Diabetes mellitus represents a cluster of metabolic disorders distinguished by persistent hyperglycemia. This condition arises from impairments in insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes is linked to long-term damage, dysfunction, and eventual failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels.
The development of diabetes involves multiple pathogenic processes. These encompass autoimmune destruction of pancreatic β-cells, leading to insulin deficiency, and abnormalities causing resistance to insulin’s actions. At the core of disrupted 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 different points in the complex hormone action pathways. Often, both impaired insulin secretion and defects in insulin action coexist within a patient, making it challenging to pinpoint the primary cause of hyperglycemia.
Symptoms of significant hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes increased appetite (polyphagia), and blurred vision. Chronic hyperglycemia can 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. They include retinopathy, potentially leading to blindness; nephropathy, which can progress 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. Individuals with diabetes also face a higher 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 fall into two main categories: type 1 and type 2 diabetes. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion, often identifiable through serological evidence of autoimmune processes in pancreatic islets and genetic markers. Type 2 diabetes, the more prevalent form, results from a combination of insulin resistance and an insufficient compensatory insulin secretion. In type 2 diabetes, hyperglycemia may be present for an extended period before diagnosis, often without noticeable clinical symptoms. During this asymptomatic phase, abnormalities in carbohydrate metabolism can be detected through plasma glucose measurements in a fasting state or after a glucose challenge.
The severity of hyperglycemia can fluctuate over time, depending on the progression of the underlying disease and its management as illustrated in Figure 1. A disease process may be present without yet causing hyperglycemia, or it might manifest as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without meeting full 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 contrast, individuals with extensive β-cell destruction and no residual insulin secretion need insulin for survival. The degree of hyperglycemia, therefore, reflects the severity of the metabolic disturbance and the effectiveness of treatment, rather than solely the nature of the underlying disease process.
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 individuals don’t fit neatly into a single category. For instance, gestational diabetes mellitus (GDM) might persist post-delivery, leading to a diagnosis of type 2 diabetes. Conversely, diabetes induced by steroid medications might resolve upon discontinuation, only to reappear years later due to pancreatitis. Similarly, thiazide-induced diabetes might actually be underlying type 2 diabetes exacerbated by the medication. For clinicians and patients, understanding the pathogenesis of hyperglycemia and effective treatment strategies is more crucial than simply labeling the diabetes type.
Type 1 Diabetes: β-cell Destruction and Insulin Deficiency
Type 1 diabetes is characterized by the destruction of pancreatic β-cells, typically leading to absolute insulin deficiency. It is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
Immune-mediated diabetes, accounting for 5-10% of diabetes cases, was previously known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes. It results from autoimmune destruction of pancreatic β-cells. Markers of this autoimmune process include 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 present in 85-90% of individuals upon initial detection of fasting hyperglycemia. The disease also has strong HLA associations, linked to DQA and DQB genes and influenced by DRB genes, with HLA-DR/DQ alleles being either predisposing or protective.
The rate of β-cell destruction varies, being rapid in infants and children and slower in adults. Some patients, especially children and adolescents, may present with diabetic ketoacidosis (DKA) as the first symptom. Others may initially have mild fasting hyperglycemia that can quickly escalate to severe hyperglycemia or DKA during infections or stress. Adults might retain enough residual β-cell function to avoid DKA for years but eventually become insulin-dependent and at risk for DKA. In advanced stages, insulin secretion is minimal or absent, indicated by low or undetectable plasma C-peptide levels. Immune-mediated diabetes is most common in childhood and adolescence but can occur at any age.
The autoimmune β-cell destruction in this type is influenced by multiple genetic predispositions and environmental factors that are still not fully understood. While patients are typically not obese at diagnosis, obesity does not rule out this diagnosis. These patients are also more susceptible to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac disease, 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 a minority of type 1 diabetes cases, predominantly affecting individuals of African or Asian descent. Patients may suffer from episodic ketoacidosis with varying degrees of insulin deficiency between episodes. This form 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 Relative Insulin Deficiency
Type 2 diabetes, accounting for 90-95% of diabetes cases, was previously termed non-insulin-dependent diabetes or adult-onset diabetes. It encompasses individuals with insulin resistance and a relative insulin deficiency. Initially and often throughout life, these individuals do not require insulin for survival. The exact causes are diverse and not fully understood, but autoimmune β-cell destruction is not involved, nor are other specific causes of diabetes.
