Diabetes mellitus represents a cluster of metabolic disorders hallmarked by hyperglycemia. This condition arises from deficiencies in insulin secretion, insulin action, or a combination of both. Chronic hyperglycemia in diabetes is linked to long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels. Understanding the diagnosis and classification of diabetes mellitus is crucial for effective diabetes care, a subject extensively discussed in publications such as Diabetes Care in 2006 and beyond.
The development of diabetes involves several pathogenic processes, ranging from autoimmune destruction of pancreatic β-cells, leading to insulin deficiency, to abnormalities causing resistance to insulin action. At the core of metabolic disruptions in diabetes lies the insufficient action of insulin on target tissues. This deficiency stems from inadequate insulin secretion and/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 pinpoint the primary cause of hyperglycemia.
Symptoms of pronounced hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes accompanied by increased hunger (polyphagia), and blurred vision. Chronic hyperglycemia may also hinder growth and increase 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 debilitating. They include retinopathy, potentially leading to vision loss; nephropathy, progressing to renal failure; peripheral neuropathy, increasing the risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy, causing gastrointestinal, genitourinary, cardiovascular symptoms, and sexual dysfunction. Furthermore, individuals with diabetes face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipid metabolism abnormalities are frequently observed in diabetic populations.
The majority of diabetes cases are categorized into two main etiopathogenetic types. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion. Individuals at higher risk can often be identified through serological evidence of autoimmune processes in pancreatic islets and genetic markers. Type 2 diabetes, the more prevalent form, results from insulin resistance combined with an insufficient compensatory insulin secretory response. In type 2 diabetes, hyperglycemia may be present for a considerable period before diagnosis, often without clinical symptoms, yet sufficient to cause pathological and functional changes in target tissues. During this asymptomatic phase, abnormal carbohydrate metabolism can be detected by measuring plasma glucose in a fasting state or after an oral glucose load.
The severity of hyperglycemia can fluctuate over time, influenced by the underlying disease progression and treatment interventions, as illustrated in Figure 1. A disease process might be present without causing immediate hyperglycemia. It can also manifest as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), conditions that do not fully meet diabetes diagnostic criteria. In some diabetic individuals, lifestyle modifications such as weight reduction, exercise, and/or oral glucose-lowering agents can achieve adequate glycemic control, negating the need for insulin. Others may require exogenous insulin despite some residual insulin secretion. Individuals with severe β-cell destruction and no residual insulin secretion depend on insulin for survival. The metabolic abnormality’s severity is dynamic, capable of progression, regression, or stabilization. Thus, the degree of hyperglycemia reflects the severity of the metabolic process and its management rather than the inherent nature of the disease 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 Categories of Glucose Regulation
Assigning a specific type of diabetes can be context-dependent at diagnosis, and many cases do not fit neatly into a single category. For instance, gestational diabetes mellitus (GDM) may transition into type 2 diabetes post-delivery. Similarly, diabetes induced by exogenous steroids might resolve upon discontinuation but reappear years later due to pancreatitis. Drug-induced diabetes, like from thiazides, often unmasks underlying type 2 diabetes rather than being a direct cause. Therefore, understanding the pathogenesis of hyperglycemia is more critical for clinicians and patients than simply labeling the diabetes type. Effective treatment strategies should be prioritized based on this understanding.
Type 1 Diabetes: Immune-Mediated and Idiopathic Forms
Type 1 diabetes is characterized by β-cell destruction, typically leading to absolute insulin deficiency. It can be further classified into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
This form, accounting for 5–10% of diabetes cases, is an autoimmune condition where the body’s immune system destroys pancreatic β-cells. Historically termed insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, it is marked by the presence of autoantibodies indicating immune destruction. These include islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and tyrosine phosphatases IA-2 and IA-2β autoantibodies. In 85–90% of individuals, one or more of these autoantibodies are detectable when fasting hyperglycemia is initially diagnosed. Genetic factors, particularly HLA associations with DQA, DQB, and DRB genes, play a significant role in susceptibility. These HLA-DR/DQ alleles can be either predisposing or protective.
