Diabetes mellitus represents a cluster of metabolic disorders distinguished by hyperglycemia. This condition arises from impairments in insulin secretion, insulin action, or a combination of both. Persistent hyperglycemia in diabetes is linked to long-term damage, dysfunction, and eventual failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels. Understanding the diagnosis and classification of diabetes mellitus, as outlined in Diabetes Care 2013 and subsequent guidelines, is crucial for effective management and care.
The development of diabetes involves several pathogenic processes. These range from autoimmune destruction of the pancreatic β-cells, leading to insulin deficiency, to abnormalities causing resistance to insulin’s action. At the core of the metabolic disruptions in carbohydrate, fat, and protein metabolism in diabetes is the insufficient action of insulin on target tissues. This deficient insulin action results either from inadequate insulin secretion or reduced tissue responsiveness to insulin at different points in the complex hormone action pathways. Often, both impaired insulin secretion and defects in insulin action coexist in a patient, making it challenging to determine the primary cause of hyperglycemia.
Symptoms of significant hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes increased appetite (polyphagia), and blurred vision. Chronic hyperglycemia may also lead to growth impairment and increased susceptibility to certain infections. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.
Long-term complications of diabetes are extensive and serious. They include retinopathy, potentially causing vision loss; nephropathy, which can lead to kidney failure; peripheral neuropathy, increasing the risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy, causing gastrointestinal, genitourinary, and cardiovascular symptoms, as well as sexual dysfunction. Individuals with diabetes also have a higher risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipid metabolism abnormalities are frequently observed in diabetic populations.
Most diabetes cases fall into two main etiopathogenetic categories, further detailed below. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion. Individuals at higher risk for type 1 diabetes can often be identified through serological evidence of autoimmune processes in the pancreatic islets and by genetic markers. In contrast, type 2 diabetes, the more prevalent form, results from a combination of resistance to insulin action and an insufficient compensatory insulin secretory response. In type 2 diabetes, hyperglycemia may be present for a considerable period before diagnosis, sufficient to cause pathological changes in target tissues but without overt clinical symptoms. During this asymptomatic phase, abnormalities in carbohydrate metabolism can be detected by measuring plasma glucose levels in a fasting state or after an oral glucose load.
The degree of hyperglycemia can fluctuate over time, influenced by the progression of the underlying disease and treatment interventions, as illustrated in Figure 1. A disease process might be present but not advanced enough to cause hyperglycemia initially. The same process can lead to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without meeting full diagnostic criteria for diabetes. Some individuals with diabetes can achieve adequate glycemic control through lifestyle modifications like weight reduction and exercise, or with oral glucose-lowering agents, thus not requiring insulin. Others may have some residual insulin secretion but need exogenous insulin for proper glycemic management, while some with extensive β-cell destruction and no residual insulin secretion are insulin-dependent for survival. The severity of metabolic abnormality can progress, regress, or remain stable, meaning hyperglycemia levels reflect the underlying metabolic process and its management more than the nature of the process itself.
Figure 1: Disorders of glycemia: etiologic types and stages. Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); *in rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival.
Classification of Diabetes Mellitus and Other Categories of Glucose Regulation
Determining the specific type of diabetes in an individual often depends on the circumstances at diagnosis, and many cases do not fit neatly into a single category. For instance, gestational diabetes mellitus (GDM) may resolve after delivery, but some women may remain hyperglycemic and be diagnosed with type 2 diabetes later. Similarly, diabetes induced by high doses of exogenous steroids might resolve upon discontinuation, only to reappear years later following pancreatitis episodes. Another example is thiazide-induced diabetes, which is often type 2 diabetes exacerbated by the drug rather than directly caused by it. Therefore, for clinicians and patients, understanding the pathogenesis of hyperglycemia and treating it effectively is more critical than simply labeling the diabetes type.
Type 1 Diabetes (β-cell Destruction, Usually Leading to Absolute Insulin Deficiency)
Type 1 diabetes is characterized by the destruction of pancreatic beta cells, leading to an absolute deficiency of insulin. This category is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
Immune-mediated diabetes, accounting for 5–10% of diabetes cases, was previously known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes. It results from autoimmune destruction of the pancreatic β-cells. Markers of this immune destruction include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to GAD (GAD65), and autoantibodies to tyrosine phosphatases IA-2 and IA-2β. One or more of these autoantibodies are present in 85–90% of individuals at the initial detection of fasting hyperglycemia. The disease also shows strong associations with HLA genes, particularly DQA and DQB, and is influenced by DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective.
