1. 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

2. 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

3. 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

4. Diagnostic Criteria for Diabetes Mellitus
Normal
Impaired
Glucose Tolerance
Diabetes Mellitus
Fasting Glucose (mg/dl)
<100
>126
2 Hour Post Glucose Load (mg/dl)
<140
>140 but <200
<200

5. Classification of Diabetes Mellitus

6. 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

7. 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)

8. 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

9. 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

10. 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

11. Secondary Diabetes
Diabetes & glucose intolerance induced by another medical condition, which then resolves following the resolution of that medical condition

12. Overlapping Forms of Diabetes Mellitus

13. 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 which is especially accelerated at puberty

14. What Causes T1DM?

15. 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

16. Factors Contributing To Development of T1DM
Genetic susceptibility
Environmental triggers
Abnormalities in immune regulation (inherited vs acquired?)
Loss of self tolerance (inherited vs acquired?)

17. 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!!!

18. Induction of Autoimmunity
Pathogenesis of T1DM
Genes Environment
Immune
Regulation
Induction of Autoimmunity
Trigger
? Virus
Beta Cell Destruction
Type 1 Diabetes

19. Viral Induction of Insulitis
Beta Cell
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

20. Natural History of T1DM -Cell mass 100% Time (Months) ? Viral Trigger
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
< % of -cells are “functional” remain
Genetic
predisposition
Insulitis -Cell injury
“Pre”-diabetes
Diabetes
Time
(Months)
Eisenbarth GS. N Engl J Med. 1986;314:

21. 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
ICA, GAD65, IA-2AA
TH1 , NKT cells
Resolution of
Viral or Autoimmune Insulitis
Variable Progression to T1DM-B
Variable Progression to T1DM-A

22. 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

23. Potential Therapeutic Targets for Preventing/Reversing T1DM

24. 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

25. What Causes T2DM?

26. Risk Factors for T2DM Family history/genetics Obesity
Western life-style
Tobacco use
Lack of exercise
Hypertension & Hyperlipidemia
Gestational diabetes

27. Impaired insulin secretion
Pathogenesis of T2DM
Genes and environment +
Impaired insulin secretion
Insulin resistance
Impaired glucose tolerance
Type 2 diabetes

28. Natural History of T2DM Post Meal Glucose Fasting Glucose
350
250
Fasting Glucose
Glucose
150 50
Insulin Resistance
300
Relative
Function
200
The relationship of increased postprandial and fasting glucose levels, insulin resistance, and insulin levels in subjects with type 2 diabetes are illustrated in this figure.
Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabetes: a systematic approach to meeting standards of care. II: Oral agents, insulin and management of complications. In Endocrinology, 4th ed, De Groo LJ and Jameson JL, editors. WB Saunders Co, Phila. (Originally published in Type 2 Diabetes BASICS, ©200 International Diabetes Center, Minneapolis). Used with permission.
100
At risk for
Diabetes
Insulin Level
Beta Cell Failure
-10 -5 5 10 15 20 25 30
Years of Diabetes
Bergenstal, ©2000 International Diabetes Center Used with permission.

29. 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

30. Visceral Fat Topography
“Bubba” depicting visceral adiposity. Visceral adipose tissue is in close proximity to vital organs including the pancreas.

31. Visceral Obesity  Insulin Resistance
Hypertrophic Fat Cells
Increased Free Fatty Acids
Cellular Defects in Insulin Signaling
Mitochondrial Dysfunction
It has been firmly established that visceral obesity leads to cellular defects in insulin signaling, hypertrophy of fat cells, increased free fatty acids, and mitochondrial dysfunction.
Smith, S. and Ravussin, E. Curr Diab Rep. 2002;2:

32. Lipotoxicity
The pathologic changes in organs resultant from elevated fat levels in blood or tissues, as in the diabetic liver.
A good general definition of lipotoxicity is the pathologic changes in organs resultant from elevated fat levels in blood or tissues, as in the diabetic liver as defined by medilexicon. However, in terms of type 2 diabetes lipotoxicity is thought of as the pathologic effect of fat on insulin signaling (i.e. insulin resistance) that manifests in glucose intolerance and T2DM.

33. Ectopic Deposition of Fat in T2DM
Hi TG’s
Hi FFA’s
Intramuscular
Islet Cells
Subcutaneous
Here Bubba is depicting ectopic deposition of fat in insulin target tissues that causes lipotoxicity.
Intrahepatic
Intra-
abdominal

34. Acylation-Stimulating Protein
Adipokines
TNF-
IL-6, IL-8
MCP-1
TGF 
FGF
EGF
IGF-1
IGFBP
Bone Morphogenic Protein
Fatty acids
Lysophospholipid
Lactate
Adenosine
Prostaglandins
Glutamine
Visfatin
Resistin
Adipose Tissue
Adiponectin
Unknown Factors
Adipsin
Agouti
Here are some of the adipokines produced from adipocytes. Most adipokines are involved in the development of insulin resistance, beta cell dysfunction and T2DM like TNFa, and IL-6. Adiponectin, on the other hand is a “good” adipokine that normally enhances insulin sensitivity, glucose tolerance, and fatty acid oxidation in muscle. However, its blood concentration is reduced in obese people and those with T2DM.
Estrogen
Retinol
Angiotensin-II
PAI-1
Leptin
Angiotensin
Acylation-Stimulating Protein

35. Insulin Signaling Defects in T2DM Mechanism of Insulin Resistance

36. This slide graphically depicts insulin signaling defects and insulin resistance.
Baudry et al., 2002

37. Natural History of T2DM Post Meal Glucose Fasting Glucose
350
250
Fasting Glucose
Glucose
150 50
Insulin Resistance
300
Relative
Function
200
The relationship of increased postprandial and fasting glucose levels, insulin resistance, and insulin levels in subjects with type 2 diabetes are illustrated in this figure.
Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabetes: a systematic approach to meeting standards of care. II: Oral agents, insulin and management of complications. In Endocrinology, 4th ed, De Groo LJ and Jameson JL, editors. WB Saunders Co, Phila. (Originally published in Type 2 Diabetes BASICS, ©200 International Diabetes Center, Minneapolis). Used with permission.
100
At risk for
Diabetes
Insulin Level
Beta Cell Failure
-10 -5 5 10 15 20 25 30
Years of Diabetes
Bergenstal, ©2000 International Diabetes Center Used with permission.

38. 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
Note to myself:
How does hyperglycemia induce adverse effects on insulin release from beta cell?

39. Glucotoxicity: Effect of Glucose Levels on Insulin Release
FPG (mg/dL)
79-89
90-99 N 24 20 7 3 12
800
600
400
200
-100 15 30 60 90
120
Relative Acute Insulin Response
(% Increase)
Fasting glucose level above 115 mg/dl will inhibit post-meal first phase insulin release by >50%!!!!
Time (minutes)

40. 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

41. Summary Glucotoxicity contributes to impaired insulin release
Impaired incretin secretion contributes to impaired insulin release & excessive glucagon secretion

42. Summary
Eventual β-Cell exhaustion & cell death are the final result of this process
Most persons with T2DM exhibit insulin deficiency by 8 years