Diabetes Diagnosis

Type 2 diabetes involves progressive loss of insulin secretion from pancreatic beta cells in the setting of insulin resistance. Type 2 diabetes affects up to 14% of the global population and is associated with preventable long-term complications such as cardiovascular disease, kidney failure, vision loss, and increased mortality. Diabetes becomes clinically evident when elevated blood glucose levels cause glycosuria with resultant polyuria, polydipsia, fatigue, blurry vision, and unintentional weight loss. 

The American Diabetes Association (ADA) published new Standards of Medical Care in Diabetes in 2011 (Diabetes Care 2011;34: Supplement 1, S11). Historically, the diagnosis of diabetes was based on fasting plasma glucose and 2 hour plasma glucose level after a 75 gram oral glucose tolerance test (OGTT). Despite being the gold standard, measurement of blood glucose is less accurate and precise than most physicians realize. Blood glucose measurements are also subject to several limitations including:

• 8-12 hour fasting specimen requirement
• Diurnal variation requiring morning collection to capture peak levels
• Large biological variation of 5-8%
• Nonstandardized instrument methods with >12% bias 
• Glycolysis after collection, even in sodium fluoride tubes

In 2009, an International Expert Committee recommended the use of the HbA1c test to diagnose diabetes, with a threshold of 6.5% or greater (Diabetes Care 2009, 32 (7):1327-1334). The American Diabetes Association adopted this criterion in 2010. The diagnostic cutoff point of 6.5% was recommended based on the risk for developing microvascular complications such as retinopathy. This HbA1c criterion identifies one third fewer cases of undiagnosed diabetes than a fasting glucose cut point of 126 mg/dL or greater. However, the advantages of using HbA1c outweigh this limitation. 

• Better index of overall glycemic exposure & risk of complications 
• Low intra-individual variability (<2%) 
• No requirement for fasting or timed specimen
• Standardized methods with precision <2%
• Less affected by acute illness or stress
• Good stability after blood collection
• Single test can be used for both diagnosis and monitoring

Today, the cutoff points recommended by the ADA and WHO for diagnosis of diabetes in non-pregnant adults are:

• HbA1c greater than or equal to 6.5%
• Fasting plasma glucose greater than or equal to 126 mg/dL. Fasting is defined as no caloric intake for at least 8 hours.
• Two hour plasma glucose greater than or equal to 200 mg/dL during a 75 gram oral glucose tolerance test 
• Random plasma glucose greater than or equal to 200 mg/dL in an individual with symptoms of diabetes such as polyuria, polydipsia, and unexplained weight loss;  

The diagnosis of diabetes requires two test results above the diagnostic threshold obtained at the same time or at two different times. The latter scenario can include either a repeat of the initial test or a different test.  

There is less than 100% concordance between fasting plasma glucose, two hour plasma glucose and HbA1c. The HbA1c cut point of ≥6.5% identifies one third fewer cases of undiagnosed diabetes than a fasting glucose cut point of ≥126 mg/dL. If two different tests are run on an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated and the diagnosis made on the basis of the confirmed test.

The diagnosis of adult onset type 1 diabetes may be misdiagnosed as type 2 diabetes. Adults with type 1 diabetes often have age less than 35 years, body mass index of less than 25, and a strong family history of diabetes. This population should be tested for islet cell autoantibodies. 

In 2014, The U.S. Preventive Services Task Force (USPSTF) issued a draft recommendation​ that expanded screening for type 2 diabetes in adults who are considered to be at risk for diabetes. The Endocrine Society endorsed the USPSTF recommendation. These organizations recommended that testing for diabetes be considered in all adults age 45 and older. If results are normal, testing should be repeated at three year intervals. Physicians should consider testing people at a younger age who are at risk of diabetes, including those who:

• are overweight or obese (BMI≥25 kg/m²)
• have a first degree relative with diabetes
• are a member of a high risk ethnic group
• have a history of gestational diabetes or delivered a baby weighing >9 lb.
• have hypertension (>=140/90)
• have HDL cholesterol </=35 mg/dL and/or triglyceride level >/=250 mg/dL
• have polycystic ovarian disease
• have other conditions associated with insulin resistance such as acanthosis nigricans
• have a history of cardiovascular disease
• have a history of HbA1c ≥5.7%, impaired fasting glucose or impaired glucose tolerance

These recommendations took into account recent scientific evidence that showed measuring blood glucose in adults at increased risk for diabetes and treating those who have IFG or IGT with intensive lifestyle interventions has a moderate benefit in decreasing the risk for progression to diabetes. USPSTF found adequate evidence that intensive lifestyle modifications result in a lower incidence of diabetes, cardiovascular mortality and all-cause mortality. The level of evidence for screening was rated B, which  qualifies it to become covered preventive service without cost-sharing under the Affordable Care Act.

The Expert Committee on Diagnosis and Classification of Diabetes Mellitus also recognized an intermediate group of individuals whose glucose or HbA1c levels are higher than normal but do not meet the diagnostic criteria for diabetes. People with fasting glucose levels between 100-125 mg/dL were defined as having impaired fasting glucose (IFG). Individuals who have a 2 hour glucose level between140-199 mg/dL were defined as having impaired glucose tolerance (IGT). Individuals with any of these intermediate laboratory values were referred to as having prediabetes. Patients with HbA1c of 5.7 to 6.4% were also included in this category. People with prediabetes are at higher risk of developing diabetes and cardiovascular disease. These patients often have abdominal obesity, dyslipidemia with low HDL cholesterol and high triglycerides and hypertension. 

HbA1c <5.7% is considered normal while a result >6.5% on two separate tests suggests diabetes. An result between 5.7 and 6.4% may mean impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). 

Random plasma glucose <140 mg/dL is considered normal while a result >200 mg/dL indicate diabetes. A random value between 140 and 199 mg/dL suggests IFG or IGT. 

Fasting plasma glucose level <100 mg/dL is considered normal while a value >126 mg/dL can mean diabetes. A fasting glucose level between 100 and 125 mg/dL can mean IFG or IGTl. 

An oral glucose tolerance test result <140 mg/dL is considered normal while a result >200 mg/dL can mean diabetes. An OGTT result between 140 and 199 mg/dL is suggestive of IFG or IGT.

Specimen requirement is one lavender top (EDTA) tube of blood for HbA1c and one grey top tube of blood for glucose. 

References

The International Expert Committee; International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care 1 July 2009; 32 (7): 1327–1334.

American Diabetes Association; Standards of Medical Care in Diabetes—2011. Diabetes Care 1 January 2011; 34 (Supplement_1): S11–S61.

Kalyani R et al. Diagnosis and Treatment of Type 2 Diabetes in Adults: A Review, JAMA, published online June 23, 2025, doi:10.1001/jama.2025.5956