Diabetes Mellitus

Diagnosis

Indications for Testing

• Known risk factors for DM type 2
  • Obesity (BMI >25 kg/m²) – consider testing to detect pre-DM and DM type 2 in asymptomatic people
  • Family history of DM type 2 in first- or second-degree relative
  • Race/ethnicity – Native American, African American, Latino, Asian American, Pacific Islander
  • Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS, low birthweight)
  • Maternal history of DM or GDM during gestation

Criteria for Diagnosis

• Consensus criteria for the diagnosis of DM, impaired glucose, or GDM (American Diabetes Association [ADA] 2011, American Association of Clinical Endocrinologists [AACE], United States Preventive Services Task Force [USPSTF], WHO [2010])
  • Diagnosis must meet one of the following
    • Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L)
      • Fasting is defined as no caloric intake for at least 8 hours
    • Symptoms of DM and a casual plasma glucose ≥200 mg/dL (11.1 mmol/L)
      • Casual is defined as any time of day without regard to time since last meal
      • Classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss
    • 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test (OGTT)
      • Test should be performed as described by WHO using a glucose load containing the equivalent of 75 grams of anhydrous glucose dissolved in water
    • HbA1c ≥6.5%
  • Impaired glucose tolerance
    • Fasting plasma glucose 100-125 mg/dL (5.6-6.9 mmol/L)
    • 2-hour plasma glucose 140-199 mg/dL (7.8-11.0 mmol/L) during OGTT
    • HbA1c 5.7-6.4%
• Testing to differentiate DM type 1 from type 2
  • Insulin antibodies
    • ADA (2008)
      • DM type 1 – results typically have antibodies and low C-peptide levels
      • Absence of antibodies or normal C-peptide levels does not rule out type 1, but likelihood of DM type 1 is low
  • C-peptide testing – use to confirm lack of insulin production, suggesting DM type 1
    • Use of C-peptide levels or insulin levels to diagnose DM is not recommended

Laboratory Testing

• Initial testing – fasting plasma glucose, 2-hour OGTT, random glucose, or HbA1c are the preferred tests to diagnose diabetes in nonpregnant adults (see Criteria for Diagnosis)

Differential Diagnosis

• DM type 2
  • Thyroid disease
• DM type 1 (ketoacidosis)
  • Infection
    • Encephalitis
    • Meningitis
    • Sepsis
  • Acute abdomen
    • Appendicitis
• GDM
  • Infection
  • Acute abdomen
    • Appendicitis
    • Cholecystitis/cholelithiasis
    • Pregnancy-related abdominal problem
      • Intrauterine infection
  • Hypoglycemia
  • Hyperglycemia
    • Infection
    • Acute abdomen
      • Appendicitis
      • Cholecystitis/cholelithiasis
      • Pregnancy-related abdominal problems
        • Intrauterine infection
  • Thyroid disease

Screening

Monitoring

Clinical Background

Diabetes mellitus (DM) is a group of metabolic diseases resulting from defects in insulin secretion and/or insulin resistance that can lead to significant morbidity and mortality in affected patients.

Classification of Diabetes Mellitus

• DM type 1 – 90-95% in pediatric population; absolute insulin deficiency
• DM type 2 – most are teenagers or older; insulin resistance
• Other types of DM due to other causes (eg, cystic fibrosis, drug-induced)
• Gestational diabetes mellitus (GDM) – exclusive to pregnant females

Diabetes Mellitus Type 1

• See Pediatrics tab

Diabetes Mellitus Type 2

• DM type 2

  Epidemiology Prevalence – affects >20 million in U.S. 6.5% of population Age – usually diagnosed >30 years Sex – M:F, equal Occurrence – increase in teenage obesity is associated with increased occurrence of DM type 2 Inheritance 75% concordance rate between identical twins Several susceptibility genes have been identified Risk Factors Obesity (BMI >25 kg/m2) Family history of DM type 2 in first- or second-degree relative Race/ethnicity – Native American, African American, Latino, Asian American, Pacific Islander Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS), low birth weight) Maternal history of DM or GDM during child’s gestation Pathophysiology Combination of progressive β-cell dysfunction with insulin secretory defect in a background of insulin resistance No known autoimmune destruction of the pancreas Clinical Presentation May have polyuria, polydipsia or polyphagia Headache, fatigue, blurred vision, recurring Candida infections More often presents with microvascular, macrovascular and neuropathic complications Tingling, numbness in extremities Lipid abnormalities Renal insufficiency Complications – hyperosmolar coma (uncommon) Long-term complications Cardiac – coronary artery disease Immunologic – recurrent infections Neurologic – neuropathy Ophthalmic – retinopathy Renal – proteinuria with renal failure Vascular – small vessel disease with extremity loss Treatment Insulin therapy required in type 1 and type 2 if patient presents with dehydration, ketosis, or acidosis

Gestational Diabetes Mellitus

• GDM

  Epidemiology Prevalence – 7% of all pregnancies Risk Factors History of previous GDM Previous birth of baby >4.5 kg Severe obesity Strong family history of DM type 2 Diagnosis of PCOS Clinical Presentation Fetus is large for gestational age Post-term delivery Neonatal hypoglycemia Premature labor Preeclampsia