The rate of β-cell destruction varies. It can be rapid, especially in children and infants, or slower, particularly in adults. Some patients, notably children and adolescents, may present with diabetic ketoacidosis as the first symptom. Others might initially 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, eventually requiring insulin and becoming susceptible to ketoacidosis. At this advanced stage, insulin secretion is minimal or absent, evidenced 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 complex genetic predispositions and environmental factors that are not yet fully understood. While patients are typically not obese at diagnosis, obesity does not rule out this type of diabetes. 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
In some cases of type 1 diabetes, the etiology remains unknown. These patients experience permanent insulinopenia and ketoacidosis but lack evidence of autoimmunity. This category is less common, predominantly affecting individuals of African or Asian descent. Idiopathic type 1 diabetes 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 can fluctuate.
Type 2 Diabetes: Insulin Resistance and Secretory Defects
Type 2 diabetes, previously known as non–insulin-dependent diabetes or adult-onset diabetes, accounts for 90–95% of diabetes cases. It is characterized by insulin resistance combined with relative insulin deficiency. Patients with type 2 diabetes usually do not require insulin for survival, especially initially and often throughout life. The exact causes are diverse and not fully understood, but autoimmune β-cell destruction is not involved, and other specific diabetes etiologies are excluded.
Obesity is a major contributing factor, with most patients being obese, as obesity itself induces insulin resistance. Even non-obese individuals may have increased abdominal fat, which is linked to insulin resistance. Ketoacidosis is rare spontaneously in type 2 diabetes, typically occurring under stress from illnesses like infections. Type 2 diabetes often remains undiagnosed for years due to gradual hyperglycemia development, which may not initially be severe enough to cause noticeable symptoms. However, these patients are at increased risk of macrovascular and microvascular complications. While insulin levels might appear normal or elevated, they are insufficient to compensate for insulin resistance, indicating defective β-cell function. Insulin resistance can improve with weight loss and medication but is rarely fully reversed. Risk factors include age, obesity, physical inactivity, prior GDM, hypertension, dyslipidemia, and specific racial/ethnic backgrounds. Type 2 diabetes has a strong genetic component, more so than autoimmune type 1 diabetes, though its genetics are complex and not fully defined.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several specific types of diabetes exist, each with distinct etiologies.
Genetic Defects of β-Cell Function
Several monogenetic defects in β-cell function lead to diabetes, often with onset before age 25. These are termed maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion with minimal insulin action defects, and are inherited in an autosomal dominant pattern. Six genetic loci on different chromosomes are implicated. The most common form involves mutations in the hepatic transcription factor hepatocyte nuclear factor (HNF)-1α on chromosome 12. Another form involves mutations in the glucokinase gene on chromosome 7p, affecting glucokinase, the “glucose sensor” for β-cells. Less common forms involve mutations in other transcription factors like HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1.
Mitochondrial DNA point mutations, particularly at position 3,243 in the tRNA leucine gene, are linked to diabetes and deafness. This mutation is also found in MELAS syndrome, but with different phenotypic expressions.
Genetic abnormalities preventing proinsulin conversion to insulin and mutations producing mutant insulin molecules with impaired receptor binding are rare, autosomal dominant, and result in mild glucose intolerance.
Genetic Defects in Insulin Action
Unusual diabetes forms arise from genetically determined abnormalities in insulin action. Mutations in the insulin receptor gene can cause a spectrum of metabolic abnormalities, from hyperinsulinemia with mild hyperglycemia to severe diabetes. Some patients may exhibit acanthosis nigricans. Women can experience virilization and polycystic ovaries. Historically, this was termed type A insulin resistance. Leprechaunism and Rabson-Mendenhall syndrome, pediatric syndromes with insulin receptor gene mutations, result in extreme insulin resistance. Leprechaunism is characterized by distinctive facial features and is often fatal in infancy, while Rabson-Mendenhall syndrome includes dental and nail abnormalities and pineal gland hyperplasia.
