Classification & Risk
Factors for
Diabetes Mellitus
Frank Schwartz, MD FACE
Prof. of Endocrinology
J O Watson Chair for Diabetes Research
Director: The OU Diabetes Institute
Objectives of Lecture
Present an overview of the
common forms of Diabetes
Mellitus
Review the pathogenesis of
each
Describe the risk factors for
developing each
Definition of
Diabetes Mellitus
A chronic disorder of
carbohydrate & fat
metabolism….. due to
absolute/or relative deficiency in
insulin secretion……. &/or
ineffective biological responses
to insulin….. resulting in
hyperglycemia
Diagnostic Criteria for
Diabetes Mellitus
Normal
Impaired
Glucose
Tolerance
Diabetes
Mellitus
Fasting
Glucose
(mg/dl)
<100
100-125
>126
2 Hour
Post
Glucose
Load
(mg/dl)
<140
>140 but
<200
<200
Classification of
Diabetes Mellitus
Two Major Forms of
Diabetes Mellitus
Type 1 Diabetes (T1DM)
-Absolute insulin deficiency resulting
from beta-cell destruction….. usually
caused by an autoimmune process
Type 2 Diabetes (T2DM)
-Biological ineffectiveness of insulin
action (Insulin resistance) and/or
beta cell secretory defects…..a major
factor is thought to be acquisition of
visceral obesity in genetically
susceptible individuals
Type 1 Diabetes Mellitus
(T1DM)
• Caused by beta cell destruction
-Pattern A: autoimmune process
-Pattern B: unknown cause (viral?)
• Occurs most commonly during
childhood, adolescence, & early
adulthood….. but can occur at any
age including persons > 40 Latent
Autoimmune Diabetes of Adulthood
(LADA)
Type 2 Diabetes Mellitus
T2DM)
Most common form of diabetes
accounting for >90 % of all
cases
Occurs most commonly in
adulthood, but prevalence in
children & adolescents is
increasing rapidly
Risk is highly correlated with
acquisition of visceral obesity ….
resulting in insulin resistance &
“relative” insulin deficiency
Other Common Forms of
Diabetes Mellitus
 Impaired Glucose Tolerance
(IGD)
-Abnormal glucose levels but not fulfilling
criteria for diagnosis of type 2 diabetes
-> 50 % risk of going on to develop DM

Gestational Diabetes (GD)
-Development of DM during pregnancy
which usually resolves following
pregnancy
Secondary Diabetes
-Glucose intolerance induced by another
disease which resolves when condition is
treated/corrected
Gestational Diabetes (GD)
Defined as onset of diabetes
induced by pregnancy which
resolves following the pregnancy
50% life-time risk of progression
to T2DM during lifetime
Can be prevented with life-style
intervention
Both T1DM & T2DM can also
occur during pregnancy
Secondary Diabetes
Diabetes & glucose intolerance
induced by another medical
condition, which then resolves
following the resolution of that
medical condition
Overlapping Forms of
Diabetes Mellitus
Double Diabetes or
Diabetes 1.5
• The occurrence of insulin
deficiency & insulin resistance in
same patient
• Children who have T1DM….but
with a family history of T2DM…..
are more prone to obesity &
insulin resistance
• Tend to have much greater
insulin requirements than other
patients their age @ which is
especially accelerated at puberty
What Causes T1DM?
Pathogenesis of T1DM
Viral or immune cell mediated
destruction of β-Cell which
results in a rapid or progressive
decline in Insulin production
“Immune markers” for T1DM
may occur years before the onset
of disease
Factors Contributing
To Development of T1DM
Genetic susceptibility
Environmental triggers
Abnormalities in immune
regulation (inherited vs
acquired?)
Loss of self tolerance
(inherited vs acquired?)
Family History & Risk For
Developing T1DM
0.4% occurrence rate in persons
with no family history of T1DM
6-11% in offspring of person
with T1DM
5% in siblings of person with
T1DM
30-40% in identical twins
> 90% of individuals with newonset T1DM have no family
history!!!
Pathogenesis of T1DM
Genes
Immune
Regulation
+
Induction of
Autoimmunity
Beta Cell
Destruction
Type 1 Diabetes
Environment
Trigger
? Virus
Viral Replication
IFIH1
ii) Induction of Innate
Immune Response & β
Cell Death
Type 1 IFNs
Viral Antigen
i) Direct β Cell
Lysis & Death
MHC Class I
CD8+ T-cell
Self Antigens: IAA, GAD
iii) Induction of Autoimmune
Response & b Cell Death
Viral Induction of Insulitis
Natural History of T1DM
? Viral Trigger
b-Cell
mass 100%
Initiation of autoimmune response
Detection of circulating autoantibodies
(ICA, GAD65, IAA, IAA-2)
Progressive loss of beta-cell
mass induced by CD4+ & CD8+
cells
Glucose
intolerance < 15-20 % of
b-cells are
“functional”
remain
Genetic
predisposition
Insulitis
b-Cell injury
Time
(Months)
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
“Pre”diabetes
Diabetes
Schematic For Viral Initiation of
T1DM
Genetic Predisposition
HLA DR3/4
SNP’s
Beta cell mass
Viral Infection of β cell
Activation of TLR3 in T cells &
Macrophages & stimulation of
NKT cell invasion
Induction of Autoimmune
Insulitis
Pathologic expression & activation of
TLR3
NF-κB, IFNγ, & STAT-3
Resolution of
Viral or Autoimmune Insulitis
Variable Progression to
T1DM-B
ICA, GAD65, IA-2AA
TH1 , NKT cells
Variable Progression to T1DM-A
Prevention of T1DM: How Can We
Approach This?