Obesity is a major factor in type 2 diabetes, with obese individuals experiencing some degree of insulin resistance. Even non-obese individuals may have increased abdominal fat, contributing to insulin resistance. Spontaneous ketoacidosis is rare in type 2 diabetes, typically occurring only under severe stress like infection. Type 2 diabetes often remains undiagnosed for years due to gradual hyperglycemia development and initially mild symptoms. However, these patients are still at increased risk of macrovascular and microvascular complications. Although 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. The risk of type 2 diabetes increases with age, obesity, physical inactivity, prior GDM, hypertension, dyslipidemia, and varies among racial/ethnic groups. It has a strong genetic predisposition, even more so than autoimmune type 1 diabetes, though the genetics are complex and not fully defined.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several specific types of diabetes exist, including those due to genetic defects, exocrine pancreas diseases, endocrinopathies, drug or chemical exposure, infections, uncommon immune-mediated forms, and other genetic syndromes.
Genetic Defects of β-cell Function
Several diabetes forms are linked to monogenetic defects in β-cell function, often presenting as hyperglycemia before age 25. These are known as 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 hepatic transcription factor HNF-1α on chromosome 12. Another form is due to glucokinase gene mutations on chromosome 7p, leading to defective glucokinase, which normally acts as a “glucose sensor” in β-cells. Less common forms involve mutations in 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 also linked to diabetes and deafness. This mutation is also seen in MELAS syndrome, but diabetes isn’t a consistent feature, suggesting variable expression of this genetic defect.
Genetic abnormalities preventing proinsulin conversion to insulin have been identified in some families, inherited autosomal dominantly, causing mild glucose intolerance. Similarly, mutant insulin molecules with impaired receptor binding have been found, also with autosomal inheritance and only mild glucose metabolism impairment.
Genetic Defects in Insulin Action
Unusual diabetes causes include genetically determined insulin action abnormalities. Insulin receptor mutations can lead to a spectrum from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some patients may exhibit acanthosis nigricans, and women may experience virilization and polycystic ovaries. Historically, this was termed type A insulin resistance. Leprechaunism and Rabson-Mendenhall syndrome are pediatric syndromes with insulin receptor gene mutations, extreme insulin resistance, characteristic facial features (leprechaunism, usually fatal in infancy), and teeth/nail abnormalities and pineal gland hyperplasia (Rabson-Mendenhall).
In insulin-resistant lipoatrophic diabetes, insulin receptor defects are not found, suggesting postreceptor signal transduction pathway lesions.
Diseases of the Exocrine Pancreas
Diffuse pancreatic injury from pancreatitis, trauma, infection, pancreatectomy, or pancreatic carcinoma can cause diabetes. Except for cancer-induced diabetes, damage must be extensive. Pancreatic cancer-related diabetes suggests mechanisms beyond β-cell mass reduction. Cystic fibrosis and hemochromatosis can also damage β-cells and impair insulin secretion if severe enough. Fibrocalculous pancreatopathy may present with abdominal pain radiating to the back and pancreatic calcifications. Autopsy findings include pancreatic fibrosis and calcium stones in exocrine ducts.
Endocrinopathies
Excess hormones like growth hormone, cortisol, glucagon, and epinephrine can antagonize insulin action, potentially causing diabetes in individuals with pre-existing insulin secretion defects. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can lead to diabetes, which typically resolves with hormone excess correction.
Somatostatinoma- and aldosteronoma-induced hypokalemia can cause diabetes by inhibiting insulin secretion, generally resolving after tumor removal.
Drug- or Chemical-Induced Diabetes
Numerous drugs can impair insulin secretion, potentially precipitating diabetes in those with insulin resistance. The classification can be unclear when β-cell dysfunction and insulin resistance interplay. Toxins like Vacor and intravenous pentamidine can permanently destroy β-cells, though such reactions are rare. Drugs and hormones like 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 common drug-, hormone-, or 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 |
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Table 1. Etiologic classification of diabetes mellitus
Insulin use at any stage does not define diabetes type itself.
Infections
Certain viruses, like congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, have been linked to β-cell destruction and diabetes. Congenital rubella-associated diabetes often shares HLA and immune markers with type 1 diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Rare immune-mediated diabetes forms include stiff-man syndrome and anti-insulin receptor antibody-related diabetes. Stiff-man syndrome, an autoimmune CNS disorder with muscle stiffness and spasms, is associated with high GAD autoantibodies, and about one-third of patients develop diabetes. Anti-insulin receptor antibodies can cause diabetes by blocking insulin binding or, paradoxically, hypoglycemia by acting as insulin agonists. These antibodies are sometimes found in systemic lupus erythematosus and other autoimmune diseases, often accompanied by acanthosis nigricans, historically 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 with β-cell absence at autopsy, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first recognized during pregnancy. While usually resolving post-delivery, the definition applies regardless of persistence and includes cases where glucose intolerance may have pre-existed or begun during pregnancy. This definition ensures consistent detection and classification of GDM, but its limitations are acknowledged, especially with rising type 2 diabetes in women of childbearing age and 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 diagnosed at their first prenatal visit using standard criteria (Table 3) be classified as having overt diabetes, not GDM. GDM complicates approximately 7% of pregnancies (1-14% depending on population and tests), affecting 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). |
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Table 3. Criteria for the diagnosis of diabetes
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
Categories of Increased Risk for Diabetes
In 1997 and 2003, expert committees recognized an intermediate group with glucose levels higher than normal but not meeting diabetes criteria. These individuals have 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 pre-diabetes, indicating a high risk of future diabetes and cardiovascular disease, not clinical entities themselves. They are intermediate stages in various disease processes (Table 1) and are associated with obesity (especially abdominal), dyslipidemia, and hypertension. Lifestyle interventions (increased physical activity, 5-10% weight loss) and some medications can prevent or delay diabetes in IGT individuals, though impact on mortality or cardiovascular disease is not yet proven. In 2003, the ADA lowered the IFG FPG cut-off from 110 mg/dL to 100 mg/dL to align IFG prevalence with IGT, but WHO and other organizations did not adopt this change.
