Diabetes mellitus represents a cluster of metabolic disorders characterized by persistent hyperglycemia. This condition arises from defects in insulin secretion, insulin action, or a combination of both. Chronic hyperglycemia is a hallmark of diabetes and is linked to long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels.
The development of diabetes involves multiple 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 metabolic disruptions in diabetes—affecting carbohydrate, fat, and protein metabolism—is 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 hormone’s action pathways. Often, both impaired insulin secretion and defects in insulin action coexist within the same patient, making it challenging to pinpoint the primary cause of hyperglycemia.
Pronounced hyperglycemia manifests through symptoms like polyuria, polydipsia, unexplained weight loss—sometimes accompanied by polyphagia—and blurred vision. Chronic hyperglycemia may also hinder growth and increase susceptibility to infections. In severe, uncontrolled diabetes, acute, life-threatening conditions such as hyperglycemia with ketoacidosis or nonketotic hyperosmolar syndrome can emerge.
Long-term diabetes complications are extensive and include retinopathy with potential vision loss, nephropathy leading to kidney failure, peripheral neuropathy increasing risks of foot ulcers, amputations, and Charcot joints, and autonomic neuropathy causing gastrointestinal, genitourinary, cardiovascular issues, and sexual dysfunction. Individuals with diabetes also 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 main categories based on their underlying causes. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion. Individuals at higher risk can often be identified through serological markers of autoimmune processes in pancreatic islets and specific genetic markers. Type 2 diabetes, the more prevalent form, results from insulin resistance combined with an insufficient compensatory insulin secretion. In type 2 diabetes, significant hyperglycemia, capable of causing tissue damage without immediate clinical symptoms, can be present for a considerable period before diagnosis. This asymptomatic phase can be detected by measuring plasma glucose levels in fasting conditions or after a glucose challenge.
The severity of hyperglycemia can fluctuate over time, influenced by the progression of the underlying disease and treatment efficacy, as illustrated in Figure 1. A disease process may be present without causing immediate hyperglycemia, or it might lead to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), conditions that do not fully meet diabetes diagnostic criteria. Some individuals with diabetes can achieve glycemic control through lifestyle modifications like weight reduction and exercise, or with oral glucose-lowering medications, thus avoiding insulin therapy. Others may require exogenous insulin despite some residual insulin secretion. In cases of extensive β-cell destruction with no residual insulin secretion, insulin is essential for survival. The metabolic abnormality’s severity can progress, regress, or remain stable, indicating that hyperglycemia levels reflect the severity of the metabolic process and its management rather than the process’s nature alone.
CLASSIFICATION OF DIABETES MELLITUS AND OTHER GLUCOSE REGULATION CATEGORIES
Assigning a specific type of diabetes can be complex and often depends on the diagnostic context. Many individuals do not fit neatly into a single classification. For example, gestational diabetes mellitus (GDM) may transition into persistent hyperglycemia post-delivery, potentially reclassified as type 2 diabetes. Conversely, diabetes induced by high doses of exogenous steroids might resolve upon discontinuation of glucocorticoids, only to reappear years later due to conditions like recurrent pancreatitis. Similarly, thiazide-induced diabetes might develop years after treatment initiation, likely indicating underlying type 2 diabetes exacerbated by the drug rather than solely caused by it. Therefore, for clinicians and patients, understanding the pathogenesis of hyperglycemia and effectively treating it is more critical than strictly labeling the diabetes type.
Type 1 Diabetes: β-cell Destruction Leading to Insulin Deficiency
Type 1 diabetes is characterized by the destruction of pancreatic β-cells, typically leading to a severe or absolute insulin deficiency. This form was previously known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes. It is primarily divided into two categories: immune-mediated and idiopathic.