Pediatrics

Diabetes Mellitus Type 1

• DM type 1

  Epidemiology Prevalence Varies by nationality >150,000 under 18 years in the U.S. have DM type 1 Age Majority diagnosed at or before adolescence Up to 1/3 diagnosed during adolescence Sex – M:F, equal Inheritance Interplay between genetic susceptibility and environmental factors Pathophysiology Insulin produced in β-cells of the islets of Langerhans of the pancreas Insulin regulates how the body stores and uses glucose Absolute insulin deficiency of DM type 1 is a result of the following Chronic inflammatory response against the islet cells Cell mediated destruction of islet cells accompanied by production of islet cell antibodies  Islet cell antibodies (ICA) May be detected years prior to clinical symptoms Almost exclusively in DM type 1 Antibody tests for four different islet cell antigens are useful to predict eventual development of DM type 1; probability increases with the number of antibodies detected IA-2 Best predictor of eventual DM type 1 in siblings of diabetic patients Glutamic acid decarboxylase (GAD65) Found in ~70% of patients with DM type 1 at diagnosis Insulin antibodies Usually detected first in young children Not useful once insulin therapy begins Zinc transporter 8 antibodies More specific for islet cells than other antibodies Clinical Presentation Polydipsia, polyuria, polyphagia Nonspecific symptoms Fatigue Nausea, emesis Weight loss Length of time from clinical presentation to diagnosis is typically a few weeks Complications – diabetic ketoacidosis Treatment Insulin therapy required in type 1 and type 2 if patient presents with dehydration, ketosis or acidosis See consensus statement on use of insulin pump therapy from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes (endorsed by the American Diabetes Association and the European Association for the Study of Diabetes)

Diabetes Mellitus Type 2

• See Clinical Background tab

Diagnosis

Indications for Testing

• Fatigue, polyuria, polydipsia, weight loss

Criteria for Diagnosis

• Refer to Diagnosis tab

Laboratory Testing

• Fasting plasma glucose, 2-hour oral glucose tolerance test (OGTT), and random glucose are the preferred tests to diagnose diabetes in children
  • No guidelines indicate hemoglobinA1c (HbA1c) has diagnostic utility in children
• C-peptide testing can be used to confirm lack of insulin production, suggesting type 1 disease
• Use of C-peptide levels or insulin levels to diagnose diabetes is not recommended
• Consider insulin antibody testing to help differentiate DM type 1 from DM type 2
  • ADA (2008)
    • Type 1 – antibodies and low C-peptide levels typical
      • Absence of antibodies or normal C-peptide levels does not rule out type 1, but it is uncommon

Screening 

• Children with known risk factors – screen at 10 years; repeat every 2 years if
  • BMI >85% and any 2 of the following
    • First- or second-degree relative with DM
    • Maternal history of DM or gestational DM
    • Member of at-risk minority group
    • Signs and symptoms of insulin resistance – PCOS, hypertension, acanthosis nigricans

Monitoring

• Hemoglobin A1c
  • Premise of testing
    • Glycation of hemoglobin is non-linear over time and occurs over the whole lifespan of the red blood cell
    • Correlates with risk of long-term complications and with diabetes control over previous 2-3 months
  • Target goal – <6.5% of glycated hemoglobin for children <6 years and <8% for ages 6-18
  • Laboratory testing recommendations 
    • 2 measurements per year for patients meeting goal of <6.5% (ADA 2008), ≤6.5% (ACE/AACE)
      • If patient is not hypoglycemic, goal should be <6%
    • More frequent monitoring in patients with HbA1c ≥7%; however, not more often than every 3 months
      • Do not use for diagnosis for diabetes
• Hypoglycemia
  • Not infrequent when children are using insulin
    • Diligence required for younger children

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Thyroid Stimulating Hormone 0070145 Method: Quantitative Chemiluminescent Immunoassay
Insulin Antibody 0099228 Method: Quantitative Radioimmunoassay	May aid in proband diagnosis or predict development of DM type 2
IA-2 Antibody 0050202 Method: Quantitative Radioimmunoassay	Aid in the diagnosis and confirmation of DM Best predictor of DM type 1 in siblings
Glutamic Acid Decarboxylase Antibody 2001771 Method: Quantitative Enzyme-Linked Immunosorbent Assay	Aid in the diagnosis and confirmation of DM May be found in patients who eventually develop DM type 1
Islet Cell Cytoplasmic Antibody, IgG 0050138 Method: Semi-Quantitative Indirect Fluorescent Antibody	Aid in the diagnosis and confirmation of DM in family members of probands
Zinc Transporter 8 Antibody 2006196 Method: Quantitative Enzyme-Linked Immunosorbent Assay	May be useful in preclinical phase to monitor progression to DM type 1 May be useful in differentiating latent autoimmune diabetes in adults (LADA) from DM type 2
C-Peptide, Serum or Plasma 0070103 Method: Quantitative Chemiluminescent Immunoassay	Not useful in DM monitoring
Insulin, Free and Total 0070155 Method: Quantitative Ultrafiltration/Quantitative Chemiluminescent Immunoassay	Not useful in DM monitoring
Insulin, Random 0070107 Method: Quantitative Chemiluminescent Immunoassay	Not useful in diagnosing or monitoring of DM
Insulin, Fasting 0070063 Method: Quantitative Chemiluminescent Immunoassay	Not useful in diagnosing or monitoring of DM
Haptoglobin (HP) Genotyping 0040116 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Not useful in diagnosis or monitoring of DM Aid in prediction of cardiovascular risk in patients with DM
PreDx Diabetes Risk Profile 2004263 Method: Immunoassay/Enzymatic/High Performance Liquid Chromatography	Component results for glucose, HbA1c, insulin, hsCRP, ferritin, adiponectin, interleukin 2 receptor alpha (IL2Ra) are used in the diabetes risk score calculation