Diabetes Mellitus

Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. DM can be classified as type 1 (characterized by insulin deficiency), the more common type 2 (characterized by insulin resistance with relative insulin deficiency), gestational diabetes mellitus (GDM) (a condition that occurs only during pregnancy), and other less common conditions (eg, monogenic DM).  Laboratory evaluations used to screen for, diagnose, and monitor DM include a fasting plasma glucose (FPG) test, a hemoglobin A1c (A1c) test, and an oral glucose tolerance test (OGTT). Those diagnosed with DM or GDM require regular laboratory evaluation to assist in glycemic management and to monitor for the development of diabetes-related complications.

Quick Answers for Clinicians

What are the limitations of hemoglobin A1c testing?

Because hemoglobin A1c (A1c) testing measures the average amount of glucose attached to hemoglobin in red blood cells over approximately 3 months, conditions that affect red blood cell turnover can skew results. These conditions include hemolytic anemia, glucose-6-phosphate dehydrogenase deficiency, recent blood transfusions, drugs that stimulate erythropoiesis, end-stage kidney disease, and pregnancy.  Hemoglobin variants (eg, the sickle cell trait caused by the hemoglobin S [HbS] variant) may also interfere with A1c results; A1c assays without interference, plasma blood glucose criteria, fructosamine, or 1,5-anhydroglucitol should be used in individuals with hemoglobin variants.  For more information on hemoglobin variants, see the Hemoglobinopathies topic.

When should diabetes-related autoantibody testing be used?

Once a diagnosis of type 1 diabetes mellitus (T1DM) has been made, autoantibody testing can be helpful in establishing an autoimmune etiology  or excluding the diagnosis of T1DM in adults without traditional risk factors for type 2 diabetes mellitus (T2DM) and/or younger age.  The American Diabetes Association (ADA) also recommends that pediatric patients who are overweight or obese and suspected of having T2DM have autoantibody testing performed to exclude the possibility of autoimmune T1DM. 

Why is it important to distinguish type 1 from type 2 diabetes mellitus?

As the prevalence of type 2 diabetes mellitus (T2DM) increases in children and adolescents, it becomes more important to distinguish type 1 diabetes mellitus (T1DM) from T2DM because long-term management of the two types differs. Individuals with T1DM usually have absolute insulin deficiency, which often necessitates insulin therapy. In those with T2DM, other treatments are recommended initially, and insulin therapy is used only when all other treatments fail to reduce hemoglobin A1c levels. 

Indications for Testing

Diabetes testing should be pursued to  

  • Screen adults ≥45 years of age, other at-risk individuals (eg, obese/overweight adolescents and adults ≤45 years of age), and pregnant women
  • Diagnose DM by confirming an abnormal test result or upon presentation of symptoms that indicate hyperglycemia
  • Monitor for adherence to glycemic targets

Laboratory Testing

The goals of laboratory testing for diabetes are manifold and include screening for high blood glucose levels, diagnosing diabetes, and monitoring for adherence to glycemic targets.

Screening

The American Diabetes Association (ADA) recommends screening all asymptomatic adults for diabetes and the increased risk of developing diabetes (prediabetes) beginning at 45 years of age. Screening should be repeated at a minimum of every 3 years, unless initial results or risk status suggests that more frequent testing is appropriate. Risk-based screening should be considered in overweight or obese adults who have more than one risk factor. Risk factors include a history of cardiovascular disease, hypertension, and high triglyceride or high-density lipoprotein (HDL) cholesterol levels; for a complete list of risk factors, see the ADA’s Standards of Medical Care in Diabetes. 

Risk-based screening should also be considered in asymptomatic children or adolescents after the onset of puberty or beginning at 10 years of age (whichever comes first) who are overweight and have at least one additional risk factor. Risk factors include a maternal history of diabetes or GDM, a race/ethnicity associated with higher risk, and signs of insulin resistance; for a complete list of risk factors, see the ADA’s Standards of Medical Care in Diabetes. Children or adolescents with normal test results should be retested every 3 years; more frequent screenings are suggested if their BMI is increasing.

In pregnant women not previously known to have DM, testing for GDM should be performed at 24-28 weeks of gestation.    ,  Testing for GDM can be performed using either a one-step or a two-step OGTT. Screening earlier in pregnancy using the same tests as those used for nonpregnant individuals may be considered in women at high risk for diabetes; those with a normal result should be screened again at 24-28 weeks. 

Specific screening recommendations have been developed for certain patients, such as those with cystic fibrosis or those who have had an organ transplantation. Refer to the ADA’s Standards of Medical Care in Diabetes for full screening recommendations, including risk factors.

Diagnosis

Diabetes is diagnosed based on plasma blood glucose or A1c criteria. Generally, the FPG, OGTT, and A1c are equally appropriate tests for screening and diagnosis; however, the ADA does note that these tests may not detect diabetes in the same individuals (as explained below).  The OGTT is required for screening and diagnosis of GDM.

