Diabetes mellitus represents a cluster of metabolic disorders distinguished by persistent hyperglycemia. This condition arises from impairments in insulin secretion, insulin action, or often, both. The enduring hyperglycemia characteristic of diabetes is linked to long-term damage, dysfunction, and eventual failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels. This article delves into the diagnosis and classification of diabetes mellitus, drawing upon the established guidelines and research prevalent in diabetes care as of 2012.
The development of diabetes involves a spectrum of 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 disturbances in carbohydrate, fat, and protein metabolism in diabetes is the insufficient action of insulin on target tissues. This deficiency stems from inadequate insulin secretion and/or reduced tissue responsiveness to insulin at various points in the intricate pathways of hormone action. It’s common for impaired insulin secretion and defects in insulin action to coexist within the same individual, often obscuring which abnormality is the primary driver of hyperglycemia.
Pronounced hyperglycemia manifests through symptoms like polyuria, polydipsia, unintentional weight loss, sometimes accompanied by polyphagia, and blurred vision. Chronic hyperglycemia can also hinder growth and increase susceptibility to infections. Acute, life-threatening consequences of uncontrolled diabetes include hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.
The long-term complications of diabetes are extensive, encompassing retinopathy with potential vision loss, nephropathy leading to renal failure, peripheral neuropathy with risks of foot ulcers, amputations, and Charcot joints, and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms, along with sexual dysfunction. Individuals with diabetes face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipoprotein metabolism abnormalities are frequently observed in diabetic populations.
Most diabetes cases fall into two primary etiopathogenetic categories. 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 markers indicating autoimmune processes in the pancreatic islets and by genetic markers. Type 2 diabetes, the more prevalent form, results from a combination of insulin resistance and an inadequate compensatory insulin secretion response. In type 2 diabetes, a level of hyperglycemia sufficient to cause pathological and functional changes in target tissues, but without overt clinical symptoms, may persist for a considerable period before diagnosis. During this asymptomatic phase, carbohydrate metabolism abnormalities can be detected by measuring plasma glucose in a fasting state or after an oral glucose challenge.
The severity of hyperglycemia can fluctuate over time, influenced by the progression of the underlying disease process (Fig. 1). A disease process might be present but not advanced enough to cause hyperglycemia. 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 glycemic control through lifestyle modifications like weight reduction and exercise, or with oral glucose-lowering agents, thus not requiring insulin. Others with some residual insulin secretion may require exogenous insulin for optimal glycemic control but can survive without it. However, individuals with extensive β-cell destruction and no residual insulin secretion necessitate insulin for survival. The degree of metabolic abnormality can progress, regress, or remain stable. Consequently, the level of hyperglycemia reflects the severity of the underlying metabolic process and its management rather than the fundamental 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
Assigning a specific type of diabetes can be complex and often depends on the clinical context at diagnosis. Many individuals do not neatly fit into a single classification. For instance, gestational diabetes mellitus (GDM) may resolve after delivery, or it might persist, evolving into type 2 diabetes. Similarly, diabetes induced by exogenous steroids may remit upon discontinuation of the glucocorticoids but reappear years later following events like pancreatitis. Thiazide-induced diabetes is another example, where the drug might exacerbate underlying type 2 diabetes rather than being the sole cause. For clinicians and patients, understanding the pathogenesis of hyperglycemia and effectively managing it is more critical than rigidly labeling the diabetes type.
Type 1 Diabetes (β-cell Destruction Leading to Insulin Deficiency)
Type 1 diabetes is characterized by β-cell destruction, typically leading to absolute insulin deficiency. It is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
Immune-mediated diabetes, formerly known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, accounts for 5–10% of all diabetes cases. It is the result of autoimmune destruction of the pancreatic β-cells. This autoimmune process is marked by the presence of islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and autoantibodies to tyrosine phosphatases IA-2 and IA-2β. One or more of these autoantibodies are detectable in 85–90% of individuals at the initial diagnosis of fasting hyperglycemia. Genetic predisposition plays a significant role, with associations to HLA genes, particularly DQA and DQB, and influence from DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective.