Insulin-resistant lipoatrophic diabetes does not show alterations in insulin receptor structure or function, suggesting defects in postreceptor signal transduction pathways.
Diseases of the Exocrine Pancreas
Pancreatic damage from pancreatitis, trauma, infection, pancreatectomy, or pancreatic carcinoma can cause diabetes. Except for cancer-induced diabetes, extensive pancreatic damage is needed. Even small pancreatic adenocarcinomas have been linked to diabetes, indicating mechanisms beyond β-cell mass reduction. Cystic fibrosis and hemochromatosis, if severe, can impair insulin secretion. Fibrocalculous pancreatopathy presents with abdominal pain, pancreatic calcifications, fibrosis, and calcium stones in pancreatic ducts.
Endocrinopathies
Excess hormones like growth hormone, cortisol, glucagon, and epinephrine can antagonize insulin action, potentially causing diabetes, particularly in individuals with pre-existing insulin secretion defects. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can induce diabetes, which typically resolves when hormone excess is corrected. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion, resolving after tumor removal.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action. While some may not directly cause diabetes, they can precipitate it in insulin-resistant individuals. Examples include Vacor (a rat poison), intravenous pentamidine, nicotinic acid, and glucocorticoids. α-interferon has been linked to diabetes with islet cell antibodies and severe insulin deficiency. Table 1 lists common drug-, hormone-, and toxin-induced diabetes forms.
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 use at any stage of diabetes does not reclassify the diabetes type.
Infections
Certain viruses can destroy β-cells. Congenital rubella is linked to diabetes, often with type 1 diabetes markers. Coxsackievirus B, cytomegalovirus, adenovirus, and mumps have also been implicated in some cases.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, an autoimmune central nervous system disorder with muscle stiffness and painful spasms, are associated with diabetes. Patients often have high GAD autoantibody titers, and about one-third develop diabetes. Anti-insulin receptor antibodies can cause diabetes by blocking insulin binding. In some cases, these antibodies act as insulin agonists, causing hypoglycemia. They are found in patients with systemic lupus erythematosus and other autoimmune diseases and are associated with acanthosis nigricans, previously termed type B insulin resistance.
Other Genetic Syndromes
Several genetic syndromes increase diabetes risk, including Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome, an autosomal recessive disorder, features insulin-deficient diabetes, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Table 1 lists additional syndromes.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first recognized during pregnancy. It usually resolves after delivery but the definition applies regardless of persistence post-pregnancy and acknowledges that glucose intolerance might predate or start during pregnancy. This definition facilitates uniform detection and classification, though its limitations are recognized. The rise in obesity and type 2 diabetes in women of childbearing age has increased undiagnosed type 2 diabetes in pregnant women.
In 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended that women with diabetes at their first prenatal visit, based on standard criteria (Table 3), be diagnosed with overt diabetes, not GDM. GDM complicates about 7% of pregnancies (1–14% depending on population and tests), affecting over 200,000 women annually.
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 (Prediabetes)
In 1997 and 2003, expert committees recognized an intermediate group with glucose levels higher than normal but not meeting diabetes criteria. This includes individuals with impaired fasting glucose (IFG) [FPG 100–125 mg/dl (5.6–6.9 mmol/l)] or impaired glucose tolerance (IGT) [2-h OGTT values 140–199 mg/dl (7.8–11.0 mmol/l)].
IFG and/or IGT are termed prediabetes, indicating a high risk of future diabetes and cardiovascular disease. They are not clinical entities but risk factors, observed in various disease processes listed in Table 1. Prediabetes is linked to obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes in IGT individuals, though impact on mortality or cardiovascular disease is unproven. In 2003, the ADA lowered the IFG threshold from 110 to 100 mg/dl (6.1 to 5.6 mmol/l) to align IFG prevalence with IGT, though the WHO and others did not adopt this change.
