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
  • DM type 1 (ketoacidosis)
  • 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

Adults (one of the following)

  • Screening criteria for diabetes mellitus

    Screening Criteria for Diabetes Mellitus

    American Diabetes Association

    U.S. Preventative Services Task Force

    • Testing should be considered in all adults who are overweight (BMI ≥25) and have additional risk factors, including the following
      • Physical inactivity
      • First-degree relative with DM
      • Member of high-risk ethnic population
      • Women who delivered a neonate weighing >9 lb or were diagnosed with GDM
      • Hypertension
      • HDL-C level <35 mg/dL or triglyceride level >250 mg/dL
      • Women with PCOS
      • IGT or IFG noted on prior test results
      • Other clinical conditions associated with insulin resistance
      • History of cardiovascular disease
    • In the absence of the above criteria, testing for DM and pre-DM should begin at 45 years
    • If results are normal, testing should be repeated at least every 3 years, with consideration of more frequent testing depending on initial results and risk status

    2008 USPSTF

    • Screening is recommended for asymptomatic adults with sustained blood pressure >135/80 mmHg
    • No recommendation for asymptomatic adults with blood pressure ≤135/80 mmHg

    Pre-2008 USPSTF

    • Screening recommended for DM type 2 in adults with hypertension or hyperlipidemia
    • Evidence is insufficient to recommend for or against routine screening of asymptomatic adults for DM type 2, IGT or IFG

Pregnant women

  • Assess risk for GDM in all pregnant women at first prenatal visit (American Congress of Obstetricians and Gynecologists [ACOG])
    • USPSTF recommends individual patient screening for at-risk patients (no recommendation for screening all pregnant patients)
  • Plasma glucose testing is an adequate initial screen during first prenatal visit
    • If initial screen is positive, follow up with OGTT
    • If initial screen is negative but patient is high risk, follow up with OGTT at 24-28 weeks gestation
  • Repeat screening 6-12 weeks postpartum only as followup for positive result during pregnancy
  • Comparison of Diagnostic Testing Recommendations for GDM

    Comparison of Diagnostic Testing Recommendations for GDM

    Guidelines

    Glucose Load

    Diagnostic Threshold (mg/dL)

    American Diabetes Association (2007)

    100 g, 3-hour glucose tolerance test (two abnormal values)

    OR

    Fasting or casual glucose

    F ≥95, 1 hr ≥180, 2 hr ≥155, 3 hr ≥140 [Carpenter and Coustan (CC), O’Sullivan and Mahan (OM)]

    F >126 or casual glucose >200 (CC, OM)

    Joslin Diabetes Center (2005)

    100 g, 3-hour or 75 g, 2-hour1 glucose tolerance test (two abnormal values)

    F>105, 1 hr >190, 2 hr >165, 3 hr  >145 [National Diabetes Data Group (NDDG)]

    International Diabetes Center (2003)

    100 g, 3-hour glucose tolerance test (two abnormal values)

    F ≥95, 1 hr  ≥180, 2 hr  ≥155, 3 hr  ≥140 (CC, OM)

    U.S. Preventative Services Task Force (2003)2

    Initial testing: 50 g, 1-hour glucose tolerance test; if abnormal (130-140 mg/dL), proceed to 100 g, 3-hour glucose tolerance test (two abnormal values)

    F ≥95, 1 hr  ≥180, 2 hr  ≥155, 3 hr  ≥140 (CC, OM)

    American College of Obstetricians and Gynecologists  (2001)

    100 g, 3-hour glucose tolerance test (two abnormal values) 

    F ≥95, 1 hr ≥180, 2 hr ≥155, 3 hr ≥140  [(OM) and (CC)]

    F ≥105, 1 hr ≥190, 2 hr ≥165, 3 hr ≥145 (NDDG)

    World Health Organization (1999)

    75 g, 2-hour glucose tolerance test

    F ≥126 or 2 hr ≥200

    National Diabetes Data Group (1979)

    100 g, 3-hour glucose tolerance test

    F >105; 1 hr >190; 2 hr >165; 3h >145

    175 g load is not as well validated by studies but is acceptable for use in diagnosis
    2Updated 2008 – evidence is insufficient to recommend for or against routine screening for GDM

Monitoring

Recommendations for physical examination (Diabetes Care; Standards of Medical Care in Diabetes, 2010)