With increased A1C use for diabetes diagnosis, it also identifies those at higher future diabetes risk. In 2009, an international expert committee noted a continuous diabetes risk with all glycemic measures and didn’t formally define an intermediate A1C category but acknowledged increased risk at A1C 6.0-6.4%, significantly higher than the general population. NHANES data suggest A1C 5.5-6.0% accurately identifies IFG/IGT individuals. DPP data showed preventive interventions effective in groups with A1C levels both below and above 5.9%. Therefore, A1C 5.5-6% is a likely range to initiate preventive measures.
Defining a lower A1C limit for intermediate risk is somewhat arbitrary due to continuous diabetes risk with glycemia. The A1C cut-off should balance false negative (missed diabetes risk) and false positive (unnecessary intervention) costs. Compared to FPG 100 mg/dL, A1C 5.7% is less sensitive but more specific and has higher positive predictive value for future diabetes. A study found A1C 5.7% has 66% sensitivity and 88% specificity for 6-year diabetes incidence. NHANES data indicate A1C 5.7% has modest sensitivity (39-45%) but high specificity (81-91%) for IFP/IGT. Other analyses suggest A1C 5.7% is associated with diabetes risk similar to high-risk DPP participants. Thus, A1C 5.7-6.4% can identify high-risk individuals for future diabetes, termed pre-diabetes if desired.
Individuals with A1C 5.7-6.4% should be informed of increased diabetes and cardiovascular disease risks and advised on lifestyle strategies like weight loss and physical activity. Risk is curvilinear with A1C, rising disproportionately at higher levels. Interventions and follow-up should be more intensive for those with A1C above 6.0%, considered at very high risk. However, even below A1C 5.7%, risk exists depending on A1C level and other factors like obesity and family history.
Table 2 summarizes increased diabetes risk categories. Risk evaluation should include global risk factor assessment for both diabetes and cardiovascular disease, considering 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% |
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Table 2. Categories of increased risk for diabetes
*For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has historically relied on glucose criteria like FPG or 75-g OGTT. In 1997, diagnostic criteria were revised based on the association between FPG levels and retinopathy prevalence to identify threshold glucose levels. 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, informing new diagnostic cut-offs: ≥126 mg/dL (7.0 mmol/L) for FPG and confirming ≥200 mg/dL (11.1 mmol/L) for 2-h PG.
A1C, a common chronic glycemia marker reflecting 2-3 month average glucose, is crucial in diabetes management, correlating with microvascular and, to a lesser extent, macrovascular complications. Prior committees didn’t recommend A1C for diagnosis due to assay standardization issues. However, with improved standardization, an international expert committee in a recent report recommended A1C for diabetes diagnosis with a ≥6.5% threshold, affirmed by the ADA. This A1C cut-off aligns with retinopathy prevalence inflection points, similar to FPG and 2-h PG thresholds. Diagnostic A1C tests should be NGSP-certified and standardized to the DCCT assay. Point-of-care A1C assays are not yet accurate enough for diagnosis.
Using a chronic marker like A1C is logical and convenient. A1C offers advantages over FPG: no fasting required, better 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 certain individuals. A1C can be misleading in anemias and hemoglobinopathies, which might have ethnic/geographic variations. For hemoglobinopathies without abnormal red cell turnover like sickle cell trait, use A1C assays without abnormal hemoglobin interference. For conditions with abnormal red cell turnover like hemolysis and iron deficiency anemias, diabetes diagnosis must rely solely on glucose criteria.
Established glucose criteria (FPG, 2-h PG) remain valid. Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in patients with severe hyperglycemia or hyperglycemic crisis can also diagnose diabetes. In such cases, A1C would likely be measured and usually be above the diagnostic cut-off. However, in rapidly developing diabetes like type 1 in children, A1C may not be significantly elevated initially.
There isn’t 100% concordance between FPG and 2-h PG or between A1C and glucose-based tests. NHANES data indicate A1C ≥6.5% identifies one-third fewer undiagnosed diabetes cases than FPG ≥126 mg/dL. However, A1C’s greater practicality might increase overall diagnoses due to wider application.