The rate of β-cell destruction in immune-mediated diabetes varies significantly. It can be rapid, especially in infants and children, or slow, mainly in adults. Some patients, particularly children and adolescents, may present with ketoacidosis as the first sign. Others may have mild fasting hyperglycemia that can quickly escalate to severe hyperglycemia and/or ketoacidosis during infections or stress. Adults may retain enough residual β-cell function to prevent ketoacidosis for years, but eventually become insulin-dependent and at risk for ketoacidosis. In the later stages, insulin secretion is minimal or absent, indicated by low or undetectable plasma C-peptide levels. Immune-mediated diabetes is most common in childhood and adolescence but can occur at any age.
The autoimmune destruction of β-cells involves multiple genetic predispositions and environmental factors that are still not fully understood. While patients are usually not obese at diagnosis, obesity is not incompatible with this diagnosis. These patients are also more susceptible to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
Idiopathic Diabetes
Idiopathic diabetes represents forms of type 1 diabetes with no known cause. These patients experience permanent insulinopenia and are prone to ketoacidosis, but lack evidence of autoimmunity. Though a minority of type 1 diabetes cases are idiopathic, they are more common in individuals of African or Asian descent. This form is characterized by episodic ketoacidosis and varying degrees of insulin deficiency between episodes. It is strongly inherited, lacks immunological markers of β-cell autoimmunity, and is not HLA associated. The need for insulin replacement therapy in these patients may be intermittent.
Type 2 Diabetes (Ranging from Predominantly Insulin Resistance with Relative Insulin Deficiency to Predominantly an Insulin Secretory Defect with Insulin Resistance)
Type 2 diabetes, accounting for approximately 90–95% of all diabetes cases, was previously known as non–insulin-dependent diabetes or adult-onset diabetes. It encompasses individuals with insulin resistance and relative insulin deficiency. Initially, and often throughout life, these individuals do not require insulin for survival. The exact causes of type 2 diabetes are diverse and not fully understood, but it is not caused by autoimmune β-cell destruction or the other specific causes listed for other diabetes types.
Obesity is a major risk factor for type 2 diabetes, contributing to insulin resistance. Even non-obese individuals may have increased abdominal fat, which also promotes insulin resistance. Ketoacidosis is rare in type 2 diabetes, typically occurring only under severe stress, such as infection. Type 2 diabetes often remains undiagnosed for years due to the gradual development of hyperglycemia and initially mild or absent symptoms. However, these patients are still at increased risk of macrovascular and microvascular complications. While insulin levels may appear normal or elevated, they are insufficient to compensate for insulin resistance, as blood glucose levels would be expected to result in even higher insulin levels in healthy individuals. Insulin secretion is thus defective. Insulin resistance can improve with weight loss and medication, but rarely returns to normal. Risk factors for type 2 diabetes include age, obesity, physical inactivity, prior GDM, hypertension, dyslipidemia, and certain racial/ethnic backgrounds. It has a strong genetic component, more so than autoimmune type 1 diabetes, although the genetics are complex and not fully defined.
Other Specific Types of Diabetes
Beyond type 1 and type 2, there are other specific types of diabetes resulting from genetic defects, diseases of the exocrine pancreas, endocrinopathies, drug or chemical induction, infections, uncommon immune-mediated forms, and genetic syndromes.
Genetic Defects of the β-Cell
Several monogenetic defects in β-cell function can cause diabetes, often manifesting as hyperglycemia at a young age (typically before 25 years). These are known as maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion with minimal insulin resistance. MODY is inherited in an autosomal dominant pattern. Mutations at six genetic loci on different chromosomes have been identified. The most common form is linked to mutations in the hepatocyte nuclear factor (HNF)-1α gene on chromosome 12. Another form involves mutations in the glucokinase gene on chromosome 7p, leading to defective glucokinase, which is crucial for glucose sensing by β-cells. Less common forms are due to mutations in other transcription factors like HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1.
Mitochondrial DNA point mutations are also associated with diabetes and deafness, particularly at position 3,243 in the tRNA leucine gene. This mutation is also seen in MELAS syndrome, but diabetes is not a typical feature of MELAS, suggesting variable phenotypic expression.
Rare genetic abnormalities affecting proinsulin conversion to insulin or resulting in mutant insulin molecules with impaired receptor binding have been identified in a few families, causing mild glucose intolerance.