  • Blood pressure – every week, including orthostatic measurements when indicated (goal <130/80 mmHg)
  • Weight – every visit (goal is BMI <25 kg/m2)
  • Funduscopic examination and dilated eye exam by expert (if first exam is normal, then every 2-3 years)
  • Thyroid palpation
  • Skin examination (for acanthosis nigricans and insulin injection sites)
  • Neurological/foot examination
    • Inspection of feet for lesions
    • Palpation of dorsalis pedis (DP) and posterior tibial (PT) artery pulses
    • Presence/absence of patellar and Achilles reflexes
    • Determination of proprioception, vibration and monofilament sensation

Laboratory Testing

  • Glycemic control

    Glycemic Control

    HbA1c

    • 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 DM control over previous 2-3 months
    • Target goal – <7% of glycated hemoglobin
    • Laboratory testing recommendations 
      • 2 measurements per year for patients meeting goal of <7% (ADA 2008), ≤6.5% (ACE/AACE)
        • If patient is not hypoglycemic, goal should be <6.5%
      • More frequent monitoring in patients with HbA1c ≥7%; however, not more often than every 3 months

    1,5-Anhydroglucitol (GlycoMark)

    • Premise of testing
      • Renal reabsorption of 1.5-anhydroglucitol is competitively inhibited by glucose and is excreted in the urine when the concentration of plasma glucose exceeds its renal threshold (~180 mg/dL)
      • Poor glycemic control leads to decreased concentrations of plasma 1,5-anhydroglucitol
      • Less sensitive to small changes in glycemic control at high HbA1c levels
        • 1.5-AG reflects postprandial glycemic changes better than other glycemic indicators and measurements may be useful for assessing postprandial hyperglycemia
    • Laboratory testing recommendations
      • Not recommended for monitoring DM
      • May be useful for identifying postprandial hyperglycemia and assessing glycemic control in patients with moderately controlled diabetes
        • In patients with normal 1.5-AG (HbA1c 6.1-7.9%), treatment should be aimed at normalizing fasting blood glucose
        • In patients with low 1.5-AG, treatment should be aimed at normalizing postprandial glucose

    Fructosamine

    • Premise of testing
      • Intermediate marker of glycemia
      • Carbonyl group of glucose reacts with an amino group of a protein
      • Provides glycemia index over 20-day period
    • Laboratory testing recommendations
      • May be useful in monitoring GDM; not recommended for other types of DM
      • May be used in patients with shortened red cell survival (eg, sickle cell disease and other hemoglobinopathies)

    Albumin, glycated

    • Premise of testing
      • Intermediate marker of glycemia
      • Measures glycation of serum albumin
      • Provides glycemia index over 20-day period
    • Laboratory testing recommendations
      • May be useful in monitoring GDM; not recommended for other types of DM
      • May be used in patients with shortened red cell survival (eg, sickle cell disease)
      • Control in patients with moderately controlled diabetes

    Insulin

    • Premise of testing
      • Circulating levels of insulin may be prognostic for likelihood of progression to insulin dependence in DM
    • Laboratory testing recommendations
      • Not recommended for monitoring DM

