Diabetes Mellitus - Type 1, Type 2, and Gestational

Medical Experts

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Pearson

Lauren N. Pearson, DO, MPH

Associate Professor of Pathology (Clinical), University of Utah

Chief Medical Officer, ARUP at University of Utah Health

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

Diabetes mellitus (DM) refers to a group of metabolic disorders characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. DM includes three main types: type 1 (T1DM), characterized by insulin deficiency; the more common type 2 (T2DM), characterized by insulin resistance with relative insulin deficiency; and gestational diabetes mellitus (GDM), a condition that only occurs during pregnancy. Other conditions, such as monogenic DM, are possible but less common.

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). When indicated, secondary testing can be used to help differentiate between types of diabetes, inform and monitor treatment, and assess etiology. Individuals diagnosed with T1DM, T2DM, or GDM require regular laboratory evaluation to assist in glycemic management and 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 glycosylated hemoglobin in red blood cells (RBCs) over approximately 3 months, conditions that affect RBC turnover can skew results. These conditions include hemolytic anemia, glucose-6-phosphate dehydrogenase deficiency, recent blood transfusions, use of drugs that stimulate erythropoiesis, end-stage kidney disease, and pregnancy. Hemoglobin variants (eg, the hemoglobin S [HbS] variant that causes the sickle cell trait) may also interfere with some A1c testing methods. 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, refer to the ARUP Consult 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. Autoantibody testing may also help to exclude the diagnosis of T1DM in adults who lack traditional risk factors for type 2 diabetes mellitus (T2DM) and/or who are younger in age. The American Diabetes Association (ADA) also recommends autoantibody testing in pediatric patients who are overweight or obese and are suspected of having T2DM in order to exclude the possibility of autoimmune T1DM.

Indications for Testing

Diabetes testing is appropriate for:

Screening adults ≥35 years of age, at-risk individuals (eg, obese/overweight adults and adolescents), and individuals with weight-related or other risk factors who are pregnant or planning to become pregnant
Diagnosing DM by confirmatory testing in the event of an abnormal test result or in patients who present with symptoms of hyperglycemia
Monitoring for adherence to glycemic targets

Laboratory Testing

Routine Screening

Guidelines from the American Diabetes Association and the American Association of Clinical Endocrinology (AACE) recommend screening all asymptomatic adults for diabetes and the increased risk of developing diabetes (prediabetes) beginning at 35 years of age. Fasting plasma blood glucose, hemoglobin A1c (A1c), and oral glucose tolerance tests are all considered appropriate to screen for diabetes and prediabetes. Screening should be repeated at a minimum of every 3 years, unless initial results or risk status suggests that more frequent testing is appropriate (eg, greater frequency may be appropriate for patients 65 years and older).

Risk-Based Screening

Risk-based screening should be considered in adults who are overweight (ie, have a BMI of ≥25 kg/m², or ≥23 kg/m² in Asian American individuals) and have at least one additional risk factor for diabetes. Screening should be repeated at least every 3 years and should increase in frequency if test results are abnormal, symptoms develop, or risk status increases. Individuals with prediabetes should be tested on an annual basis. Risk factors include a family history of diabetes, signs of insulin resistance or related conditions, hypertension, and dyslipidemia; for a complete list of risk factors by patient population, refer to the ADA’s Standards of Care in Diabetes.

Screening should also be considered in asymptomatic children or adolescents who are overweight (ie, ≥85th percentile) and have at least one additional risk factor. Testing should occur at least every 3 years beginning at 10 years of age or at pubertal onset (whichever comes first) and should occur more frequently if BMI or risk increases.

Screening for DM is recommended in all individuals planning to become pregnant who have associated risk factors. Pregnant individuals at high risk for diabetes should be tested before 15 weeks of gestation; A1c testing may be used for early screening in pregnant individuals but is not reliable at or after 15 weeks of gestation. In pregnant individuals 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. Individuals with GDM should be screened for diabetes or prediabetes at 4-12 weeks postpartum and then every 3 years thereafter.

Specific screening recommendations have been developed for patients with certain conditions (eg, cystic fibrosis or HIV) or those who have undergone organ transplantation. Refer to the ADA’s Standards of 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 tests are equally appropriate for screening and diagnosis; however, the ADA does note that these tests may not uniformly detect diabetes in the same individuals (as explained in following sections). The OGTT is required for screening and diagnosis of GDM.

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 result in more diabetes diagnoses than either the FPG or A1c tests. FPG testing may be preferred over other methods (eg, A1c) to screen for and diagnose diabetes in groups with certain conditions (eg, HIV). Refer to the ADA’s Standards of Care in Diabetes for condition-specific testing recommendations.

Oral Glucose Tolerance Test

The 2-hour plasma glucose (PG) OGTT, often referred to as the “one-step approach,” is used to assess 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. Testing should occur in the morning after an overnight fast or after a fast of at least 8 hours.

