1

2
IAA, autoantibodies to insulin; GADA, glutamic acid decarboxylase;
IA-2A, the tyrosine phosphatase insulinoma antigen; ZnT8A, zinc transporter 8; T1aD, type 1a
(autoimmune) diabetes; T2D, type 2 diabetes.
*Needs to be refined for non-white population groups.
Rewers M. Diabetes Metab J. 2012;36:90-97.

3
Usual clinical course
Usual age of onset
Body weight
Onset
Ketosis prone
Family history
Ethnicity
Frequency of HLA-DR3, DR4,
DQB1*0201, *0302
Islet autoantibodies
(GADA, ICA, IA-2A, IAA)
Type 1 Diabetes
Insulin-dependent
<20 years (but ~50% over 20 years)
Usually lean
Often acute
Yes

15% with 1 st -degree relative
Predominantly white
Increased
Present
Type 2 Diabetes
Initially non-insulin-dependent
>40 years but increasingly earlier
Usually obese
Subtle, slow
No
Common
More common in minorities
Not increased
Absent
IAA, autoantibodies to insulin; GADA, glutamic acid decarboxylase; IA-2A, the tyrosine phosphatase insulinoma antigen; ZnT8A, zinc transporter 8; T1aD, type 1a (autoimmune) diabetes; T2D, type 2 diabetes.
*Needs to be refined for nonwhite population groups.
Rewers M. Diabetes Metab J. 2012;36:90-97.

“Etiological” Classification of Diabetes
4
APS1, autoimmune polyendocrine syndromes 1;
IPEX, immunodeficiency, polyendocrinopathy, enteropathy, X-linked syndrome;
MODY, maturity-onset diabetes of the young.
Rewers M. Diabetes Metab J. 2012;36:90-97.

5
• Chromosome 12, HNF-1α (MODY3)
• Chromosome 7, glucokinase (MODY2)
• Chromosome 20, HNF-4α (MODY1)
• Chromosome 13, insulin promoter factor-1
(IPF-1; MODY4)
• Chromosome 17, HNF-1β (MODY5)
• Chromosome 2, NeuroD1 (MODY6)
• Mitochondrial DNA
American Diabetes Association.
Diabetes Care.
2013;36(suppl 1):S67-S74.

6
Presenting Symptoms:
Percentage of Patients
96%
Percentage of Patients
With DKA at
Presentation
42%
61%
52%
33% with pH
7.1-7.3
9% with pH
<7.1
Polyuria Weight
Loss
Fatigue DKA
DKA, diabetic ketoacidosis.
Levy-Marchal C, et al. Diabetol . 2001;44 (Suppl 3):B75-B80.

• Islet cell autoantibodies
• Autoantibodies to insulin
• Autoantibodies to GAD (GAD65)
• Autoantibodies to the tyrosine phosphatases
IA-2 and IA-2b
7
When fasting hyperglycemia is first detected, one and usually more than one of these autoantibodies are present in 85%-90% of individuals
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.

8
• Strong HLA associations, with linkage to the DQA and DQB genes
• Influenced by the DRB genes
• HLA-DR/DQ alleles can be either predisposing or protective
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.

9
• Can be quite variable
– Rapid in some individuals (mainly infants and children)
– Slow in others (mainly adults)
• Children and adolescents often present with ketoacidosis as the first manifestation of T1DM
• Other patients have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other environmental triggers
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.

10
• Adults may retain residual β-cell function sufficient to prevent ketoacidosis for many years
– These patients eventually become insulin-dependent and are at risk for ketoacidosis
– They have low or undetectable levels of plasma C-peptide
• Immune-mediated diabetes commonly occurs in childhood and adolescence but can occur at any age
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.

11
• Although T1DM patients are rarely obese when they present, the presence of obesity is not incompatible with T1DM
• These patients are also prone to other autoimmune disorders
– For example, Addison’s disease, autoimmune hepatitis, celiac sprue, Graves ’ disease,
Hashimoto ’s thyroiditis, vitiligo, myasthenia gravis, pernicious anemia
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.

12
• Typically characterized by the acute onset of the classic symptoms of diabetes
– Polyuria, polydipsia, weight loss
• Course of autoimmune diabetes is characterized by ongoing β-cell destruction
• Patients with T1DM require exogenous insulin for survival and should be identified as soon as possible to avoid high morbidity due to a delay in insulin treatment

13
• Diabetes of “unknown etiology”
• Patients may have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity
• Strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not
HLA associated
– Most who fall into this category are of African or
Asian ancestry
• Often suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes
American Diabetes Association. Diabetes Care . 2013;36(suppl 1):S67-S74.