    C-peptide

    • Premise of testing
      • C-peptide connects the A & B chains of proinsulin
      • Released in equimolar concentrations with insulin
      • Reflects endogenous insulin production
    • Laboratory testing recommendations
      • Not recommended for monitoring or diagnosis of DM
      • May be useful for assessing endogenous insulin production to confirm need for insulin therapy or to aid in confirmation of DM type 1
  • Dyslipidemia
    • Lipid panel
      • Premise of testing
        • Patients with DM have an increased incidence of lipid abnormalities
        • Lipid-lowering therapies have been demonstrated to reduce macrovascular disease
      • Target goal – LDL <100 mg/dL (moderate risk patient); LDL <70 mg/dL (high risk patient); HDL >40 mg/dL, triglycerides <150 mg/dL
      • Laboratory testing recommendations
        • Initial evaluation and annually thereafter if goals are met
          • More often if goals are not met
        • Treat aggressively with statins if goals not met
  • Hepatic function
    • Premise of testing
      • Patients with DM are at risk for steatohepatitis
    • Laboratory testing recommendations
      • Liver function tests –  AST, ALT, alkaline phosphatase and bilirubin
      • Initial evaluation and annually thereafter if values are normal on initial testing
  • Renal function
    • Creatinine 
      • Premise of testing
        • Many drugs require adjusted dosing based on creatinine, creatinine clearance or estimated glomerular filtration rates (eGFR)
        • Absolute creatinine values do not reflect glomerular filtration rates in many patients
          • Diabetic nephropathy diminishes creatinine clearance
          • Renal function thereby diminishes clearance and glomerular filtration rate
        • Creatinine and eGFR are broad measures of renal function
      • Target goal
        • Normal ranges
          • Males – 97-113 mL/min
          • Females – 88-128 mL/min
      • Laboratory testing recommendations
        • Serum creatinine and eGFR (calculated) annually
  • Microalbumin (urine)
    • Premise of testing
      • Diabetic nephropathy occurs in 20-40% of patients with DM and is the single leading cause of end-stage renal disease
      • Microalbuminuria or persistent albuminuria (range 30-299 mg/g creatinine, 30-299 mg/24 hours) signifies the earliest stage of diabetic nephropathy
    • Target goal
      • <30 mg/g creatinine, <30 mg/24 hour urine
    • Laboratory testing recommendations
      • Spot urine or 24-hour urine for microalbumin annually
      • Addition of angiotensin converting enzyme inhibitors to diabetes regimen is renoprotective if microalbuminuria is present
  • Thyroid function
    • TSH
      • Premise of testing
      • Laboratory testing recommendations
        • Initial evaluation and, if normal, every 3 years thereafter
  • Other possible testing
    • Haptoglobin (HP) genotyping – predictor of cardiovascular disease in diabetics
      • Hp1-1 genotype – predicts lowest risk
      • Hp2-2 genotype – predicts highest risk
      • Hp1-2 genotype – predicts intermediate risk

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

    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

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
Test Name and Number Recommended Use Limitations Follow Up
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Diagnose DM

   
Glucose Tolerance Test 0020542
Method: Quantitative Enzymatic

Diagnose DM

Components include glucose, fasting and glucose, 2-hour

   
Hemoglobin A1c 0070426
Method: Quantitative High Performance Liquid Chromatography/Boronate Affinity

Diagnose or monitor DM (in adults)

Diagnosis should be confirmed with a repeated test

Unstable hemoglobins or hemolytic anemia may yield falsely low results

Iron deficiency anemia may yield falsely high results

 
Glucose Screen, Pregnancy 0020047
Method: Quantitative Enzymatic

Screen for GDM

   
Microalbumin, Urine 0050203
Method: Quantitative Immunoturbidimetry

Monitor diabetic nephropathy in DM

   
Lipid Panel 0020421
Method: Quantitative Enzymatic

Use for monitoring for dyslipidemia in DM

Panel includes total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol (calculated), appearance, VLDL cholesterol (calculated)

   
Glomerular Filtration Rate, Estimated 0020725
Method: Quantitative Enzymatic

Use for monitoring for renal insufficiency in DM

   
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Assess and monitor risk for steatohepatitis

Panel includes albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, and protein

   
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay
Assess and monitor risk for thyroid disease    
Albumin, Glycated 0080700
Method: Quantitative Boronate Affinity Chromatography/Immunoturbidimetry

Use for monitoring GDM or shortened red-cell survival

   
Fructosamine 0099012
Method: Quantitative Spectrophotometry

Alternative, not first-line, means of monitoring DM

Variations in levels of serum proteins can affect results

High levels of ascorbic acid interfere with the assay

 
1,5 Anhydroglucitol Quantitative, Serum or Plasma 0081335
Method: Quantitative Enzymatic

Monitoring postprandial hyperglycemia and short-term glycemic control when hemoglobin A1c is 6.1-7.9%

Do not use in poorly controlled disease because test is not sensitive

In patients with poorly controlled DM 1,5-AG is less sensitive to modest changes in glycemic control due to continuous glycosuria

Decreased in individuals with renal glucose thresholds that are markedly different from 180 mg/dL (eg, chronic renal failure, pregnancy, dialysis) and in those undergoing steroid therapy

Alpha-glucosidase inhibitors can decrease 1,5-AG by interfering with intestinal absorption

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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

Screening for diabetic patients at risk for cardiovascular disease or diabetic patients considering cardiovascular treatment options