The rate of β-cell destruction in immune-mediated diabetes varies. It can be rapid, especially in infants and children, or slower in adults. Some patients, particularly children and adolescents, may present with diabetic ketoacidosis as the first sign. Others may initially have mild fasting hyperglycemia that quickly progresses 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. At this advanced stage, 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 is influenced by multiple genetic factors and poorly understood environmental triggers. Although patients are typically not obese at diagnosis, obesity does not exclude this diagnosis. These individuals are also more susceptible to other autoimmune disorders like Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
Idiopathic Diabetes
Idiopathic diabetes represents type 1 diabetes with no known cause. These patients experience permanent insulinopenia and are prone to ketoacidosis but lack evidence of autoimmunity. While a minority of type 1 diabetes cases are idiopathic, they are more prevalent in individuals of African or Asian descent. This form is characterized by episodic ketoacidosis and fluctuating insulin deficiency between episodes. It exhibits strong heritability, lacks immunological markers of β-cell autoimmunity, and is not associated with HLA. The requirement for insulin replacement therapy can be intermittent in affected individuals.
Type 2 Diabetes (Insulin Resistance to Insulin Secretory Defect)
Type 2 diabetes, previously termed non–insulin-dependent diabetes or adult-onset diabetes, accounts for the vast majority of diabetes cases (∼90–95%). It encompasses individuals with insulin resistance and typically relative insulin deficiency. Initially, and often throughout life, these patients do not require insulin for survival. Type 2 diabetes is likely multifactorial in etiology, but it is not characterized by autoimmune β-cell destruction or other specific causes of diabetes.
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 unless triggered by severe illness, such as infection. The onset of hyperglycemia is often gradual and initially asymptomatic, leading to delayed diagnosis, sometimes years after onset. Despite the lack of early symptoms, patients are at increased risk of macrovascular and microvascular complications. While insulin levels may appear normal or elevated, they are insufficient to compensate for the degree of insulin resistance, indicating defective β-cell function. Insulin resistance can improve with weight loss and medication, but rarely returns to normal. The risk of type 2 diabetes increases with age, obesity, physical inactivity, prior GDM, hypertension, dyslipidemia, and varies among racial and ethnic groups. Genetic predisposition is strong, possibly stronger than in autoimmune type 1 diabetes, but the genetics are complex and not fully understood.
Other Specific Types of Diabetes
Beyond type 1 and type 2 diabetes, several specific types are recognized, often stemming from genetic defects, pancreatic diseases, endocrinopathies, drugs, infections, and uncommon immune-mediated conditions.
Genetic Defects of the β-cell
Several monogenic defects in β-cell function can cause diabetes, often manifesting as hyperglycemia at a young age (typically before 25). These are known as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal insulin resistance. MODY is inherited in an autosomal dominant pattern. Mutations in several genes have been identified, including hepatocyte nuclear factor (HNF)-1α on chromosome 12 (MODY3) and glucokinase gene on chromosome 7p (MODY2). Glucokinase acts as the glucose sensor in β-cells; defects require higher glucose levels to stimulate insulin secretion. Other less common MODY forms involve mutations in transcription factors like HNF-4α (MODY1), HNF-1β (MODY5), insulin promoter factor (IPF)-1 (MODY4), and NeuroD1 (MODY6).
Mitochondrial DNA mutations, particularly at position 3,243 in the tRNA leucine gene, are also linked to diabetes and deafness. This mutation is also associated with MELAS syndrome, but diabetes is not consistently a feature, suggesting variable phenotypic expression.
Rare genetic abnormalities affecting proinsulin conversion to insulin or producing mutant insulin molecules with impaired receptor binding have been identified, typically inherited in an autosomal dominant manner and resulting in mild glucose intolerance.
Genetic Defects in Insulin Action
Rare forms of diabetes result from genetically determined defects in insulin action. Mutations in the insulin receptor can cause a spectrum of metabolic abnormalities, from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some individuals may present with acanthosis nigricans. Women may exhibit virilization and polycystic ovaries. Historically, this was 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 characterized by distinctive facial features, while Rabson-Mendenhall syndrome involves dental and nail abnormalities and pineal gland hyperplasia.