Immune-Mediated Diabetes
This subtype, accounting for 5–10% of diabetes cases, is an autoimmune condition where the body’s immune system mistakenly attacks and destroys pancreatic β-cells. Key markers of this autoimmune destruction include islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and autoantibodies to tyrosine phosphatases IA-2 and IA-2β. In newly diagnosed individuals with fasting hyperglycemia, 85–90% exhibit one or more of these autoantibodies. 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 either increase susceptibility or offer protection.
The rate of β-cell destruction in immune-mediated diabetes varies significantly. It can be rapid, especially in infants and children, or slower in adults. Some patients, particularly younger individuals, may present with ketoacidosis as the initial symptom. Others might have mild fasting hyperglycemia that can quickly escalate to severe hyperglycemia or ketoacidosis when faced with infection or stress. Adults may retain enough residual β-cell function to prevent ketoacidosis for years but eventually become insulin-dependent and prone to ketoacidosis. At this advanced stage, insulin secretion is minimal or absent, evidenced by low or undetectable plasma C-peptide levels. While commonly diagnosed in childhood and adolescence, immune-mediated diabetes can occur at any age.
The autoimmune destruction of β-cells is influenced by both genetic predisposition and environmental factors that are not yet fully understood. Although patients are often not obese at diagnosis, obesity does not preclude 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 type 1 diabetes refers to cases with no known cause. These patients experience permanent insulinopenia and are prone to ketoacidosis but lack evidence of autoimmunity. This category is less common, predominantly affecting individuals of African or Asian descent. A characteristic feature is episodic ketoacidosis with varying degrees of insulin deficiency between episodes. This form is strongly hereditary, lacks immunological markers of β-cell autoimmunity, and is not associated with HLA. The need for insulin replacement therapy in these patients can be intermittent.
Type 2 Diabetes: Insulin Resistance and Relative Insulin Deficiency
Type 2 diabetes, accounting for 90–95% of diabetes cases, is characterized by insulin resistance and a relative insulin deficiency. Previously known as non–insulin-dependent diabetes or adult-onset diabetes, it includes individuals who, at least initially, do not require insulin for survival, although they may need it later to manage the disease. The exact causes are varied and complex, but unlike type 1, it is not associated with autoimmune destruction of β-cells, nor is it linked to other specific causes of diabetes.
Obesity is a major contributing factor, causing insulin resistance in many patients. Even those not traditionally classified as obese may have increased abdominal fat, which exacerbates insulin resistance. Ketoacidosis is rare in type 2 diabetes, typically occurring only under severe stress from illnesses like infections. Type 2 diabetes often remains undiagnosed for years due to the gradual onset of hyperglycemia and initially mild symptoms. However, even in early stages, patients are at increased risk for macrovascular and microvascular complications. While insulin levels in type 2 diabetics may appear normal or even elevated, they are insufficient to compensate for insulin resistance, indicating defective β-cell function. 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 immune-mediated type 1 diabetes, though the genetics are complex and not fully understood.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several specific types of diabetes are recognized, often resulting from genetic defects, pancreatic diseases, endocrinopathies, drug use, infections, or rare immune conditions.
Genetic Defects of β-cell Function
Several monogenetic defects can impair β-cell function, leading to diabetes typically diagnosed before age 25. These are known as maturity-onset diabetes of the young (MODY). MODY subtypes are characterized by impaired insulin secretion with minimal insulin resistance and are inherited in an autosomal dominant pattern. Mutations at various genetic loci have been identified, including:
- HNF-1α (MODY3): Mutations in the hepatocyte nuclear factor-1α gene on chromosome 12 are the most common cause of MODY.
- Glucokinase (MODY2): Mutations in the glucokinase gene on chromosome 7p result in a defective glucokinase molecule, which is crucial for glucose sensing by β-cells.
- HNF-4α (MODY1): Mutations in the hepatocyte nuclear factor-4α gene on chromosome 20.
- IPF-1 (MODY4): Mutations in the insulin promoter factor-1 gene on chromosome 13.