Initial Testing

Fasting Plasma Blood Glucose

An FPG test measures the amount of sugar in the blood without the effect of food intake and is a good indicator of glucose metabolism. Fasting is required for at least 8 hours. The concordance between the FPG and OGTT is imperfect; the OGTT tends to diagnose more individuals with diabetes than measurements of either FPG or A1c. 

Oral Glucose Tolerance Test

The 2-hour plasma glucose (PG) OGTT assesses the body’s response to sugar and is performed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water.  The 2-hr PG OGTT is often referred to as the “one-step approach” for testing for GDM in pregnant women at 24-28 weeks gestation. This approach is widely accepted; 95% of U.S. obstetricians prefer it as the universal screening tool.  The more rigorous “two-step approach” involves administering a 50-g oral glucose solution followed by measurement of venous glucose after 1 hour. Women whose glucose levels meet or exceed an institution’s screening threshold then undergo a 3-hour diagnostic OGTT using 100 g of an oral glucose solution.

Random Plasma Glucose

A random plasma glucose (RPG) level does not take into account the time since the patient’s last meal and is affected by food eaten. An RPG test may be used in the diagnosis of type 1 diabetes mellitus (T1DM) when a patient presents with classic symptoms of hyperglycemia or is experiencing a hyperglycemic crisis.  

Hemoglobin A1c

The A1c test is an important tool for assessing glycemic control; the results reflect the average glycemia (glucose concentration) over approximately 3 months. It may be preferred when fasting is not feasible or for its preanalytic stability; however, the test has lower sensitivity at the designated cut point and higher cost, and there is imperfect correlation between the A1c concentration and the average glucose concentration in some individuals. In individuals with hemoglobin variants, A1c assays without interference from those variants should be used to avoid skewed results.  Additionally, in conditions with an altered relationship between A1c and glycemia due to increased red blood cell turnover (eg, pregnancy, HIV, hemodialysis), only plasma blood glucose criteria should be used to diagnose diabetes. 

Some studies have questioned the validity of A1c test usage in children, but the ADA continues to recommend A1c measurements for diagnosis of type 2 diabetes mellitus (T2DM) in pediatric patients. 

Diagnostic Criteria

Except in cases with a clear clinical diagnosis (eg, hyperglycemic crisis or individuals with symptoms of hyperglycemia and an RPG ≥200 mg/dL), diagnosis requires two abnormal test results from the same sample or two separate samples.  If two samples are tested, the second test should be performed promptly and may be either the same test that was performed on the initial sample or a different test.

Diabetes Diagnostic Criteriaa
Laboratory Test Diabetes Criteria Definition
FPG ≥126 mg/dL (7.0 mmol/L)
2-hr PG during OGTT ≥200 mg/dL (11.1 mmol/L)
A1c ≥6.5% (48 mmol/mol)
RPG ≥200 mg/dL (11.1 mmol/L)b
aDefinitions of prediabetes (either impaired fasting glucose or impaired glucose tolerance) can be found in the ADA’s Standards of Medical Care in Diabetes.

bIn addition to classic symptoms of hyperglycemia or hyperglycemic crisis

Sources: AACE,  ADA,  WHO 

GDM Diagnostic Criteriaa
  One-Step Approachb (mg/dL) Two-Step Approachc (mg/dL)
Fasting 92 95 (CC) or 105 (NDDG)
1 hr 180 180 (CC) or 190 (NDDG)
2 hr 153 155 (CC) or 165 (NDDG)
3 hr n/a 140 (CC) or 145 (NDDG)
aPerformed at 24-28 weeks in women not previously diagnosed with diabetes.

bThe one-step approach is a 75-g OGTT with PG measurements at fasting, 1 hr, and 2 hrs. A diagnosis is made when any PG values are met or exceeded.

cThe two-step approach is a 50-g glucose load test (nonfasting) with PG measurement at 1 hr. If PG is ≥130 mg/dL, 135 mg/dL, or 140 mg/dL, a 100-g OGTT follows (step two). Either Carpenter-Coustan or National Diabetes Data Group cutoffs may be used.

CC, Carpenter-Coustan; n/a, not applicable; NDDG, National Diabetes Data Group

Sources: ADA,  ACOG 

Secondary Testing

Diabetes-Related Autoantibodies

Differentiation between T1DM and T2DM is often made using patient factors (eg, age and weight), but the classic distinctions may not always be appropriate, as some cases have overlapping features. Diabetes-related autoantibody testing can be helpful in establishing an autoimmune etiology in individuals with previously diagnosed T1DM  and to exclude the diagnosis of T1DM in adults without traditional risk factors for T2DM and/or younger age.  The ADA also recommends that pediatric patients who are overweight or obese and suspected of having T2DM have autoantibody testing to exclude the possibility of autoimmune T1DM. 

