Diagnosis of Type 1 Diabetes

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Diagnosis of Type 1 Diabetes

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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.

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A Growing Issue: Differentiating T1DM and T2DM

Type 1 Diabetes Type 2 DiabetesUsual 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.

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“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.

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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. 2012;35:S64-S71.

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Symptoms and Severity of T1DM at Presentation: EURODIAB

DKA, diabetic ketoacidosis. Levy-Marchal C, et al. Diabetol. 2001;44 (Suppl 3):B75-B80.

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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


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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


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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


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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


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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


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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

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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


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Fulminant T1DM

• Recently discovered subtype of T1DM• Presents with extremely high glucose levels

with diabetic ketoacidosis (DKA), yet on average only 4 days of hyperglycemia

• Normal or near-normal A1C• Often preceded by common cold–like and

gastrointestinal symptoms• Sometimes associated with pregnancy• Pancreatic enzymes often elevated

Hanafusa T, Imagawa A. Nat Clin Pract Endocrinol Metab. 2007;3:36-45.

Diagnosis of Type 1 Diabetes

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