A1C is increasingly used to identify those at higher diabetes risk. The International Expert Committee in 2009 noted a diabetes risk continuum with glycemic measures but didn’t formally define an intermediate A1C category. They noted increased risk at A1C levels above the lab “normal” range but below the diabetes diagnostic cut point (6.0-6.5%). Incidence rates at A1C 6.0–6.5% are significantly higher than in the general US population. NHANES data suggest A1C 5.5–6.0% best identifies IFG/IGT. DPP data showed preventive interventions effective in groups with A1C both below and above 5.9%. Thus, A1C 5.5–6% is a likely threshold for preventive interventions.
Defining a lower limit for intermediate A1C is arbitrary, as diabetes risk is continuous across glycemia ranges. An A1C cut point should balance “false negatives” (missing future diabetes cases) against “false positives” (unnecessary interventions). Compared to FPG 100 mg/dl (5.6 mmol/l), A1C 5.7% is less sensitive but more specific and has higher positive predictive value for diabetes risk. A study found A1C 5.7% had 66% sensitivity and 88% specificity for 6-year diabetes incidence. NHANES data suggest A1C 5.7% has modest sensitivity (39-45%) but high specificity (81-91%) for IFP/IGT. A1C 5.7% is associated with diabetes risk similar to high-risk DPP participants. Therefore, A1C 5.7–6.4% reasonably identifies high-risk individuals, termed prediabetes.
Individuals with A1C 5.7–6.4% should be informed of increased diabetes and cardiovascular disease risk and counseled on risk-reducing strategies like weight loss and physical activity. Risk increases disproportionately with A1C rise. Interventions and follow-up should be intensified for those with A1C above 6.0%. However, even below A1C 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 global risk factor assessment for both diabetes and cardiovascular disease, within the context of comorbidities, life expectancy, lifestyle change capacity, and 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 long relied on glucose criteria, FPG or 75-g OGTT. In 1997, diagnostic criteria were revised based on the association between FPG levels and retinopathy. Studies showed glycemic levels below which retinopathy was minimal and above which it increased linearly. Retinopathy onset deciles were consistent across glycemic measures and populations. This informed the new FPG diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) 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 glucose over 2–3 months. It is vital in diabetes management, correlating with microvascular and macrovascular complications, and is a standard for glycemic control. Prior 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 at a threshold of ≥6.5%, affirmed by the ADA. This A1C cut point, like FPG and 2-h PG thresholds, aligns with retinopathy prevalence inflection points. Diagnostic tests should use NGSP-certified methods standardized to the DCCT assay. Point-of-care A1C assays are currently unsuitable for diagnosis.
Using a chronic marker like A1C has inherent logic over acute markers. A1C is convenient (no fasting), has greater preanalytical stability, and less day-to-day variability. However, it is more costly, less available in developing regions, and has incomplete correlation with average glucose in some individuals. A1C can be misleading in certain anemias and hemoglobinopathies, which may have ethnic/geographic variations. For hemoglobinopathies with normal red cell turnover like sickle cell trait, A1C assays without interference should be used (www.ngsp.org/prog/index3.html). For conditions with abnormal red cell turnover, glucose criteria must be used exclusively.
Established glucose criteria (FPG, 2-h PG) remain valid. Random plasma glucose ≥200 mg/dl (11.1 mmol/l) in patients with severe hyperglycemic symptoms or crisis also diagnoses diabetes. A1C would likely also be measured and be above the diagnostic cut point in such cases. However, in rapidly evolving diabetes like type 1 in children, A1C may not be elevated despite frank diabetes.
Concordance between A1C, FPG, and 2-h PG is not 100%. NHANES data suggest A1C ≥6.5% identifies one-third fewer undiagnosed diabetes cases than FPG ≥126 mg/dl (7.0 mmol/l). However, wider A1C use may increase diagnoses due to its greater practicality.
