Type 1 Diabetes Mellitus Workup

Updated: Jul 03, 2023
  • Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
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Laboratory Studies

Plasma glucose

Patients with type 1 diabetes mellitus (DM) typically present with symptoms of uncontrolled hyperglycemia (eg, polyuria, polydipsia, polyphagia). In such cases, the diagnosis of DM can be confirmed with a random (nonfasting) plasma glucose concentration of 200 mg/dL or a fasting plasma glucose concentration of 126 mg/dL (6.99 mmol/L) or higher. [2, 100]

A fingerstick glucose test is appropriate in the emergency department (ED) for virtually all patients with diabetes. All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis. All other laboratory studies should be selected or omitted on the basis of the individual clinical situation. Intravenous (IV) glucose testing may be considered for possible early detection of subclinical diabetes.

Individually measured glucose levels may differ considerably from estimated glucose averages calculated from measured hemoglobin A1c (HbA1c) levels. [102] Therefore, caution is urged when the decision is made to estimate rather than actually measure glucose concentration; the difference between the 2 has a potential impact on decision making.

Hemoglobin A

HbA1c is the stable product of nonenzymatic irreversible glycation of the beta chain of hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma glucose levels. HbA1c levels provide an estimate of plasma glucose levels during the preceding 1-3 months. The reference range for nondiabetic people is 6% in most laboratories. Glycated hemoglobin levels also predict the progression of diabetic microvascular complications.

American Diabetes Association (ADA) guidelines recommend measuring HbA1c at least every 6 months in patients with diabetes who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA1c testing every 3 months. [5]

In the past, HbA1c measurements were not considered useful for the diagnosis of DM. Drawbacks included a lack of international standardization and insensitivity for the detection of milder forms of glucose intolerance.

In a 2009 report, however, an international expert committee appointed by the ADA, the European Association for the Study of Diabetes (EASD), and the International Diabetes Association recommended the HbA1c assay for diagnosing type 1 and type 2 DM. [3] In the case of type 1 DM, however, the committee recommended using the test only when the condition is suspected but the classic symptoms of type 1 DM—polyuria, polydipsia, polyphagia, a random glucose level of 200 mg/dL, and unexplained weight loss—are absent.

The committee noted the improvement in standardization and cited the following advantages of HbA1c testing over glucose measurement:

  • Ability to capture long-term glucose exposure

  • Less biologic variability

  • No requirement for fasting or timed samples

  • Current use in guiding management decisions

Consequently, since 2010 the ADA has included an HbA1c level of 6.5% or higher as a criterion for diabetes diagnosis, with confirmation from repeat testing (unless clinical symptoms are present and the glucose level exceeds 200 mg/dL). HbA1c testing cannot be used in patients with abnormal red blood cell (RBC) turnover (as in hemolytic or iron-deficiency anemia). In children with rapidly evolving type 1 DM, HbA1c may not be significantly elevated despite frank diabetes. [2]

One study found seasonal variability in HbA1c levels of school-age children with higher levels (0.44%) coinciding with colder outdoor temperatures, fewer hours of sunlight, and lower levels of solar irradiance. [103] This effect was seen in school-aged children but not preschoolers and may hold importance for studies using HbA1c as a primary endpoint and HbA1c -based diagnosis of diabetes.

HbA1c cannot be used as an indicator of glycemic control in patients with neonatal diabetes mellitus (NDM) because of the high levels of fetal hemoglobin (HbF) remaining in the blood. A study by Suzuki et al found that glycated albumin, which is not affected by HbF levels, more strongly correlated with 1-month average postprandial blood glucose and was therefore a better marker of diabetes in neonates. This finding is important to neonatologist and those caring for newborns. [104]

Moreover, the overall efficacy of HbA1c testing in diabetes diagnosis remains uncertain. A study presented in 2019, using data derived from 9000 adults, reported diabetes diagnosis with the HbA1c blood test to be unreliable. The investigators found evidence that in comparison with the oral glucose tolerance test, HbA1c testing would lead to a 42% overdiagnosis of glucose tolerance and a 73% underdiagnosis of diabetes, in adults. [105]

ADA guidelines recommend measuring HbA1c at least every 6 months year in patients who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA1c testing every 3 months. [5]

Other laboratory studies

Fructosamine levels also test for glucose levels. Fructosamine is formed by a chemical reaction of glucose with plasma protein and reflects glucose control in the previous 1-3 weeks. This assay, therefore, may show a change in control before HbA1c and often is helpful when applying intensive treatment and in short-term clinical trials.