Autoimmune markers, including islet cell antibodies (ICAs), insulin antibodies (IAs), glutamic acid decarboxylase antibodies (GADAs, or GAD 65), insulinoma-associated antigen 2, and zinc transporter (ZnT8) antibodies, may be present in cases of T1DM. The persistence of two or more of these autoantibodies predicts clinical DM. If pursuing antibody testing, at least two autoantibody tests should be ordered (in most cases, a GADA/GAD 65 test in combination with another test).   However, the specificity of these tests is not perfect: some individuals with T1DM have no autoantibodies, and some individuals with latent autoimmune diabetes or T2DM may have one or more antibodies present. 

Routine screening for T1DM risk with autoantibodies is recommended only in the setting of a research trial or in first-degree family members of a proband with T1DM. 

Molecular Analysis

Genetic testing is recommended in patients suspected of monogenic diabetes syndromes, such as neonatal diabetes or maturity-onset diabetes of the young, to verify genetic etiology, establish treatment, and identify affected family members. 

Monitoring

Routine Glycemic Control

The A1c concentration has strong predictive value for diabetes complications, and A1c testing should be performed routinely in all patients with diabetes; clinicians should use judgment when using A1c to monitor patients with conditions that affect red blood cell turnover and in those with hemoglobin variants.  The ADA and the American Association of Clinical Endocrinologists (AACE) recommend that an A1c test be performed at initial assessment and approximately every 3 months to determine whether glycemic targets have been reached and maintained; at that point, A1c should be measured at least twice a year in those with stable glycemic control. In individuals whose therapy has changed or who are not meeting glycemic goals, quarterly measurements are appropriate.   Although A1c testing is the primary assessment tool for glycemic control, self-monitoring of blood glucose (SMBG) is recommended in certain patients to help with self-management and medication adjustments, especially for hypoglycemia prevention. Other tests used to monitor glycemic control might include fructosamine and 1,5-anhydroglucitol, but the prognostic value of those tests is not as clear as it is for A1c. 

The primary means of assessing glycemic control in pregnant women found to have GDM should be patient SMBG; A1c can be used as a secondary measure, as intraindividual results vary less.  Additionally, because GDM may represent preexisting undiagnosed T2DM or T1DM, women with GDM should be tested at 4-12 weeks postpartum with a 75-g PG OGTT.   A1c testing is not recommended for this postpartum testing because increased red blood cell turnover related to pregnancy and/or blood loss at delivery can still affect A1c results and because the OGTT is more sensitive at detecting glucose intolerance.  If test results are normal, women should continue to be monitored for the development of diabetes every 1-3 years thereafter; more frequent testing should be considered based on risk factors (eg, family history).   This ongoing evaluation can be performed with any recommended glycemic test.

Ideal A1c targets by population are listed in the table below, but treatment goals should be determined and individualized based on patient circumstances. Refer to the ADA’s Standards of Medical Care in Diabetes for full listing of glycemic targets for all individuals.

ADA A1c Targets by Population
Population Ideal A1c Target (%)
Nonpregnant individuals <7a,b
Children <7c
Pregnant women <6d
aMore stringent (<6.5%) or less stringent (<8%) targets may be used for select patients.

bAACE suggests ≤6.5% as a target goal and 7-8% for less stringent target goals.

cMore stringent (<6.5%) targets may be appropriate for select individuals if achievable without significant hypoglycemia.

dIf target cannot be achieved without significant hypoglycemia, adjust goal to <7%.

Source: AACE,  ADA 

Long-Term Complications

Individuals with DM usually have other cardiovascular disease risk factors, including dyslipidemia, and should be treated and monitored for dyslipidemia. For information on monitoring for dyslipidemia, see the Atherosclerotic Cardiovascular Disease Risk Markers topic.

Other testing recommendations for those diagnosed with diabetes include the following :

  • Screen for diabetic kidney disease using urinary albumin and estimated glomerular filtration rate testing at least once a year in patients who have had T1DM for ≥5 years and in those with T2DM or comorbid hypertension.
  • Consider screening patients with T1DM for autoimmune thyroid disease and celiac disease soon after diagnosis, as autoimmune diseases occur more frequently in individuals with T1DM.
  • Consider screening for hypogonadism with a morning serum testosterone measurement in men with diabetes who have signs or symptoms of hypogonadism.

Individuals diagnosed with cystic fibrosis-related diabetes should be monitored annually for complications of diabetes beginning 5 years after the diagnosis. 

ARUP Lab Tests

Tests Used for Diagnosis and Monitoring
Diabetes-Associated Autoantibody Tests Used to Establish Autoimmune Etiology in Individuals with Previously Diagnosed T1DM
Other Testing

May aid in monitoring glucose control for diabetes in specific disorders

Medical Experts

Contributor

Kroner

 
Grace M. Kroner, PhD
Clinical Chemistry Fellow at ARUP Laboratories and University of Utah
Contributor

Pearson

Lauren N. Pearson, DO, MPH
Assistant Professor of Clinical Pathology, University of Utah
Co-Director, Clinical Laboratories, University Hospital; Medical Director, South Jordan Health Center Clinical Laboratory, ARUP Laboratories
Contributor

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