- HNF-1β (MODY5): Mutations in the hepatocyte nuclear factor-1β gene on chromosome 17.
- NeuroD1 (MODY6): Mutations in the NeuroD1 gene on chromosome 2.
- Mitochondrial DNA: Point mutations in mitochondrial DNA, particularly at position 3,243 in the tRNA leucine gene, are associated with diabetes and deafness.
- Proinsulin Conversion Defects: Genetic abnormalities affecting the conversion of proinsulin to insulin are rare and cause mild glucose intolerance.
- Mutant Insulin Molecules: Production of mutant insulin molecules with impaired receptor binding is also rare and results in mild glucose metabolism issues.
Genetic Defects in Insulin Action
Rare forms of diabetes arise from genetic defects affecting insulin action. Mutations in the insulin receptor gene can cause a spectrum of conditions from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some individuals may exhibit acanthosis nigricans. In women, virilization and polycystic ovaries can occur. Syndromes like leprechaunism and Rabson-Mendenhall syndrome, both pediatric conditions, are characterized by insulin receptor gene mutations, extreme insulin resistance, and severe symptoms. Lipoatrophic diabetes with insulin resistance, however, does not show alterations in the insulin receptor itself, suggesting defects in postreceptor signaling pathways.
Diseases of the Exocrine Pancreas
Damage to the pancreas from conditions like pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma can lead to diabetes. Extensive pancreatic damage is usually required, except in cases of pancreatic cancer where even small tumors can induce diabetes, possibly through mechanisms beyond β-cell reduction. Cystic fibrosis and hemochromatosis, if severe enough, can also impair insulin secretion. Fibrocalculous pancreatopathy, characterized by abdominal pain, pancreatic calcifications, and ductal stones, is another pancreatic cause of diabetes.
Endocrinopathies
Excess of hormones that counter insulin action, such as growth hormone, cortisol, glucagon, and epinephrine, can cause diabetes. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can induce hyperglycemia, typically in individuals with pre-existing insulin secretion defects. Hyperglycemia usually resolves when the hormonal imbalance is corrected. Somatostatinoma and aldosteronoma, through hypokalemia, can also inhibit insulin secretion and lead to diabetes, which generally resolves post-tumor removal.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action, potentially causing or exacerbating diabetes, especially in those with insulin resistance. Toxins like Vacor and intravenous pentamidine can permanently destroy β-cells. Drugs such as nicotinic acid and glucocorticoids can impair insulin action. Alpha-interferon treatment has been linked to diabetes with islet cell antibodies and severe insulin deficiency. Table 1 lists commonly recognized drugs, hormones, and toxins associated with 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 for any form of diabetes at some point, but it does not define the type of diabetes.
Infections
Certain viral infections have been linked to β-cell destruction. Congenital rubella is a known cause of diabetes, often showing HLA and immune markers similar to type 1 diabetes. Other viruses like coxsackievirus B, cytomegalovirus, adenovirus, and mumps have also been implicated in diabetes development in some cases.
Uncommon Forms of Immune-Mediated Diabetes
Two recognized conditions and potentially others fall into this category of rare immune-mediated diabetes. Stiff-man syndrome, an autoimmune neurological disorder, is characterized by muscle stiffness and painful spasms. It often involves high titers of GAD autoantibodies, and about a third of patients develop diabetes. Anti-insulin receptor antibodies can cause diabetes by blocking insulin binding, although paradoxically, in some cases, they can also act as insulin agonists, causing hypoglycemia. These antibodies are sometimes found in patients with systemic lupus erythematosus and other autoimmune diseases, often accompanied by acanthosis nigricans, and were previously termed type B insulin resistance.
Other Genetic Syndromes Associated with Diabetes
Several genetic syndromes are associated with a higher incidence of diabetes, including chromosomal abnormalities like Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome, a recessive disorder, is characterized by insulin-deficient diabetes, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness, with β-cell absence at autopsy. Table 1 lists additional syndromes linked to diabetes.