Genetic Defects in Insulin Action
Unusual forms of diabetes can arise from genetically determined abnormalities in insulin action. Mutations in the insulin receptor gene can cause a spectrum of metabolic abnormalities, from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some individuals may present with acanthosis nigricans. Women may experience virilization and polycystic ovaries. These conditions were historically termed type A insulin resistance. Leprechaunism and Rabson-Mendenhall syndrome are pediatric syndromes involving insulin receptor gene mutations, leading to extreme insulin resistance. Leprechaunism is typically fatal in infancy and has distinctive facial features, while Rabson-Mendenhall syndrome is associated with dental and nail abnormalities and pineal gland hyperplasia.
In insulin-resistant lipoatrophic diabetes, insulin receptor structure and function are normal, suggesting defects in postreceptor signal transduction pathways.
Diseases of the Exocrine Pancreas
Any disease that extensively damages the pancreas can lead to diabetes. Acquired conditions include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma. Except for cancer-related diabetes, significant pancreatic damage is usually required. Pancreatic cancers, even when small, can cause diabetes, suggesting mechanisms beyond simple β-cell mass reduction. Cystic fibrosis and hemochromatosis, if extensive, can also impair insulin secretion. Fibrocalculous pancreatopathy may present with abdominal pain and pancreatic calcifications.
Endocrinopathies
Excess of hormones like growth hormone, cortisol, glucagon, and epinephrine, which antagonize insulin action, can cause diabetes (e.g., acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma). This usually occurs in individuals with pre-existing insulin secretion defects, and hyperglycemia often resolves when hormone levels normalize. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion, generally resolving after tumor removal.
Drug- or Chemical-Induced Diabetes
Many drugs can impair insulin secretion and may precipitate diabetes in susceptible individuals with insulin resistance. Toxins like Vacor and intravenous pentamidine can permanently destroy pancreatic β-cells. Drugs such as nicotinic acid and glucocorticoids can impair insulin action. α-interferon has been reported to induce diabetes with islet cell antibodies and severe insulin deficiency. Table 1 lists commonly recognized drug-, hormone-, or toxin-induced forms of diabetes.
Table 1. Etiologic classification of diabetes mellitus
| 1. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) | 1. Immune mediated | 2. Idiopathic |
|---|---|---|
| 2. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) | ||
| 3. Other specific types | 1. Genetic defects of β-cell function | 1. Chromosome 12, HNF-1α (MODY3) |
| 2. Chromosome 7, glucokinase (MODY2) | ||
| 3. Chromosome 20, HNF-4α (MODY1) | ||
| 4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) | ||
| 5. Chromosome 17, HNF-1β (MODY5) | ||
| 6. Chromosome 2, NeuroD1 (MODY6) | ||
| 7. Mitochondrial DNA | ||
| 8. Others | ||
| 2. Genetic defects in insulin action | 1. Type A insulin resistance | |
| 2. Leprechaunism | ||
| 3. Rabson-Mendenhall syndrome | ||
| 4. Lipoatrophic diabetes | ||
| 5. Others | ||
| 3. Diseases of the exocrine pancreas | 1. Pancreatitis | |
| 2. Trauma/pancreatectomy | ||
| 3. Neoplasia | ||
| 4. Cystic fibrosis | ||
| 5. Hemochromatosis | ||
| 6. Fibrocalculous pancreatopathy | ||
| 7. Others | ||
| 4. Endocrinopathies | 1. Acromegaly | |
| 2. Cushing’s syndrome | ||
| 3. Glucagonoma | ||
| 4. Pheochromocytoma | ||
| 5. Hyperthyroidism | ||
| 6. Somatostatinoma | ||
| 7. Aldosteronoma | ||
| 8. Others | ||
| 5. Drug or chemical induced | 1. Vacor | |
| 2. Pentamidine | ||
| 3. Nicotinic acid | ||
| 4. Glucocorticoids | ||
| 5. Thyroid hormone | ||
| 6. Diazoxide | ||
| 7. β-adrenergic agonists | ||
| 8. Thiazides | ||
| 9. Dilantin | ||
| 10. γ-Interferon | ||
| 11. Others | ||
| 6. Infections | 1. Congenital rubella | |
| 2. Cytomegalovirus | ||
| 3. Others | ||
| 7. Uncommon forms of immune-mediated diabetes | 1. “Stiff-man” syndrome | |
| 2. Anti-insulin receptor antibodies | ||
| 3. Others | ||
| 8. Other genetic syndromes sometimes associated with diabetes | 1. Down syndrome | |
| 2. Klinefelter syndrome | ||
| 3. Turner syndrome | ||
| 4. Wolfram syndrome | ||
| 5. Friedreich ataxia | ||
| 6. Huntington chorea | ||
| 7. Laurence-Moon-Biedl syndrome | ||
| 8. Myotonic dystrophy | ||
| 9. Porphyria | ||
| 10. Prader-Willi syndrome | ||
| 11. Others | ||
| 4. Gestational diabetes mellitus |
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Table 1: Etiologic classification of diabetes mellitus
Insulin use does not classify the type of diabetes, as patients with any form may require insulin at some point.