In insulin-resistant lipoatrophic diabetes, insulin receptor defects are not evident, suggesting defects in postreceptor signal transduction pathways.
Diseases of the Exocrine Pancreas
Diffuse pancreatic injury from conditions like pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma can induce diabetes. Except for cancer-related diabetes, significant pancreatic damage is usually necessary. Pancreatic cancer, even when localized, can sometimes cause diabetes, suggesting mechanisms beyond simple β-cell reduction. Cystic fibrosis and hemochromatosis, if extensive, can also impair insulin secretion. Fibrocalculous pancreatopathy may manifest with abdominal pain, pancreatic calcifications, fibrosis, and ductal calcium stones.
Endocrinopathies
Excessive amounts of hormones like growth hormone, cortisol, glucagon, and epinephrine, which antagonize insulin action, can cause diabetes. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can lead to diabetes, often in individuals with pre-existing insulin secretion defects. Hyperglycemia usually resolves upon correction of the hormonal excess.
Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes, partly by inhibiting insulin secretion. Hyperglycemia typically resolves after tumor removal.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action. These may not cause diabetes alone but can precipitate it in individuals with insulin resistance. Toxins like Vacor and intravenous pentamidine can cause permanent β-cell destruction. Drugs such as nicotinic acid and glucocorticoids can impair insulin action. Alpha-interferon has been associated with diabetes and islet cell antibodies, sometimes leading to severe insulin deficiency. Table 1 lists examples of drug-, hormone-, or toxin-induced 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 |
|---|
Insulin treatment may be necessary at some point in any type of diabetes and does not, by itself, classify the diabetes type.
Infections
Certain viral infections have been linked to β-cell destruction. Congenital rubella is associated with diabetes, often with HLA and immune markers resembling type 1 diabetes. Coxsackievirus B, cytomegalovirus, adenovirus, and mumps have also been implicated in some cases.
Uncommon Forms of Immune-Mediated Diabetes
Uncommon immune-mediated diabetes includes conditions like stiff-man syndrome, an autoimmune central nervous system disorder characterized by muscle stiffness and painful spasms. Patients often have high GAD autoantibody titers, and about one-third develop diabetes. Anti-insulin receptor antibodies can also cause diabetes by blocking insulin binding to its receptor. Paradoxically, in some cases, these antibodies can act as insulin agonists, causing hypoglycemia. They are found in patients with systemic lupus erythematosus and other autoimmune diseases and are often 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, involves insulin-deficient diabetes, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness, with β-cell absence at autopsy. Table 1 lists additional syndromes associated with diabetes.
Gestational Diabetes Mellitus (GDM)
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 begun concurrently with pregnancy. This definition provides a consistent approach for GDM detection and classification, though its limitations have long been acknowledged. The increasing prevalence of obesity and type 2 diabetes in women of childbearing age has led to a rise in undiagnosed type 2 diabetes in pregnant women.
In 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended that women with high risk factors found to have diabetes at their first prenatal visit using standard criteria (Table 3) should be diagnosed with overt diabetes, not GDM. GDM complicates approximately 7% of pregnancies, with prevalence ranging from 1 to 14% depending on the population and diagnostic tests.
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). |
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
Categories of Increased Risk for Diabetes
In 1997 and 2003, expert committees recognized an intermediate category of individuals with glucose levels higher than normal but not meeting diabetes criteria. These categories are impaired fasting glucose (IFG) [fasting plasma glucose (FPG) 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)] and impaired glucose tolerance (IGT) [2-h OGTT values 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 high risk for future diabetes. IFG and IGT are not clinical entities themselves but rather risk factors for diabetes and cardiovascular disease. They can represent intermediate stages in various diabetes-related disease processes (Table 1). IFG and IGT are associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions (increased physical activity and 5–10% weight loss) and some medications can prevent or delay diabetes onset in people with IGT, although their impact on mortality or cardiovascular disease incidence is not yet established. In 2003, the ADA lowered the IFG threshold from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l) to align IFG prevalence with IGT prevalence, although 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. While the International Expert Committee in 2009 acknowledged the continuous risk of diabetes across glycemic measures, they did not formally define an A1C-equivalent intermediate category. They noted that A1C levels above the lab “normal” range but below the diabetes diagnostic cut point (6.0 to 6.4%) indicate increased risk. Epidemiological data suggest that A1C values between 5.5 and 6.0% accurately identify people with IFG or IGT. Data from the Diabetes Prevention Program (DPP) also suggest that preventive interventions are effective in individuals with A1C levels in the 5.5–6% range. Therefore, an A1C level above 5.5–6% is likely appropriate for initiating preventive measures.