Gestational Diabetes Mellitus (GDM)
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first detected during pregnancy. While it usually resolves after delivery, the definition applies regardless of persistence postpartum and includes cases where glucose intolerance may have pre-existed or started with the pregnancy. This definition aimed to standardize GDM detection and classification but has limitations, especially with the rising prevalence of type 2 diabetes in women of childbearing age, leading to increased cases of undiagnosed type 2 diabetes in pregnancy.
In 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), including the American Diabetes Association (ADA), recommended that women with high-risk factors found to have diabetes at their first prenatal visit based on standard criteria (Table 3) should be diagnosed with overt diabetes, not GDM. GDM complicates approximately 7% of pregnancies, with rates varying from 1 to 14% depending on the population and diagnostic methods, resulting in over 200,000 cases 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
In 1997 and 2003, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus recognized an intermediate group of individuals with glucose levels higher than normal but not meeting diabetes criteria. These categories include impaired fasting glucose (IFG), defined as fasting plasma glucose (FPG) levels between 100 mg/dl (5.6 mmol/l) and 125 mg/dl (6.9 mmol/l), and impaired glucose tolerance (IGT), defined as 2-hour values in a 75-g oral glucose tolerance test (OGTT) between 140 mg/dl (7.8 mmol/l) and 199 mg/dl (11.0 mmol/l).
Individuals with IFG and/or IGT are considered to have pre-diabetes, indicating a heightened risk of developing diabetes. IFG and IGT are not clinical entities themselves but rather risk factors for both diabetes and cardiovascular disease. They can represent intermediate stages in various disease processes associated with diabetes (Table 1). IFG and IGT are linked to obesity, especially abdominal obesity, dyslipidemia (high triglycerides and/or low HDL cholesterol), and hypertension. Lifestyle interventions focusing on increased physical activity and a 5–10% body weight reduction, along with certain medications, have shown effectiveness in preventing or delaying diabetes onset in people with IGT. However, their impact on reducing mortality or cardiovascular disease incidence is still under investigation. The ADA in 2003 lowered the FPG cut point for IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l) to align IFG prevalence with IGT. However, the World Health Organization (WHO) and many other diabetes organizations have not adopted this change.
With the increasing use of A1C for diabetes diagnosis, it also serves to identify those at higher risk. The International Expert Committee in 2009 noted the continuous risk of diabetes across glycemic measures but did not formally define an intermediate A1C category. They observed that individuals with A1C levels above the laboratory normal range but below the diabetes diagnostic threshold (6.0 to 6.4%) are at increased risk. Data from NHANES suggest that an A1C between 5.5 and 6.0% best identifies people with IFG or IGT. The Diabetes Prevention Program (DPP) showed that interventions are effective for individuals with A1C levels both above and below 5.9%. Thus, an A1C level around 5.5–6% is likely a suitable threshold for initiating preventive interventions.
Defining a lower limit for an intermediate A1C category is somewhat arbitrary due to the continuous nature of diabetes risk across glycemic levels. An appropriate A1C cut point should balance the identification of true positives (those who will develop diabetes) against false positives (those who will not). An A1C cut point of 5.7% is less sensitive but more specific than a fasting glucose cut point of 100 mg/dl (5.6 mmol/l) and has a higher positive predictive value for future diabetes. Studies indicate that a 5.7% A1C cut point has a sensitivity of 66% and specificity of 88% for predicting 6-year diabetes incidence. Analyses suggest that an A1C of 5.7% is associated with a diabetes risk similar to high-risk participants in the DPP. Therefore, an A1C range of 5.7 to 6.4% can be considered indicative of high risk for future diabetes, termed pre-diabetes if preferred.
