Classification & Risk Factors for

Diabetes Mellitus

Frank Schwartz, MD FACEProf. of Endocrinology

J O Watson Chair for Diabetes ResearchDirector: 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 susceptibilityEnvironmental triggersAbnormalities 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 new-onset T1DM have no family

history!!!

Pathogenesis of T1DM

Genes + Environment

Type 1 Diabetes

Beta Cell Destruction

Induction of Autoimmunity

Immune Regulation

Trigger? Virus

Viral Replication

i) Direct β CellLysis & Death

iii) Induction of Autoimmune Response & Cell Death

IFIH1 ii) Induction of Innate Immune Response & β

Cell DeathType 1 IFNs

MHC Class I

CD8+ T-cell

Viral Antigen

Self Antigens: IAA, GAD

Viral Induction of Insulitis

? Viral Trigger

Detection of circulating autoantibodies (ICA, GAD65, IAA, IAA-2)

Initiation of autoimmune response

Progressive loss of beta-cell mass induced by CD4+ & CD8+

cellsGlucose

intolerance < 15-20 % of-cells are

“functional” remain

Time(Months)

-Cell mass 100%

“Pre”-diabetes

Geneticpredisposition

Insulitis-Cell injury

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Diabetes

Natural History of T1DM

Schematic For Viral Initiation of T1DM

Viral Infection of β cellActivation of TLR3 in T cells

& Macrophages & stimulation of

NKT cell invasion

Variable Progression to T1DM-B

Induction of Autoimmune Insulitis

Pathologic expression & activation of TLR3

NF-κB, IFNγ, & STAT-3

Resolution of Viral or Autoimmune Insulitis

Variable Progression to T1DM-A

Genetic PredispositionHLA DR3/4

SNP’sBeta cell mass

ICA, GAD65, IA-2AATH1 , NKT cells

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

Type 2 diabetes

Impaired glucose tolerance

Impaired insulin secretion

Insulin resistance+

Natural History of T2DM

0

100

200

300

-10 -5 0 5 10 15 20 25 30

50

150

250

350

At risk for Diabetes

Glucose

Relative Function

Post Meal Glucose

Fasting Glucose

Insulin Resistance

Insulin LevelBeta Cell Failure

Years of DiabetesBergenstal, ©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

Smith, S. and Ravussin, E. Curr Diab Rep. 2002;2:223-230.

Visceral Obesity

Cellular Defects in Insulin Signaling

Hypertrophic Fat Cells

Increased Free Fatty Acids

Mitochondrial Dysfunction

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’sHi FFA’s

Intramuscular

Intrahepatic

Subcutaneous

Intra-abdominal

Islet Cells

Unknown Factors

Agouti

Retinol

PAI-1

Leptin

Acylation-Stimulating ProteinAngiotensin

Angiotensin-II

Adiponectin

Adipsin

Resistin

Bone Morphogenic ProteinIGF-1IGFBP

TNF-IL-6, IL-8MCP-1TGF FGFEGF

Fatty acidsLysophospholipid

LactateAdenosine

ProstaglandinsGlutamine

Estrogen

Visfatin

Adipose Tissue

Adipokines

Insulin Signaling Defects in T2DM

Mechanism of Insulin Resistance

Baudry et al., 2002

Natural History of T2DM

0

100

200

300

-10 -5 0 5 10 15 20 25 30

50

150

250

350

At risk for Diabetes

Glucose

Relative Function

Post Meal Glucose

Fasting Glucose

Insulin Resistance

Insulin LevelBeta Cell Failure

Years of DiabetesBergenstal, ©2000 International Diabetes Center

Used with permission.

Glucotoxicity

As the beta cell begins to decompensate, post-prandial & then fasting glucose levels rise

Once BS’s are elevated…..Hyperglycemia itself has an adverse effect on insulin release from beta cell

Glucotoxicity: Effect of Glucose Levels on Insulin Release

FPG (mg/dL)79-8990-99

100-114115-149150-349

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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

Eventual β-Cell exhaustion & cell death are the final result of this process

Most persons with T2DM exhibit insulin deficiency by 8 years

Summary