What Causes Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes?

Charles A. Reasner, MD

Professor of Medicine

University of Texas Health Science Center

San Antonio, Texas

Type 2 Diabetes MellitusEvery 24 Hours

CDC. National Diabetes Fact Sheet, 2007. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf.

Why does this occur?

How do we prevent this morbidity and mortality?

New cases 4384

Amputations 195 >60% of nontraumatic amputations annually

Blindness 66 Number 1 cause

Kidney failure 128

Deaths 640 68% due to cardiovascular disease,2- to 4-fold higher than in adults without diabetes

Physiologic Defects Associated with Type 2 Diabetes Mellitus

Regulation of Normal Glucose Homeostasis

LiverMuscle

Adipose

tissue

Blood glucoseGlucose output

Glucose uptake

Glucagon(alpha cell)

Insulin(beta cell)

Pancreas

Fasting state Fed state

Porte D Jr, et al. Clin Invest Med. 1995;18:247-254. Kahn CR, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:145-168.

With permission from DeFronzo RA. Diabetes. 1988;37:667-687.

Insulin Resistance and Insulin Deficiency

OB-DIABLo INS

LEANNGT

OB-DIABHi INS

OB-IGT

OBNGT

Insulin-mediatedglucoseuptake

(mg/m2 • min)

300

250

200

150

100

Meanplasma insulinduring OGTT

(µU/mL)

Meanplasma glucose

during OGTT(mg/dL)

140

100

60

20400

300

200

100

Abbreviations: DIAB, diabetes; Hi INS, hyperinsulinemic; IGT, impaired glucose tolerance; Lo INS, hypoinsulinemic; NGT, normal glucose tolerance; OB, obese; OGTT, oral glucose tolerance test.

InsulinReceptor

Plasma Membrane

Insulin Signal Transduction System in Humans

Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.

p85Akt

PI-3-kinase

p110

IRS-1

IRS-1

GlucoseGLUT 4

Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide synthase; PI-3-kinase, phosphatidylinositol 3-kinase.

Beta Cell Dysfunction Ultimately, it is a defect in insulin secretion,

not insulin resistance, that causes hyperglycemia and progression of type 2 diabetes mellitus1

Initially, beta cells increase secretion of insulin to compensate for demands of insulin-resistant tissues2

– Functional and morphologic changes to beta cells allow them to keep pace1

– In some people, this compensation remains adequate lifelong

It is only when beta cell dysfunction develops that T2DM progresses11. Del Prato S, et al. Horm Metab Res. 2004;36:775-781. 2. Polonsky KS. Int J Obesity. 2000;24(suppl 2):S29-S31.

Current Theories on Development of Beta Cell Dysfunction

Chronic insulin overproduction may deplete the supply of releaseable insulin (beta cell exhaustion)1

Glucotoxicity: chronic hyperglycemia may be toxic to beta cells2

Lipotoxicity: chronic exposure to excess free fatty acids may be toxic to beta cells2

Glucotoxicity and lipotoxicity may activate apoptotic signaling pathways, leading to islet cell loss2

Amyloid deposits noted in islet cells of T2DM patients may be a contributing factor3

1. Rustenbeck I. Biochem Pharmacol. 2002;63:1921-1935. 2. Del Prato S, et al. Horm Metab Res. 2004;36:775-781. 3. Lorenzo A, et al. Nature. 1994;368:756-760.

Beta Cell Dysfunction Studies

1. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 2. Ferrannini E, et al. J Clin Endocrinol Metab. 2005;90:493-500. 3. Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435.

Number of Patients

Study NGT IGT T2DM

SAM1 138 49 201

Ferrannini et al2 61 22 105

VAGES3 117 93 0

TOTAL 316 164 306

Abbreviations: IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance tests; SAM, San Antonio Metabolism Study; T2DM, type 2 diabetes mellitus; VAGES, Veterans Administration Genetic Epidemiology Study.

All 3 studies used OGTT and insulin clamp

IGT

<16

0<

180

<20

0

<16

0<

180

<20

0

IGT

Plasma Glucose and Insulin AUC

0

4

8

12

Glu

cose

AU

C(m

mo

l/L

12

0 m

in)

0

4

8

12

Insu

lin A

UC

(pm

ol/L

1

20

min

)

NG

T

NG

TT2DM

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

T2DM Graphic courtesy of Dr. Ralph A. DeFronzo.