Individuals with an A1C of 5.7–6.4% should be informed about their increased risk for diabetes and cardiovascular disease and counseled on risk-reduction strategies like weight loss and physical activity. As diabetes risk increases disproportionately with rising A1C, interventions and follow-up should be more intensive for those with A1C levels above 6.0%, who are at very high risk. However, even those with A1C levels below 5.7% may still be at risk, depending on their A1C level and other risk factors like obesity and family history.
Table 2 summarizes the categories of increased diabetes risk. Risk evaluation should include a comprehensive assessment for both diabetes and cardiovascular disease. Screening and counseling should consider the patient’s comorbidities, life expectancy, capacity for lifestyle changes, 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 fasting plasma glucose (FPG) or the 75-g oral glucose tolerance test (OGTT). In 1997, the diagnostic criteria were revised based on the association between FPG levels and retinopathy. Studies examining retinopathy prevalence in relation to FPG, 2-hour plasma glucose (2-h PG), and A1C levels identified glycemic thresholds above which retinopathy risk increased linearly. These thresholds were consistent across different populations and glycemic measures, leading to the adoption of ≥126 mg/dl (7.0 mmol/l) for FPG and confirming ≥200 mg/dl (11.1 mmol/l) for 2-h PG as diagnostic cut points.
A1C is a key marker of chronic glycemia, reflecting average blood glucose over 2–3 months. It is crucial in diabetes management as it correlates with microvascular and, to a lesser extent, macrovascular complications, serving as a standard for assessing glycemic control. Earlier committees did not recommend A1C for diagnosis due to assay standardization issues. However, with improved standardization, an International Expert Committee in 2009 recommended A1C for diabetes diagnosis with a threshold of ≥6.5%, a decision affirmed by the ADA. This A1C cut point, like FPG and 2-h PG thresholds, is associated with an inflection point for retinopathy prevalence. Diagnostic A1C testing should use NGSP-certified methods 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 required), greater preanalytical stability, and less variability during stress or illness. However, A1C testing is more costly, less available in developing regions, and may not perfectly correlate with average glucose in all individuals. It can also be misleading in patients with certain anemias and hemoglobinopathies. For these conditions, glucose criteria should be used for diabetes diagnosis. For patients with hemoglobinopathies like sickle cell trait but normal red cell turnover, A1C assays without interference from abnormal hemoglobins should be used.
Established glucose criteria (FPG and 2-h PG) remain valid. Random plasma glucose ≥200 mg/dl (11.1 mmol/l) in patients with classic hyperglycemia symptoms or hyperglycemic crisis also remains a diagnostic criterion. While A1C is often measured in such cases and is usually above the diagnostic cut point, it may not be elevated in rapidly developing diabetes, such as type 1 diabetes in children.
Concordance between A1C and glucose-based tests is not complete. NHANES data suggest that an A1C ≥6.5% identifies fewer undiagnosed diabetes cases than FPG ≥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 A1C and glucose tests, which may arise from measurement variability, time-related changes, or the tests measuring different physiological processes. Discordant results might indicate differences in postprandial glucose levels or glycation rates (elevated A1C but non-diabetic FPG) or hepatic glucose production or glycation rates (high FPG but A1C below cut point).
As with most diagnostic tests, a diabetes diagnosis based on a test result should be confirmed by repeat testing, unless clinical presentation is clear, such as in hyperglycemic crisis. Repeating the same test is preferable for confirmation. If two different tests (e.g., FPG and A1C) are both above diagnostic thresholds, diabetes is confirmed. If results are discordant, the test above the threshold should be repeated, and diagnosis is based on the confirmed result. If a repeated test falls below the diagnostic cut point, close monitoring and repeat testing in 3–6 months may be appropriate, as results may be near diagnostic margins.
The choice of diagnostic test should be made by the healthcare professional, considering test availability and practicality. Ensuring diabetes testing is performed when indicated is crucial. Evidence suggests that many at-risk patients still do not receive adequate testing and counseling for diabetes or related cardiovascular risk factors. Table 3 summarizes current diagnostic criteria for diabetes.