Infections
Certain viruses are linked to β-cell destruction. Congenital rubella is associated with diabetes, often showing HLA and immune markers typical of type 1 diabetes. Coxsackievirus B, cytomegalovirus, adenovirus, and mumps have also been implicated in some cases.
Uncommon Forms of Immune-Mediated Diabetes
Two known conditions fall into this category, with others likely to exist. Stiff-man syndrome, an autoimmune CNS disorder causing muscle stiffness and spasms, is associated with high titers of GAD autoantibodies, and about a third of patients develop diabetes. Anti-insulin receptor antibodies can cause diabetes by blocking insulin binding to its receptor. Paradoxically, in some cases, these antibodies can act as insulin agonists, causing hypoglycemia. These antibodies are sometimes found in systemic lupus erythematosus and other autoimmune diseases and are associated with acanthosis nigricans, previously termed type B insulin resistance.
Other Genetic Syndromes Sometimes Associated with Diabetes
Several genetic syndromes increase diabetes risk, including Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome, an autosomal recessive disorder, is characterized by insulin-deficient diabetes and β-cell absence at autopsy, along with diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Table 1 lists additional syndromes.
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first recognized during pregnancy. While most cases resolve after delivery, the definition applies regardless of persistence post-pregnancy and includes cases where glucose intolerance may have pre-existed or started with the pregnancy. This definition facilitates consistent GDM detection and classification, although its limitations have long been recognized. The increasing prevalence of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, increasing the number of pregnant women with undiagnosed type 2 diabetes.
In 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), including the American Diabetes Association (ADA), recommended diagnosing overt diabetes, not gestational diabetes, in high-risk women found to have diabetes at their initial prenatal visit using standard criteria (Table 3). Approximately 7% of pregnancies are complicated by GDM.
Table 3. Criteria for the diagnosis of diabetes
| 1. A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* |
|---|
| OR |
| 2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* |
| OR |
| 3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* |
| OR |
| 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l). |
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Table 3: Criteria for the diagnosis of diabetes. In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.*
Categories of Increased Risk for Diabetes
The Expert Committee on Diagnosis and Classification of Diabetes Mellitus in 1997 and 2003 recognized an intermediate group with glucose levels higher than normal but not meeting diabetes criteria. These individuals were defined as having impaired fasting glucose (IFG) [fasting plasma glucose (FPG) 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)], or impaired glucose tolerance (IGT) [2-h values in the oral glucose tolerance test (OGTT) 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)].
Individuals with IFG and/or IGT are considered to have pre-diabetes, indicating a higher risk of developing diabetes. IFG and IGT are not clinical entities themselves but rather risk factors for diabetes and cardiovascular disease, and can be intermediate stages in any of the disease processes listed in Table 1. They are associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes in people with IGT, although their impact on mortality or cardiovascular disease incidence is not yet fully demonstrated. The ADA Expert Committee in 2003 lowered the IFG cut point from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l) to align IFG prevalence with IGT, though the WHO and other organizations did not adopt this change.
As A1C becomes more common for diabetes diagnosis, it also identifies those at higher risk. The International Expert Committee in 2009 noted a continuum of diabetes risk with glycemic measures but did not formally define an intermediate A1C category. However, they noted increased risk for A1C levels above the lab “normal” range but below the diabetes cut point (6.0 to 6.5%). Data suggest an A1C value between 5.5 and 6.0% best identifies people with IFG or IGT. The Diabetes Prevention Program (DPP) showed preventive interventions are effective in people with A1C levels both below and above 5.9%. Therefore, an A1C level above 5.5–6% is likely appropriate for initiating preventive interventions.