IGT

<200

<160

<180

Insulin Secretion/Insulin Resistance (DISPOSITION) Index During OGTT

30

20

10

0

40

Insu

lin S

ecre

tion/

Insu

lin R

esis

tanc

e (I

R)

Inde

x(∆

Ins

ulin

/∆ G

luco

se ÷

IR

) Lean

NGT

<100

<120

<140

Obese

2-h plasma glucose(mg/dL)<2

40<2

80<3

60<3

20>4

00<4

00

T2DM

Obese = BMI ≥30 kg/m2

Graphic courtesy of Dr. Ralph A. DeFronzo.

Fasting Plasma Glucose and Beta Cell Volume in Obese Patients

With permission from Butler AE, et al. Diabetes. 2003;52:102-110.

FP

G

(mg

/dL

)ß

-Cel

l Vo

lum

e (%

)

4

3

2

1

0

250

200

150

100

50

NGT

NGT

IFG

IFG

*

T2DM

T2DM

*

**

*Statistically significant

Increased glucagon output

Hyperglycemia

Decreased glucose uptake

Increasedhepatic glucose

production

Del Prato S, et al. Horm Metab Res. 2004;36:775-781. Porte D Jr, et al. Clin Invest Med. 1995;18:247-254.

Major Pathophysiologic Defects inType 2 Diabetes Mellitus

Impaired insulin secretionIslet cell dysfunction

Insulin resistance

Incretins

Time (min)

IR In

sulin

(m

U/L

)

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect in Subjects with and Without Type 2 Diabetes Mellitus

Control Subjects (n = 8)

Patients with Type 2 Diabetes (n = 14)

Time (min)

IR In

sulin

(m

U/L

)

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load

Intravenous glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

With permission from Nauck M, et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Incretins

GLP-1

GIP

Mixed Meal

L-cells

K-cells

SatietyGastric emptying

Glucagon

Insulin

DPP-4

Preventing Microvascular Complications

Diabetes Control and Complications (DCCT) Study Design

Primary prevention (n = 726)

Secondary intervention*

(n = 715)

Patients with type 1 diabetes (N = 1441)

Conventional(n = 378)

Intensive(n = 348)

Conventional (n = 352)

Intensive(n = 363)

Randomize Randomize

DCCT Research Group. N Engl J Med. 1993;329:977-986.Graphic courtesy of Dr. Charles A. Reasner.

*Patients with retinopathy.

DCCT Treatment Conditions

Abbreviation: DCCT, Diabetes Control and Complications.1. DCCT Research Group. N Engl J Med. 1993;329:977-986. 2. Lachin JM, et al. Diabetes. 2008;57:995-1001.

Conventional (n = 730) Intensive (n = 711)

Aim1 Avoid hyper-/hypoglycemia Symptom-free + plasma glucose 3.9–6.7 mmol/L

before meals, <10 mmol/L after

meals, >3.6 mmol/L at 3:00 AM (measured weekly), and

HbA1c <6.05% (measured monthly)

Administration1 1 or 2 insulin injections/d

+ initial diet and exercise education

≥3 insulin injections/d or insulin pump

Monitoring1 Daily self-monitoring 4 daily blood glucose tests

Follow-up clinic visits1

Quarterly Monthly

Mean HbA1c2 9.5% 7.2%

DCCTIntensive Therapy Reduced Microvascular

Complications

34% reduction76% reduction

*Urinary albumin excretion ≥40 mg/24 hours.Abbreviation: DCCT, Diabetes Control and Complications.DCCT Research Group. N Engl J Med. 1993;329:977-986.

Retinopathy Microalbuminuria*0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5 4.7

3.4

1.2

2.2

Conventional treatment

Intensive treatment

Rat

e/10

0 P

atie

nt-Y

ears

Main randomization of UKPDS4209 patients in 23 centers

Metformin Study1704 overweight patients in

15 centers

UKPDSRandomization of Overweight Patients

Conventional tx (diet)411

Intensive tx1293

Metformin342

Sulphonylurea or insulin 542 409

Abbreviations: tx, treatment; UKPDS, United Kingdom Prospective Diabetes Study.UKPDS Group. Lancet. 1998;352:854-865.