Defining a lower limit for an intermediate A1C category is somewhat arbitrary, as diabetes risk is a continuum even within normal ranges. The A1C cut point should balance the costs of false negatives (missing those who will develop diabetes) against false positives (unnecessary interventions).
Compared to the FPG cut point of 100 mg/dl, an A1C cut point of 5.7% is less sensitive but more specific and has a higher positive predictive value for identifying future diabetes risk. A large study showed a 5.7% A1C cut point has 66% sensitivity and 88% specificity for predicting 6-year diabetes incidence. Analyses of US data suggest a 5.7% A1C has modest sensitivity but high specificity for identifying IFG or IGT. It is associated with diabetes risk similar to 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 if desired.
Individuals with A1C of 5.7–6.4% should be informed of their increased risk for diabetes and cardiovascular disease and advised on lifestyle strategies like weight loss and physical activity. As A1C rises, diabetes risk increases disproportionately, making intensive interventions and vigilant follow-up especially important for those with A1C above 6.0%. However, even with A1C below 5.7%, risk is not negligible, depending on A1C level and other risk factors like obesity and family history.
Table 2 summarizes categories of increased diabetes risk. Risk evaluation should include a global assessment for both diabetes and cardiovascular disease. Screening and counseling should consider comorbidities, life expectancy, lifestyle change capacity, and overall health goals.
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% |
*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 traditionally relied on glucose criteria, either FPG or 75-g OGTT. In 1997, diagnostic criteria were revised based on the association between FPG levels and retinopathy. Data from epidemiological studies showed a glycemic threshold below which retinopathy prevalence was low and above which it increased linearly. These studies informed the diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed the 2-h PG value of ≥200 mg/dl (11.1 mmol/l).
A1C is a key marker of chronic glycemia, reflecting average blood glucose over 2–3 months. It is crucial in diabetes management, correlating with microvascular and, to a lesser extent, macrovascular complications, serving as a standard for glycemic control assessment. Earlier committees did not recommend A1C for diagnosis due to assay standardization concerns. 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 6.5% cut point aligns with the retinopathy prevalence inflection point, similar to FPG and 2-h PG thresholds. Diagnostic A1C testing should use NGSP-certified methods standardized to the DCCT assay. Point-of-care A1C tests are not yet sufficiently accurate for diagnosis.
Using A1C offers advantages over FPG, including convenience (no fasting required), greater preanalytical stability, and less variability during stress or illness. However, A1C is more costly, less available in developing regions, and has incomplete correlation with average glucose in some individuals. It can also be misleading in certain anemias and hemoglobinopathies. For patients with hemoglobinopathies but normal red cell turnover, interference-free A1C assays should be used. For conditions with abnormal red cell turnover, glucose criteria remain the primary diagnostic tools.
Established glucose criteria (FPG and 2-h PG) remain valid. Patients with severe hyperglycemia, such as those with classic hyperglycemic symptoms or crisis, can be diagnosed with a random plasma glucose ≥200 mg/dl (11.1 mmol/l). In such cases, A1C would likely also be measured and usually be above the diagnostic threshold. However, in rapidly developing diabetes, like type 1 in children, A1C may not be elevated despite frank diabetes.
There is not complete concordance between FPG, 2-h PG, and A1C tests. NHANES data indicate that an A1C cut point of ≥6.5% identifies fewer undiagnosed diabetes cases than an FPG cut point of ≥126 mg/dl (7.0 mmol/l). However, the convenience of A1C testing may lead to wider application and potentially increase overall diagnoses.