Defining a lower limit for intermediate A1C is somewhat arbitrary as diabetes risk is a continuum. The A1C cut point should balance the costs of false negatives and false positives in preventive interventions. Compared to the fasting glucose cutpoint of 100 mg/dl (5.6 mmol/l), an A1C cutpoint of 5.7% is less sensitive but more specific and has a higher positive predictive value for future diabetes risk. Studies indicate a 5.7% cutpoint has reasonable sensitivity and high specificity for identifying 6-year diabetes incidence and is associated with similar diabetes risk as high-risk DPP participants. Thus, an A1C range of 5.7 to 6.4% can identify individuals at high risk for future diabetes, termed pre-diabetes.
Individuals with A1C of 5.7–6.4% should be informed of their increased diabetes and cardiovascular disease risk and advised on lifestyle strategies like weight loss and physical activity. As A1C rises, diabetes risk increases disproportionately, making interventions and follow-up particularly important for those with A1C above 6.0%. However, even individuals with A1C below 5.7% may still be at risk depending on their A1C level and other risk factors.
Table 2 summarizes categories of increased risk for diabetes. Risk evaluation should include a global risk factor assessment for both diabetes and cardiovascular disease, considering comorbidities, life expectancy, and patient capacity for lifestyle change.
Table 2. Categories of increased risk for diabetes*
| FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) [IFG] |
|---|
| 2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT] |
| A1C 5.7–6.4% |
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Table 2: Categories of increased risk for diabetes. For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.*
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has historically relied on glucose criteria, FPG or 75-g OGTT. In 1997, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus revised these criteria, using the correlation between FPG levels and retinopathy prevalence to define threshold glucose levels. Studies demonstrated glycemic levels below which retinopathy was rare and above which it increased linearly. The glycemic levels at which retinopathy began to increase were consistent across different measures (FPG, 2-h PG, and A1C) and populations. This led to a new diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed the established 2-h PG value of ≥200 mg/dl (11.1 mmol/l).
A1C, reflecting average blood glucose over 2-3 months, is a key marker of chronic glycemia. It is crucial in diabetes management due to its correlation with microvascular and macrovascular complications and is a standard biomarker for glycemic control. Earlier Expert Committees did not recommend A1C for diagnosis due to assay standardization issues. However, A1C assays are now highly standardized. In 2009, an International Expert Committee recommended A1C for diabetes diagnosis with a threshold of ≥6.5%, a decision affirmed by the ADA. This A1C cut point aligns with the retinopathy prevalence inflection point, similar to FPG and 2-h PG thresholds. Diagnostic A1C tests should be NGSP certified and standardized to the Diabetes Control and Complications Trial reference assay. Point-of-care A1C assays are not yet accurate enough for diagnostic use.
Using A1C offers advantages over FPG, including convenience (no fasting), greater preanalytical stability, and less variability during stress or illness. However, A1C is more expensive, less available in developing regions, and may not perfectly correlate with average glucose in all individuals. A1C can also be misleading in patients with certain anemias and hemoglobinopathies. For hemoglobinopathies with normal red cell turnover, specific A1C assays without interference should be used. For conditions with abnormal red cell turnover, glucose criteria must be used exclusively.
The established glucose criteria (FPG and 2-h PG) remain valid. Additionally, patients with severe hyperglycemia, presenting with classic symptoms or hyperglycemic crisis, can be diagnosed with a random plasma glucose of ≥200 mg/dl (11.1 mmol/l). In such cases, A1C is often also measured and is usually above the diagnostic cut point. However, in rapid-onset diabetes, like type 1 in children, A1C may not be significantly elevated despite frank diabetes.
There is not full concordance between A1C and glucose-based tests. NHANES data indicate that an A1C cut point of ≥6.5% identifies fewer undiagnosed diabetes cases compared to an FPG cut point of ≥126 mg/dl (7.0 mmol/l). However, the greater convenience of A1C may lead to wider testing and potentially more diagnoses.
Further research is needed to understand discrepancies between different tests (A1C vs. FPG). Discordance may arise from measurement variability, time changes, or because each test measures different physiological processes. Elevated A1C with nondiabetic FPG might indicate higher postprandial glucose or increased glycation rates. High FPG with normal A1C might suggest augmented hepatic glucose production or reduced glycation rates.
As with most diagnostic tests, a diabetes diagnosis should be confirmed with repeat testing, unless clinically obvious (e.g., hyperglycemic crisis). Repeating the same test is preferable for confirmation. If two different tests are both above diagnostic thresholds, diabetes is confirmed.
