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 Mellitus
Every 24 Hours
New cases
Amputations
4384
195
Blindness
Kidney failure
Deaths
66
128
640
Why does this
occur?
>60% of nontraumatic
amputations annually
Number 1 cause
68% due to
cardiovascular disease,
2- to 4-fold higher than in
adults without diabetes
How do we prevent this
morbidity and mortality?
CDC. National Diabetes Fact Sheet, 2007. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf.
Physiologic Defects Associated with
Type 2 Diabetes Mellitus
Regulation of Normal Glucose
Homeostasis
Glucagon
(alpha cell)
Fasting state
Fed state
Pancreas
Insulin
(beta cell)
Glucose uptake
Glucose output
Blood glucose
Liver
Muscle
Adipose
tissue
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.
Insulin Resistance and Insulin Deficiency
300
140
Insulin250 mediated
glucose
200
uptake
(mg/m2 • min)
150
Mean
plasma insulin 100
during OGTT
(µU/mL)
60
20
400
100
Mean
300
plasma glucose
during OGTT
200
(mg/dL)
100
LEAN OB OBNGT NGT IGT
OBDIAB
Hi INS
OBDIAB
Lo INS
Abbreviations: DIAB, diabetes; Hi INS, hyperinsulinemic; IGT, impaired glucose tolerance; Lo INS, hypoinsulinemic;
NGT, normal glucose tolerance; OB, obese; OGTT, oral glucose tolerance test.
With permission from DeFronzo RA. Diabetes. 1988;37:667-687.
Insulin Signal Transduction
System in Humans
Insulin
Receptor
GLUT 4
Glucose
Plasma Membrane
IRS-1
p85
p110
Akt
PI-3-kinase
Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide
synthase; PI-3-kinase, phosphatidylinositol 3-kinase.
Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.
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 progresses1
1. 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
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
All 3 studies used OGTT and insulin clamp
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.
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.
Glucose AUC
(mmol/L  120 min)
0
NGT
<160
<180
<200
Q1
Q2
Q3
Q4
IGT
T2DM
Graphic courtesy of Dr. Ralph A. DeFronzo.
0
<160
<180
<200
Q1
Q2
Q3
Q4
4
NGT
8
Insulin AUC
(pmol/L  120 min)
Plasma Glucose and Insulin AUC
12
12
8
4
IGT
T2DM
Insulin Secretion/Insulin Resistance
(IR) Index
(∆ Insulin/∆ Glucose ÷ IR)
Insulin Secretion/Insulin Resistance
(DISPOSITION) Index During OGTT
40
Obese =
BMI ≥30 kg/m2
Lean
30
20
10
Obese
2-h plasma
glucose
(mg/dL)
0
NGT
Graphic courtesy of Dr. Ralph A. DeFronzo.
IGT
T2DM
Fasting Plasma Glucose and Beta Cell
Volume in Obese Patients
FPG
(mg/dL)
250
*
200
*
150
100
50
ß-Cell Volume
(%)
NGT
IFG
T2DM
4
3
*
2
*
1
0
NGT
*Statistically significant
With permission from Butler AE, et al. Diabetes. 2003;52:102-110.
IFG
T2DM
Major Pathophysiologic Defects in
Type 2 Diabetes Mellitus
Increased glucagon output
Impaired insulin secretion
Islet cell dysfunction
Hyperglycemia
Increased
hepatic
glucose
production
Insulin
resistance
Decreased glucose uptake
Del Prato S, et al. Horm Metab Res. 2004;36:775-781. Porte D Jr, et al. Clin Invest Med. 1995;18:247-254.
Incretins
The Incretin Effect in Subjects with and
Without Type 2 Diabetes Mellitus
Control Subjects
(n = 8)
0.6
Incretin
Effect
60
80
0.4
20
0.1
0
0
0
60
120
Time (min)
180
60
0.5
0.4
nmol/L
0.2
nmol/L
0.3
40
0.6
The incretin effect
is diminished
in type 2 diabetes.
0.5
IR Insulin (mU/L)
80
IR Insulin (mU/L)
Patients with Type 2 Diabetes
(n = 14)
0.3
40
0.2
20
0.1
0
0
0
60
120
Time (min)
Oral glucose load
Intravenous glucose infusion
With permission from Nauck M, et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
180
Incretins
Mixed Meal
Gastric emptying
K-cells
L-cells
Satiety
Glucagon
GLP-1
GIP
Insulin
DPP-4
Preventing Microvascular
Complications
Diabetes Control and Complications
(DCCT) Study Design
Patients with type 1 diabetes
(N = 1441)
Primary prevention
(n = 726)
Secondary intervention*
(n = 715)
Randomize
Conventional
(n = 378)
*Patients with retinopathy.
