA-B%)

Tan MG et al: Diabetes Care 2005; 28:544-50

* p < 0,001‡ p < 0,01† p < 0.05

Pioglitazone

* * * * * *

‡

‡

‡

* *

Gliclazide

Effect of PIO versus GLIC on CISI

Change from baseline at 52 weeksChange from baseline at 52 weeks

0

0,5

1

1,5

-1

0

1

2

Effect of PIO versus MET on CISI

N=113, baseline CISI = 2,53GLIC

GLIC Gliclazide; MET Metformin; PIO Pioglitazone; SU Sulfonylurea

N=187, baseline CISI = 2,68MET

**

N=129, baseline CISI = 2,72

p<0.0001 between treatments

PIO

**

*p<0.05 between treatments

N=194, baseline CISI = 2,76PIO

*

Composite Insulin Sensitivity Index (CISI) for 3 different Monotherapies

Effect of PIO+SU vs MET+SU on CISI Effect of PIO+MET vs GLIC+MET on CISI

-0,5

0

0,5

1

1,5

Change from baseline at 52 weeks

0

0,5

1

1,5

Change from baseline at 52 weeks

GLIC Gliclazide; MET Metformin; PIO Pioglitazone; SU Sulfonylurea

N=62, baseline CISI = 2,73GLIC + METN=95, baseline CISI = 2,49MET + SU

**

N=54, baseline CISI = 2,61

p<0.0001 between treatments

PIO + MET

**

* p<0.05 between treatments

N=105, baseline CISI = 2,51PIO + SU

*

Composite Insulin Sensitivity Index for 2 different Combination Therapies

Ceriello et al (Diabetes Care 2005; 28:266)

Treatment-induced changes in Insulin-mediated Glucose Uptake (M value) with Metformin and Thiazolidinediones

Metformin Thiazolidinediones

50

40

30

20

10

0

-10

-20Open Double-blind/

placebo-controlled

Open

Insu

lin

-med

iate

d g

luc

ose u

pta

ke

(% c

han

ge

)

Double-blind/placebo-controlled

+ 34 %

+ 36 %

+ 11 %

+ 18 %

Effect of Weight Loss induced by Gastroplastic Surgery

on Diabetes and Glucose Intolerance

0

10

20

30

40

50

60

70

Diabetes (DM) Impaired GT Normal GT

37 % 40 %

Preoperative BMI (49±7 kg/m2)

Weight 136±23 kg

23 %

Prevalence

of DM, IGT,

NGT (%)

33 %

64 %

3 %

Postoperative BMI (33±6 kg/m2) Weight 92±17 kg

Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G

Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Arterioscler Thromb Vasc Biol. 2003;23:1042-1047

Postoperative

33± 6

Preoperative

BMI:49±7Glu

co

se,

mg

/dL

Insu

lin

, m

U/m

L

HOMA-insulin resistance

Glucose and insulin levels and HOMA-insulin resistance in morbidly obese patients before and after bariatric surgery

0

1

2

3

4

5

6

7

Preoperative Postoperative

8

9

10

0

50

100

150

200

Fasting 1-Hour 2-Hour

*

**

*p=0.0001

Fasting 1-Hour 2-Hour0

30

60

90

120

150

*

*p=0.0001

*

*

p=0.0001

Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Arterioscler Thromb Vasc Biol. 2003;23:1042-1047

Adipose tissue: A major secretory organ

Triglycerides

Free fatty Acids

Lipoprotein lipase

Vascular endothelial growth factor

MCP 1

Resistin

Adiponectin

Adipsin (Complement D)

Leptin

Visfatin RBP4

IGF-1

TNF-

Angiotensinogen

PAI-1 IL-6 IL-18

Adipose tissue, adipokines and atherogenesisTNF, IL6, PAI-1, angiotensinogen, CRP, adiponectin, leptin, resistin

MMP activity

EC and SMC apoptosis

Platelet adhesion

Thrombosis

Plaque progression:

Plaque destabilisation:

Endothelial dysfunction:

Plaque initiation:

Foam cell formation

SMC proliferation and migration

ICAM-1 and VCAM-1

MCP-1

CD40/CD40L

Leukocyte adhesion and transmigration

NO

ET-1

ATII

oxLDL

ADMA

Effects of weight reduction induced by bariatric surgery

Before weight loss After weight loss1. Kopp CW, Obesity Research 2003;11:950; 2. Kopp HP, Internat J Obes 005:766;