In discordant results, the test above the diagnostic cut point should be repeated, and diagnosis is based on the confirmed test. If a repeated test falls below the diagnostic cut point, patients likely have borderline results. Close monitoring and repeat testing in 3–6 months may be appropriate.
The choice of diagnostic test should be at the health care professional’s discretion, considering test availability and practicality. The most crucial aspect is ensuring diabetes testing is performed when indicated, as evidence suggests many at-risk patients do not receive adequate testing or counseling. Table 3 summarizes current diagnostic criteria for diabetes.
Diagnosis of GDM
At the time of this publication, GDM diagnostic criteria are those of Carpenter and Coustan. The ADA’s Fourth International Workshop-Conference on Gestational Diabetes Mellitus supports using Carpenter/Coustan criteria or a diagnostic 75-g 2-h OGTT. These criteria are detailed below.
Testing for Gestational Diabetes
Previous guidelines recommended universal GDM screening. However, women meeting all of the following low-risk criteria do not need screening:
- Age <25 years
- Normal body weight
- No first-degree relative with diabetes
- No history of abnormal glucose metabolism
- No history of poor obstetric outcome
- Not from a high-risk ethnic/racial group (Hispanic American, Native American, Asian American, African American, Pacific Islander)
Risk assessment should occur at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should be tested immediately. If not diagnosed with GDM initially, they should be retested at 24–28 weeks of gestation. Average-risk women should be tested at 24–28 weeks.
An FPG >126 mg/dl (7.0 mmol/l) or random plasma glucose >200 mg/dl (11.1 mmol/l) meets diabetes diagnostic threshold and requires confirmation on a subsequent day, precluding further glucose challenge. In the absence of this hyperglycemia, GDM evaluation in average or high-risk women follows one of two approaches:
One-Step Approach
Perform a diagnostic OGTT without initial glucose screening. This may be cost-effective in high-risk populations.
Two-Step Approach
Initial screening with a 50-g oral glucose load (glucose challenge test [GCT]), measuring plasma glucose at 1 hour. A diagnostic OGTT is performed on women exceeding a glucose threshold on the GCT. A threshold of >140 mg/dl (7.8 mmol/l) identifies ~80% of GDM cases, increased to 90% with a cutoff of >130 mg/dl (7.2 mmol/l).
In either approach, GDM diagnosis is based on an OGTT. Criteria for the 100-g OGTT are from O’Sullivan and Mahan, modified by Carpenter and Coustan, shown in Table 4. Alternatively, a 75-g glucose load with corresponding threshold values (Table 4) can be used, though less validated than the 100-g OGTT.
Table 4. Diagnosis of GDM with a 100-g or 75-g glucose load
| mg/dl | mmol/l | |
|---|---|---|
| 100-g glucose load | ||
| Fasting | 95 | 5.3 |
| 1-h | 180 | 10.0 |
| 2-h | 155 | 8.6 |
| 3-h | 140 | 7.8 |
| 75-g glucose load | ||
| Fasting | 95 | 5.3 |
| 1-h | 180 | 10.0 |
| 2-h | 155 | 8.6 |
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Table 4: Diagnosis of GDM with a 100-g or 75-g glucose load. Two or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis. The test should be done in the morning after an overnight fast of between 8 and 14 h and after at least 3 days of unrestricted diet (≥150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated and should not smoke throughout the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a continuous increase in adverse pregnancy outcomes with maternal glycemia at 24–28 weeks, even within previously normal ranges. This has prompted reconsideration of GDM diagnostic criteria. The IADPSG recommended a 75-g OGTT at 24–28 weeks for all women without prior diabetes, and established diagnostic cut points for fasting, 1-h, and 2-h plasma glucose measurements based on odds ratios for adverse outcomes from the HAPO study.
At the time of this update, the ADA is considering adopting the IADPSG diagnostic criteria in collaboration with obstetrical organizations, acknowledging that while this will increase GDM prevalence, evidence suggests treating even mild GDM reduces morbidity for both mother and baby.
Acknowledgments
The American Diabetes Association expresses gratitude to the volunteer members of the writing group for updating sections on diagnosis and risk categories: Silvio Inzucchi, MD; Richard Bergenstal, MD; Vivian Fonseca, MD; Edward Gregg, PhD; Beth Mayer-Davis, MSPH, PhD, RD; Geralyn Spollett, MSN, CDE, ANP; and Richard Wender, MD.