There are no specific genetic
markers
Most patients with new-onset
T1DM have no family history
Detection of Islet-Cell
antibodies (ICA’s) are not 100%
specific…. & these are usually
only checked in first degree
relatives of persons with
diabetes
Potential Therapeutic Targets
for Preventing/Reversing T1DM
Conclusions
There are at least two patterns of
T1DM…one is autoimmune
mediated (Pattern A) & the other
(Pattern B) is probably viral
mediated
Onset of T1DM following initiation
of insulitis is variable &
spontaneous recovery can occur
These patients require life-long
insulin therapy
What Causes T2DM?
Risk Factors for T2DM
Family history/genetics
Obesity
Western life-style
Tobacco use
Lack of exercise
Hypertension &
Hyperlipidemia
Gestational diabetes
Pathogenesis of
T2DM
Genes and environment
Impaired insulin
secretion
+
Insulin resistance
Impaired glucose
tolerance
Type 2 diabetes
Natural History of T2DM
Post Meal Glucose
350
250
Glucose
Fasting Glucose
150
50
300
Insulin Resistance
Relative 200
Function
100
At risk for
Diabetes
0
-10
-5
Insulin Level
Beta Cell Failure
0
5
10
15
20
25
30
Years of Diabetes
Bergenstal, ©2000 International Diabetes Center
Used with permission.
Major Factors Involved In
Pathogenesis of T2DM
 Insulin Resistance
-Acquisition of visceral obesity…leads to
Lipotoxicity, & impaired Insulin signaling
 Beta Cell Secretory Defects
-Impaired first phase insulin release
secondary to Lipotoxicity, Glucotoxicity, &
loss of Incretion secretion
Visceral Fat Topography
Visceral Fat
Visceral Obesity  Insulin
Resistance
Visceral Obesity
Hypertrophic Fat
Cells
Cellular Defects in
Insulin Signaling
Mitochondrial
Dysfunction
Increased Free
Fatty Acids
Smith, S. and Ravussin, E. Curr Diab Rep. 2002;2:223-230.
Lipotoxicity
The pathologic changes in organs resultant
from elevated fat levels in blood or tissues,
as in the diabetic liver.
http://www.medilexicon.com/medicaldictionary.php?t=50859
Ectopic Deposition of Fat in
T2DM
Hi TG’s
Hi FFA’s
Intramuscular
Islet Cells
Subcutaneous
Intrahepatic
Intraabdominal
Adipokines
TNF-
IL-6, IL-8
MCP-1
TGF b
IGF-1
FGF
Bone Morphogenic Protein IGFBP
Fatty acids
EGF
Lysophospholipid
Visfatin
Lactate
Adenosine
Resistin
Adipose Tissue
Prostaglandins
Glutamine
Adiponectin
Unknown Factors
Adipsin
Agouti
Estrogen
Retinol
PAI-1
Angiotensin-II
Angiotensin
Leptin
Acylation-Stimulating Protein
Insulin Signaling
Defects in T2DM
Mechanism of Insulin
Resistance
Baudry et al., 2002
Natural History of T2DM
Post Meal Glucose
350
250
Glucose
Fasting Glucose
150
50
300
Insulin Resistance
Relative 200
Function
100
At risk for
Diabetes
0
-10
-5
Insulin Level
Beta Cell Failure
0
5
10
15
20
25
30
Years of Diabetes
Bergenstal, ©2000 International Diabetes Center
Used with permission.
Glucotoxicity
As the beta cell begins to
decompensate, postprandial & then fasting
glucose levels rise
Once BS’s are
elevated…..Hyperglycemia
itself has an adverse effect
on insulin release from beta
cell
800
FPG (mg/dL)
79-89
90-99
100-114
115-149
150-349
600
(% Increase)
Relative Acute Insulin Response
Glucotoxicity: Effect of Glucose
Levels on Insulin Release
N
24
20
7
3
12
400
200
0
-100
0
15
30
60
Time (minutes)
90
120
Summary
 Acquisition of visceral
obesity, ectopic fat
deposition in liver, muscle, &
beta cells are major factors
in pathogenesis of T2DM
 Excessive adipokine
production by visceral
adipocytes are key
contributors to the
development of Lipotoxicity
& Insulin Resistance
Summary
Glucotoxicity contributes to
impaired insulin release
Impaired incretin secretion
contributes to impaired insulin
release & excessive glucagon
secretion
Summary
 Eventual β-Cell exhaustion &
cell death are the final result
of this process
 Most persons with T2DM
exhibit insulin deficiency by
8 years