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1
Diagnosis of Type 1 Diabetes
2
Classifying Diabetes
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
A Growing Issue: Differentiating T1DM and T2DM
Type 1 Diabetes Type 2 Diabetes
Usual clinical course Insulin-dependent Initially non-insulin-dependent
Usual age of onset <20 years (but ~50% over 20 years)
>40 years butincreasingly earlier
Body weight Usually lean Usually obese
Onset Often acute Subtle, slow
Ketosis prone Yes No
Family history 15% with 1st-degree relative Common
Ethnicity Predominantly white More common in minorities
Frequency of HLA-DR3, DR4, DQB1*0201, *0302
Increased Not increased
Islet autoantibodies (GADA, ICA, IA-2A, IAA)
Present 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.
4
“Etiological” Classification of Diabetes
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
Other Specific Types of Diabetes: Genetic Defects of Beta-Cell Function
• 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
Symptoms and Severity of T1DM at Presentation: EURODIAB
DKA
42%
Percentage of Pa-tients With DKA at
Presentation
33%with pH 7.1-7.3
9% with pH <7.1
Polyuria Weight Loss
Fatigue
96%
61%52%
Presenting Symp-toms: Percentage of
Patients
DKA, diabetic ketoacidosis. Levy-Marchal C, et al. Diabetol. 2001;44 (Suppl 3):B75-B80.
7
Markers of Immune Destruction of the Beta Cell in T1DM
• Islet cell autoantibodies• Autoantibodies to insulin• Autoantibodies to GAD (GAD65)• Autoantibodies to the tyrosine phosphatases
IA-2 and IA-2b
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
Genetic Markers
• 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
Beta-Cell Destruction in T1DM• 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
Beta-Cell Destruction in T1DM
• 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
T1DM and BMI
• 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
T1DM: Clinical Course
• 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
Idiopathic Diabetes• 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.