3. Schernthaner GH, IDF 2006; 4. Krzyzanowska K, Obesity 2006;14:1886;

5. Kopp HP, Obes Surg 2006;16;1214; 6. Kopp HP, ATVB 2003;23:1042; 7.

Schernthaner GH, Obes Surg 2006;16:709; 8. Krzyzanowska K, JCEM

2004;89:6277; 9. Schernthaner GH, EJCI 2006; 36:333

Visfatin 4Leptin 1 Adiponectin 2 Resistin 3 RBP-4 3

0

5

10

15

20

25

0

5

10

15

20

25

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

µg/mlng/ml µg/ml ng/mlµg/ml

16

12

87

7771

p=0.0005

61

p=0.001

24

p=0.0001

29

p=0.01

11

p=0.007

86

-62 %

+100 %-31 %

-30 %

+ 21 %

On adipokines On hemostasis

µMng/mlpg/l ng/ml

Free TFPI 1 Fibrinogen 1Total TFPI 1TF 1

ng/ml

F VIII 1

nMPTF 1.2 1

p=0.041 p=0.023 p=0.036p=0.039 p=0.019p=0.0370

50

100

150

200

250

300

350 314

235

-71 %

0

20

40

60

80

100

120

140 130

113

-13 %

0

0.5

1.0

1.5

2.0

2.5

3.0

2.4

1.1

-53 %

0

10

20

30

40

50

60

70

8069

64

-7 %

0

10

20

30

40

50

60

4844

-8 %

0

2

4

6

8

10

12 11.010.3

-6 %µM

On sexual hormones On vascular inflammation

µMng/ml nmol/l

Index Free Androgene 5

Cortisol 5Testosterone 5Androstendione 5

µg/ml

DHEA-S 5

nmol/lSHBG 1.2 5

p>0.001 p=0.01 p<0.001p<0.001 p=0.001p<0.001

µg/dl

0

0.5

1.0

1.5

2.0

2.5

2.05

1.40

-32 %

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.01.72

1.49

-13 %

0

10

20

30

40

50

60

70

80

17

70

+311 %

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0 1.88

1.16

-38 %

0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16 0.15

0.02

-87 %

0

5

10

15

20

25

20

15

-25 %3.7

0

1

2

3

4

ng/ml

1.06

0

0,2

0,4

0,6

0,8

1

mmol/l

0

1

2

3

4

5

6

7

8

9

mg/l

581

0

100

200

300

400

500

600

pg/ml

8.6

ADMA 8 sCD40L 9MCP-1 7CRP 6

5.1

1

2

3

4

5

pg/ml

IL-6 6

6

0

51,210 7001526

0

200

400

600

800

1000

1200

1400

pg/ml

IL-18 7

1600

p<0.006

2.5

-71 %

p<0.02

3.9

-24 %

p<0.001

309

-47 %

p<0.001

960

-37 %

2.2

p<0.001

-41 %

p<0.00001

0.81

-24 %

Complex Pathophysiology of Type 2 Diabetes:

Hyperglycaemia is the result of multiple organ dysfunction

High

blood

glucose

Pancreas

Insulin secretion

Glucagon secretion

Muscle

Glucose uptakev

Adipose tissue

FFA

Adiponectin

Inflammatory cytokines

Kidneys

Gluconeogenesis

Glucose reabsorption

Liver

Gluconeogenesis

Gut

GLP-1 secretion

Brain

Satiety

1. International Diabetes Federation Diabetes Atlas 2015. 2. Cornell Ther Clin Risk Manag 2015;11:621–32. 3. DeFronzo RA et al. Diabetes Care 2013;36:3169–76.

Summary and Conclusion

• ß-cell dysfunction and Insulin resistance are the key players in the

development and progression of type 2 diabetes

• Decline of ß-cell function increases the severity of diabetes with the need

of complex glucose lowering therapies

• The Insulin resistant state is a life long problem of type 2 diabetes, which

is associated with many abnormalities believed to be involved in the

development/and or progression of macrovascular disease

• Effective therapeutic strategies should focus to improve both ß-cell

dysfunction and insulin resistance