The more rigorous “two-step approach” involves administering 50 g of an oral glucose solution followed by measurement of venous glucose after 1 hour. Individuals 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.

The 2-hour PG OGTT is widely accepted and preferred to screen for GDM. Testing for GDM should be performed at 24-28 weeks of gestation in individuals not previously diagnosed with diabetes. Because GDM may represent preexisting undiagnosed T2DM or T1DM, patients with GDM should be tested 4-12 weeks postpartum with a 2-hour PG OGTT. In addition to screening for GDM, OGTT is preferred to screen for diabetes in individuals with cystic fibrosis and patients who have undergone recent organ transplantation.

Because limiting carbohydrate intake can interfere with glucose levels during an OGTT, a diverse diet containing a minimum of 150 g of carbohydrates should be consumed each day for 3 days before testing.

Hemoglobin A1c

A1c testing is primarily used to assess and monitor glycemic control, although it may also aid in the diagnosis of DM. According to ADA guidelines, if A1c is utilized for diagnostic purposes, testing should be performed in a laboratory setting on a U.S. Food and Drug Administration (FDA)-approved device. In contrast, AACE guidelines recommend the use of A1c testing for screening purposes only.

A1c test results reflect the average glycemia (glucose concentration) over approximately 3 months. Because A1c testing has better preanalytic stability and does not require fasting, it may be preferred in certain circumstances; however, it has a lower sensitivity at the designated cut point and a higher cost. Additionally, the correlation between the A1c concentration and the average glucose concentration is imperfect in some individuals.

In individuals with hemoglobin variants, A1c assays without interference from those variants should be used to avoid skewed results. For those with conditions that cause an altered relationship between A1c and glycemia due to increased red blood cell (RBC) 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 T2DM in pediatric patients.

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 T1DM when a patient presents with classic symptoms of hyperglycemia or is experiencing a hyperglycemic crisis.

Diagnostic Criteria

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

Diabetes Diagnostic Criteria
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), plus classic symptoms of hyperglycemia or hyperglycemic crisis
Sources: Blonde, 2022; ADA, 2024

GDM Diagnostic Criteria^a
	One-Step OGTT (mg/dL)	Two-Step OGTT (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)
^aOne-step and two-step criteria are suitable for use only in the mid to late stages of pregnancy. Standard diagnostic criteria apply in early stages of pregnancy. CC, Carpenter-Coustan; n/a, not applicable; NDDG, National Diabetes Data Group Sources: Blonde, 2022; ADA, 2024; ACOG, 2018

Secondary Testing

Diabetes-Related Autoantibodies

Although differentiation between T1DM and T2DM is often made using patient factors (eg, age and weight), the classic distinctions may not always be appropriate, given that some cases have overlapping features. Diabetes-related autoantibody testing can be helpful to establish an autoimmune etiology in individuals with previously diagnosed T1DM or to exclude a diagnosis of T1DM in adults who lack traditional risk factors for T2DM and/or are younger in 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. When evaluating for an autoimmune etiology, tests for at least two autoantibodies 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 autoantibody testing 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 having monogenic diabetes syndromes, which include neonatal diabetes (ND) and maturity-onset diabetes of the young (MODY), in order to verify genetic etiology, establish treatment, and identify affected family members. For additional information on the clinical characteristics of monogenic diabetes, refer to the ADA’s Standards of Care in Diabetes.

Monitoring

Routine Glycemic Control

A1c concentration has a 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 hemoglobin variants or conditions that affect RBCs. The ADA and the AACE recommend that an A1c test be performed at initial assessment and approximately every 3 months until glycemic targets are met and maintained. At that point, A1c (or another appropriate glycemic measure) should be evaluated 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. Refer to the ADA’s Standards of Care in Diabetes for a full listing of glycemic targets for all individuals.

Although A1c testing is the primary assessment tool for glycemic control, self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) is recommended in certain patients (eg, children, adolescents, and older adults with T1DM) to help with self-management and medication adjustments, especially for hypoglycemia prevention. Fructosamine and 1,5-anhydroglucitol tests can be considered for glycemic control monitoring, but the prognostic value of those tests is not as clear as that of A1c.

A1c testing is not recommended during the postpartum period because increased RBC turnover related to pregnancy and/or blood loss at delivery can affect A1c results and because the OGTT is more sensitive at detecting glucose intolerance. If test results are normal, patients should continue to be monitored for the development of diabetes at least every 3 years thereafter; more frequent testing should be considered based on risk. This ongoing evaluation can be performed with any recommended glycemic test.

Long-Term Complications

Individuals with DM usually have other cardiovascular disease risk factors and should be treated and monitored for dyslipidemia. For information on monitoring for dyslipidemia, refer to the ARUP Consult 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.
Screen 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.