DCCT Research Group. N Engl J Med. 1993;329:977-986.
Graphic courtesy of Dr. Charles A. Reasner.
Intensive
(n = 363)
DCCT Treatment Conditions
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
Daily self-monitoring
4 daily blood glucose
tests
Quarterly
Monthly
9.5%
7.2%
Monitoring1
Follow-up clinic
visits1
Mean HbA1c2
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.
DCCT
Intensive Therapy Reduced Microvascular
Complications
Rate/100 Patient-Years
76% reduction
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
34% reduction
4.7
3.4
Conventional
treatment
2.2
Intensive
treatment
1.2
Retinopathy
*Urinary albumin excretion ≥40 mg/24 hours.
Abbreviation: DCCT, Diabetes Control and Complications.
DCCT Research Group. N Engl J Med. 1993;329:977-986.
Microalbuminuria*
UKPDS
Randomization of Overweight Patients
Main randomization of UKPDS
4209 patients in 23 centers
Metformin Study
1704 overweight patients in
15 centers
Conventional tx (diet)
411
Intensive tx
1293
Sulphonylurea or insulin
542
409
Abbreviations: tx, treatment; UKPDS, United Kingdom Prospective Diabetes Study.
UKPDS Group. Lancet. 1998;352:854-865.
Metformin
342
Adjusted Rate of Microvascular Events*
Microvascular Endpoints
N = 4585
70
57.8
60
50
40.4
40
30
22.8
20
10
14.2
6.1
9.3
0
<6%
6%–7%
7%–8% 8%–9% 9%–<10%
HbA1c
≥10%
*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.
Stratton IM, et al. BMJ. 2000;321:404-412.
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
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
Weiss R, et al. N Engl J Med. 2004;350:2362-2374.
Graphic courtesy of Dr. Charles A. Reasner.
Childhood and Adolescent Metabolic
Characteristics
Glucose and Insulin
Glucose
P = .06
Insulin
P <.001
91
90
90
89
88
87
87
87
86
Control
Overweight Moderately Severely
Obese
Obese
Weiss R, et al. N Engl J Med. 2004;350:2362-2374.
Insulin Level ( μU/mL)
Glucose Level (mg/dL)
91
45
40
35
30
25
20
15
10
5
0
39
31
15
10
Control
Overweight
Moderately Severely
Obese
Obese
Childhood and Adolescent Metabolic
Characteristics
Mean Triglyceride Level (mg/dL)
Triglycerides
120
105
97
100
83
80
60
48
40
20
0
Control
Overweight
Weiss R, et al. N Engl J Med. 2004;350:2362-2374.
Moderately
Obese
Severely
Obese
Childhood and Adolescent Metabolic
Characteristics
HDL Cholesterol Level (mg/dL)
HDL Cholesterol
70
60
59
47
50
40
41
40
Moderately
Obese
Severely
Obese
30
20
10
0
Control
Overweight
Abbreviation: HDL, high-density lipoprotein.
Weiss R, et al. N Engl J Med. 2004;350:2362-2374.
Childhood and Adolescent Metabolic
Characteristics
Systolic Blood Pressure (mm Hg)
Systolic Blood Pressure
130
124
125
121
120
116
115
110
106
105
100
95
Control
Overweight
Weiss R, et al. N Engl J Med. 2004;350:2362-2374.
Moderately
Obese
Severely
Obese
Insulin Signal Transduction
System in Humans
Insulin
Receptor
GLUT 4
Glucose
Plasma Membrane
IRS-1
p85
p110
Akt
PI-3-kinase
+
Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide
synthase; PI-3-kinase, phosphatidylinositol 3-kinase.
Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.
Artery
Insulin Signal Transduction
System in Type 2 Diabetes Mellitus
Insulin
Receptor
 Insulin
 Glucose
GLUT 4
Plasma Membrane
IRS-1
p85
p110
Akt
PI-3-kinase
+
Artery
Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.
Insulin Signal Transduction
System in Type 2 Diabetes Mellitus
Insulin
Receptor

Glucose GLUT 4

Insulin
Plasma Membrane
IRS-1
p85
p110
Akt
PI-3kinase
Shc
+
Inflammation Arter
Cell growth/proliferation
y
Atherosclerosis
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.
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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