Microvascular Endpoints

Stratton IM, et al. BMJ. 2000;321:404-412.

<6% 6%–7% 7%–8% 8%–9% 9%–<10%

≥10%0

10

20

30

40

50

60

70

6.19.3

14.2

22.8

40.4

57.8

HbA1c

Adj

uste

d R

ate

of M

icro

vasc

ular

Eve

nts*

*Rates/1000 person-years’ follow-up adjusted in Poisson regression model to white men age 50 to 54 years at diagnosis of diabetes and followed up for 7.5 to <12.5 years.

N = 4585

What About Macrovascular Disease?

Why Doesn’t Glucose Reduction Lower the Risk of Macrovascular Disease?

Risk factors include not only hyperglycemia but also– Elevated LDL cholesterol– Low HDL cholesterol– Hypertension– Smoking– Obesity

These risk factors are common in diabetic populations

Adolescent Obesity and Metabolic Impairment

Weiss R, et al. N Engl J Med. 2004;350:2362-2374.Graphic courtesy of Dr. Charles A. Reasner.

Control Overweight Moderately Obese Severely Obese

No. of patients 20 31 244 195

Mean age (years) 12 12 13 11

BMI (kg/m2) 18 25 33 41

Weight (kg) 42 57 86 100

Childhood and Adolescent Metabolic CharacteristicsGlucose and Insulin

GlucoseP = .06

Glu

cose

Lev

el (

mg

/dL

)

87 87

91

90

86

87

88

89

90

91

Control Overweight ModeratelyObese

SeverelyObese

Insulin

Insu

lin

Lev

el (

μU

/mL

)

P <.001

1015

31

39

0

5

10

15

20

25

30

35

40

45

Control Overweight ModeratelyObese

SeverelyObese

Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

Childhood and Adolescent Metabolic Characteristics

Triglycerides

0

20

40

60

80

100

120

Control Overweight ModeratelyObese

SeverelyObese

Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

48

83

10597

Me

an

Tri

glyc

eri

de L

eve

l (m

g/d

L)

Childhood and Adolescent Metabolic Characteristics

HDL Cholesterol

0

10

20

30

40

50

60

70

59

4741 40

Control Overweight ModeratelyObese

SeverelyObese

Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

HD

L C

hole

ster

ol L

evel

(m

g/dL

)

Abbreviation: HDL, high-density lipoprotein.

Childhood and Adolescent Metabolic Characteristics

Systolic Blood Pressure

95

100

105

110

115

120

125

130

106

116

121124

Control Overweight ModeratelyObese

SeverelyObese

Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

Sys

tolic

Blo

od P

ress

ure

(mm

Hg)

InsulinReceptor

Plasma Membrane

Insulin Signal Transduction System in Humans

Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.

NOS

+

Artery

p85Akt

PI-3-kinase

p110

IRS-1

IRS-1

GlucoseGLUT 4

Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide synthase; PI-3-kinase, phosphatidylinositol 3-kinase.

NOS

+

Artery

InsulinReceptor

Plasma Membrane

p85 p110Akt

Insulin Signal Transduction System in Type 2 Diabetes Mellitus

PI-3-kinase

IRS-1

GLUT 4 Glucose Insulin

Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.

Insulin Signal Transduction System in Type 2 Diabetes Mellitus

Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.Cusi K, et al. J Clin Invest. 2000;105:311-320. Osman N, et al. Cardiovasc Hematol Disord Drug Targets. 2008;8:287-292.

NOS

+

Artery

IRS-1

InsulinReceptor

Plasma Membrane

p85 p110Akt

InflammationCell growth/proliferationMAP

kinase

Shc

PI-3-kinase

IRS-1

GLUT 4

Glucose

Insulin

Atherosclerosis

Summary

There are 3 primary physiologic defects in patients with type 2 diabetes mellitus– Insulin resistance– Beta cell failure– Increase in glucagon

Glucose control is critical in reducing microvascular complications

Treatment of the components of the metabolic syndrome is necessary to reduce macrovascular disease

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