Further research is needed on patients with discordant glycemic status by different tests. Discordance may arise from measurement variability, time changes, or tests measuring different physiological processes. Elevated A1C with “nondiabetic” FPG may indicate higher postprandial glucose or glycation rates. High FPG with A1C below the cut point may indicate augmented hepatic glucose production or reduced glycation rates.
Like most diagnostic tests, a diabetes-diagnostic result should be repeated to rule out lab error, unless clinically clear (e.g., hyperglycemic crisis). Repeating the same test is preferable for confirmation. For discordant results from different tests, the test above the diagnostic cut point should be repeated, and diagnosis is based on the confirmed test. If A1C meets diabetes criteria (two results ≥6.5%) but FPG does not, diabetes is confirmed.
When a test above the threshold is repeated and the second value is below the cut point, patients likely have borderline results. Close monitoring and repeat testing in 3–6 months may be warranted.
Test selection for diabetes assessment is at the healthcare professional’s discretion, considering test availability and practicality. More crucial than test choice is ensuring testing is done when indicated. Under-testing and under-counseling at-risk patients for diabetes and cardiovascular risk factors remain concerning. Table 3 summarizes current diagnostic criteria.
Diagnosis of GDM
GDM diagnostic criteria at this publication time are the Carpenter and Coustan criteria. The Fourth International Workshop-Conference on Gestational Diabetes Mellitus supports Carpenter/Coustan criteria and the alternative 75-g 2-h OGTT.
Testing for Gestational Diabetes
Previous recommendations included universal GDM screening. However, low-risk women may not need screening. Low-risk criteria include women who:
- Are under 25 years of age
- Are of normal body weight
- Have no family history (first-degree relative) of diabetes
- Have no history of abnormal glucose metabolism
- Have no history of poor obstetric outcome
- Are not members of a high-risk ethnic/racial group (Hispanic American, Native American, Asian American, African American, Pacific Islander)
Risk assessment for GDM should be done at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should be tested immediately. If negative initially, retest at 24–28 weeks. Average-risk women should be tested at 24–28 weeks.
FPG >126 mg/dl (7.0 mmol/l) or casual plasma glucose >200 mg/dl (11.1 mmol/l) meets diabetes threshold. Confirmation is needed on a subsequent day unless unequivocal hyperglycemia is present. Confirmation negates the need for 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 prior glucose screening, potentially cost-effective in high-risk groups.
Two-Step Approach
Initial screening with 50-g oral glucose load (glucose challenge test [GCT]), followed by diagnostic OGTT for women exceeding the GCT glucose threshold. A threshold >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).
Either approach uses OGTT for GDM diagnosis. Diagnostic criteria for 100-g OGTT (Carpenter and Coustan modified from O’Sullivan and Mahan) are in Table 4 (top). Alternatively, 75-g glucose load criteria (fasting, 1-h, 2-h values in Table 4, bottom) can be used, though less validated than 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 |
Two or more venous plasma concentrations must be met or exceeded for a positive diagnosis. Test in the morning after 8–14 h overnight fast, after ≥3 days of unrestricted diet (≥150 g carbohydrate/day) and unlimited physical activity. Subject should remain seated and not smoke during the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study showed continuous increase in adverse outcomes with maternal glycemia at 24–28 weeks, even within previously normal ranges. The IADPSG recommended 75-g OGTT for all women without prior diabetes at 24–28 weeks, with diagnostic cut points for fasting, 1-h, and 2-h plasma glucose linked to an odds ratio of ≥1.75 for adverse outcomes in the HAPO study.
At this update’s publication, ADA is working with obstetrical organizations to consider adopting IADPSG diagnostic criteria and discuss implications. This change will significantly increase GDM prevalence, but evidence suggests treating even mild GDM reduces morbidity for both mother and baby.
Acknowledgments
The American Diabetes Association acknowledges the contributions of 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, for updating the sections on diagnosis and risk categories.