Diagnosis of GDM
At the time of this publication, GDM diagnostic criteria are based on Carpenter and Coustan. Recommendations from the Fourth International Workshop-Conference on Gestational Diabetes Mellitus support using Carpenter/Coustan criteria or a diagnostic 75-g 2-h OGTT.
Testing for Gestational Diabetes
Universal screening for GDM in all pregnancies was previously recommended. However, women meeting specific low-risk criteria may not need screening. Low-risk criteria include being under 25 years old, normal weight, no family history of diabetes (first-degree relative), no history of abnormal glucose metabolism or poor obstetric outcomes, and not belonging to a high-risk ethnic/racial group.
Risk assessment for GDM should occur at the first prenatal visit. Women at high risk (marked obesity, prior GDM, glycosuria, strong family history) should be tested immediately. If initial tests are negative, they should be retested at 24–28 weeks of gestation. Women at average risk 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 diagnostic thresholds and requires confirmation on a subsequent day, precluding the need for a glucose challenge test. For others, GDM evaluation follows a one-step or two-step approach.
One-Step Approach
This involves performing a diagnostic OGTT without initial glucose screening, potentially cost-effective for high-risk groups.
Two-Step Approach
This involves an initial screening with a 50-g oral glucose load (glucose challenge test [GCT]), measuring plasma glucose at 1 hour. A diagnostic OGTT is then performed on women exceeding a glucose threshold on the GCT. A threshold >140 mg/dl (7.8 mmol/l) identifies about 80% of GDM cases, increasing to 90% at a cutoff of >130 mg/dl (7.2 mmol/l).
GDM diagnosis in either approach is based on OGTT. Criteria for the 100-g OGTT from O’Sullivan and Mahan, modified by Carpenter and Coustan, are in Table 4. Alternatively, a 75-g glucose load with glucose thresholds for fasting, 1-hour, and 2-hour measurements can be used, 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 | 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 meet or exceed these values for a positive GDM diagnosis. The test should be done in the morning after an 8–14 hour overnight fast, following at least 3 days of unrestricted diet (≥150 g carbohydrate daily) and normal 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 pregnancy outcomes increases continuously with maternal glycemia, even within previously considered normal ranges. This has prompted reconsideration of GDM diagnostic criteria. The IADPSG recommends a 75-g OGTT at 24–28 weeks for all women without prior diabetes and has proposed diagnostic cut points for fasting, 1-hour, and 2-hour plasma glucose levels that indicate an odds ratio of at least 1.75 for adverse outcomes compared to women with mean glucose levels in the HAPO study.
As of this publication, the ADA is working with obstetrical organizations to consider adopting the IADPSG diagnostic criteria and discuss the implications, noting that while this change will increase GDM prevalence, evidence suggests treating even mild GDM reduces morbidity for mothers and babies.
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 their work on updating the sections on diagnosis and risk categories.
References
1. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183–97
2. American Diabetes Association: Clinical practice recommendations 2003. Diabetes Care 2003; 26(Suppl 1):S33–S50
3. International Expert Committee: International expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009; 32:1327–34
8. Engelgau MM, Thompson TJ, Herman WH, et al.: Comparison of fasting plasma glucose and HbA1c levels for diagnosing diabetes: diagnostic criteria and performance characteristics in a U.S. population. Diabetes Care 2000; 23:163–69
9. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393–403
10. Nichols GA, Hillier TA, Brown JB: Normal fasting plasma glucose and risk of type 2 diabetes diagnosis. Am J Med 2008; 121:519–24
11. Carpenter JP, Coustan DR: Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 1982; 144:768–73
12. O’Sullivan JB, Mahan CM: Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964; 13:278–85
13. Metzger BE, Lowe LP, Dyer AR, et al.: Hyperglycemia and Adverse Pregnancy Outcomes Study Group: Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358:2467–76
14. Landon MB, Spong CY, Thom E, et al.: Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network: A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361:1339–48