A white blood cell (WBC) count and blood and urine cultures may be performed to rule out infection.

Urine ketones are not reliable for diagnosing or monitoring diabetic ketoacidosis (DKA), although they may be useful in screening to see whether a hyperglycemic individual may have some degree of ketonemia. The plasma acetone level—specifically, the beta-hydroxybutyrate level—is a more reliable indicator of DKA, along with measurement of plasma bicarbonate or arterial pH as clinically required. (See the Medscape Reference Laboratory Medicine article Ketones.)

Screening for type 1 DM in asymptomatic low-risk individuals is not recommended. [2] However, in patients at high risk (eg, those who have first-degree relatives with type 1 DM), it may be appropriate to perform annual screening for anti-islet antibodies before the age 10 years, along with 1 additional screening during adolescence. [4]


Tests to Differentiate Type 1 from Type 2 Diabetes

Although the oral glucose tolerance test with insulin levels is usually considered unnecessary for diagnosing type 1 DM, the dramatic increase of type 2 DM in the young suggests that assessment of insulin secretion may become more important. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines note that to help distinguish between the 2 types in children, physicians should measure insulin and C-peptide levels and immune markers (eg, glutamic acid decarboxylase [GAD] autoantibodies), as well as obtain a detailed family history. [100]

C-peptide is formed during conversion of proinsulin to insulin. An insulin or C-peptide level below 5 µU/mL (0.6 ng/mL) suggests type 1 DM; a fasting C-peptide level greater than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 (ie, residual beta-cell function). An exception is the individual with type 2 DM who presents with a very high glucose level (eg, >300 mg/dL) and a temporarily low insulin or C-peptide level but who will recover insulin production once normal glucose is restored.

Most patients who present with undiagnosed type 1 DM have the classic symptoms of uncontrolled hyperglycemia, including polyuria, polydipsia, nocturia, fatigue, and weight loss. In these patients, a confirmatory random plasma glucose level of greater than 200 mg/dL is adequate to establish the diagnosis of DM. On occasion, a patient who is ultimately found to have type 1 DM presents with subtle symptoms because of residual insulin secretion.

Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1 but not type 2 DM. Measurements of IA2 autoantibodies within 6 months of diagnosis can help differentiate between type 1 and type 2 DM. These titers decrease after 6 months. Anti-GAD65 antibodies can be present at diagnosis of type 1 DM and are persistently positive over time. (See also Type 2 Diabetes Mellitus.)

Testing for islet autoantibodies can substitute for expensive genetic testing in those patients suspected of having maturity-onset diabetes of the young (MODY). The prevalence of these antibodies is the same in patients with MODY as in the healthy population. A positive test for positive islet autoantibodies makes MODY highly unlikely. [106]

ADA/EASD consensus statement

A consensus statement published in 2021 by the ADA and the EASD provided an algorithm meant to aid in avoiding the misdiagnosis of adult-onset type 1 DM. In the algorithm, which was devised using data from White European populations, an islet autoantibody test is first carried out; if positive, type 1 diabetes is diagnosed. A negative test in a patient younger than 35 years and with no signs of type 2 diabetes means that C-peptide testing is advised. A C-peptide level below 200 pmol/L points to a diagnosis of type 1 diabetes, while a level above 200 pmol/L indicates that genetic testing for monogenic diabetes should be carried out. If signs of type 2 diabetes exist and/or the patient is over age 35 years, the individual most likely has type 2 diabetes. [107, 108, 109, 110]