Further research is needed to understand discrepancies between different tests (e.g., FPG and A1C). Discordance may arise from measurement variability, time-related changes, or because these tests measure different physiological processes. Elevated A1C with non-diabetic FPG may suggest higher postprandial glucose or increased glycation rates. High FPG with non-diabetic A1C might indicate augmented hepatic glucose production or reduced glycation rates.
A diabetes diagnostic test result should be repeated to rule out lab error, unless clinically evident (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 cases of discordant results from two different tests, 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 glucose levels near the diagnostic threshold and should be monitored closely with repeat testing in 3–6 months.
The choice of diagnostic test is at the healthcare professional’s discretion, considering test availability and practicality. The most critical aspect is ensuring diabetes testing is performed when indicated, as evidence suggests under-testing and under-counseling for at-risk individuals. Table 3 summarizes current diagnostic criteria for diabetes.
Diagnosis of GDM
At the time of this publication (2012), GDM diagnostic criteria are those of Carpenter and Coustan. The Fourth International Workshop-Conference on Gestational Diabetes Mellitus supports using Carpenter/Coustan criteria and alternatively, a diagnostic 75-g 2-h OGTT. These criteria are outlined below.
Testing for Gestational Diabetes
Previous guidelines recommended universal GDM screening. However, women meeting specific low-risk criteria may not need screening. Low-risk criteria include:
- Age <25 years
- Normal body weight pre-pregnancy
- No family history of diabetes (first-degree relative)
- No history of abnormal glucose metabolism
- No history of poor obstetric outcomes
- Not belonging to a high-risk ethnic/racial group (Hispanic American, Native American, Asian American, African American, Pacific Islander)
Risk assessment for GDM should occur at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should undergo glucose testing as soon as feasible. If initial screening is negative, retesting should occur at 24–28 weeks gestation. Average-risk women should be tested at 24–28 weeks.
FPG >126 mg/dl (7.0 mmol/l) or random plasma glucose >200 mg/dl (11.1 mmol/l) meets diabetes diagnostic thresholds. Confirmation is needed on a subsequent day unless unequivocal hyperglycemia is present, precluding the need for glucose challenge. In the absence of such hyperglycemia, GDM evaluation in average or high-risk women follows one of two approaches.
One-Step Approach
Perform a diagnostic OGTT without prior 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 1 hour post-load. Perform a diagnostic OGTT on women exceeding a glucose threshold on the GCT. A threshold of >140 mg/dl (7.8 mmol/l) identifies approximately 80% of GDM cases, increasing to 90% with a cutoff of >130 mg/dl (7.2 mmol/l).
With either approach, GDM diagnosis relies on OGTT. 100-g OGTT diagnostic criteria from O’Sullivan and Mahan, modified by Carpenter and Coustan (Table 4, top), require two or more venous plasma glucose concentrations to meet or exceed thresholds for a positive diagnosis. Alternatively, a 75-g glucose load with specified fasting, 1-h, and 2-h glucose threshold values can be used (Table 4, bottom), though it is 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 |
| 1-h | 180 |
| 2-h | 155 |
| 3-h | 140 |
| 75-g glucose load | |
| Fasting | 95 |
| 1-h | 180 |
| 2-h | 155 |
The OGTT should be performed in the morning after an 8–14 hour overnight fast, following at least 3 days of unrestricted diet (≥150 g carbohydrate/day) and usual physical activity. Subjects should remain seated and not smoke during the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated that the risk of adverse maternal, fetal, and neonatal outcomes increases continuously with maternal glycemia at 24–28 weeks, even within previously considered normal ranges. The IADPSG recommended that all women without known prior diabetes undergo a 75-g OGTT at 24–28 weeks, establishing diagnostic cut points for fasting, 1-h, and 2-h plasma glucose measurements associated with an odds ratio of at least 1.75 for adverse outcomes compared to women with mean glucose levels in the HAPO study.
As of 2012, the ADA was working with obstetrical organizations to consider adopting the IADPSG diagnostic criteria and their implications. This change would significantly increase GDM prevalence, but evidence suggests that treating even mild GDM reduces morbidity for both mother and baby.
References
References are provided in the original article, and should be consulted for specific citations. For a comprehensive understanding of diabetes diagnosis and classification as of 2012, refer to the original publication in Diabetes Care, 2012.