Further research is needed on patients with discordant glycemic status from different tests. Discordance might arise from measurement variability, changes over time, or tests measuring different physiological processes. Elevated A1C with non-diabetic FPG might suggest higher postprandial glucose or glycation rates. High FPG with A1C below cut-off might indicate increased hepatic glucose production or reduced glycation rates.
Like most diagnostic tests, a positive diabetes test should be repeated to rule out errors, unless clinically obvious (hyperglycemic symptoms or crisis). Repeating the same test is preferable for confirmation. For example, A1C 7.0% confirmed by 6.8% confirms diabetes. If different tests (e.g., FPG and A1C) both exceed diagnostic thresholds, diabetes is confirmed.
In case of discordant results, the test above the cut-off should be repeated, and diagnosis is based on the confirmed test. For example, if A1C criteria are met (two results ≥6.5%) but not FPG.
If a repeated test falls below the diagnostic threshold, it’s more likely for 2-h PG, less for FPG, and least for A1C, barring lab error. Such patients likely have borderline results and should be closely followed with repeat testing in 3-6 months.
The choice of diagnostic test is at the healthcare professional’s discretion, considering test availability and practicality. More critical than the specific test is ensuring diabetes testing is performed when indicated, as evidence suggests under-testing and under-counseling for at-risk patients and accompanying cardiovascular risk factors. Table 3 summarizes current diabetes diagnostic criteria.
Diagnosis of GDM
GDM diagnosis criteria currently follow Carpenter and Coustan, supported by ADA’s Fourth International Workshop-Conference on Gestational Diabetes Mellitus in 1997, which also endorsed using a diagnostic 75-g 2-h OGTT.
Testing for Gestational Diabetes
Universal GDM screening was previously recommended. However, low-risk women need not be screened. Low-risk criteria include: age <25 years, normal weight, no first-degree relative with diabetes, no abnormal glucose metabolism history, no poor obstetric outcome history, and not belonging to a high-prevalence ethnic/racial group.
GDM risk assessment should occur at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should undergo immediate glucose testing. If initial screening is negative, retest at 24-28 weeks gestation. Average-risk women should be tested at 24-28 weeks.
FPG >126 mg/dL or random plasma glucose >200 mg/dL meets diabetes diagnostic threshold. Confirm diagnosis on a subsequent day. Confirmation negates need for glucose challenge. Without this hyperglycemia level, GDM evaluation for average or high-risk women follows one of two approaches.
One-Step Approach
Perform diagnostic OGTT without prior glucose screening, potentially cost-effective in high-risk patients/populations.
Two-Step Approach
Initial screening with 50-g oral glucose load (glucose challenge test [GCT]), measuring 1-h plasma glucose. Diagnostic OGTT follows for women exceeding GCT glucose threshold. A GCT threshold >140 mg/dL identifies ~80% of GDM cases, increasing to 90% with a >130 mg/dL cut-off.
Both approaches use OGTT for GDM diagnosis. 100-g OGTT criteria from O’Sullivan and Mahan, modified by Carpenter and Coustan (Table 4, top), or 75-g glucose load criteria (Table 4, bottom) can be used. The 75-g test is less validated.
Table 4. Diagnosis of GDM with a 100-g or 75-g glucose load
| mg/dl | mmol/l | |
|---|---|---|
| 100-g glucose load | ||
| Fasting | 95 | 5.3 |
| 1-h | 180 | 10.0 |
| 2-h | 155 | 8.6 |
| 3-h | 140 | 7.8 |
| 75-g glucose load | ||
| Fasting | 95 | 5.3 |
| 1-h | 180 | 10.0 |
| 2-h | 155 | 8.6 |
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Table 4. Diagnosis of GDM with a 100-g or 75-g glucose load
Two or more venous plasma concentrations must be met or exceeded for a positive GDM diagnosis. Test in the morning after 8-14 hour overnight fast, following ≥3 days of unrestricted diet (≥150g carbohydrate/day) and activity. Subject seated, non-smoking during test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, a large multinational study (~25,000 pregnant women), showed continuous risk increase of adverse outcomes with maternal glycemia at 24-28 weeks, even within previously normal pregnancy ranges, often without risk thresholds. These results prompted GDM diagnostic criteria reconsideration. IADPSG recommended 75-g OGTT for all women without prior diabetes at 24-28 weeks, establishing diagnostic cut-offs for fasting, 1-h, and 2-h plasma glucose that conveyed an odds ratio for adverse outcomes of at least 1.75 compared to women with mean glucose levels in HAPO study.
As of this update, ADA is collaborating with US obstetrical organizations to consider adopting IADPSG diagnostic criteria and discussing implications of this change. 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 thanks the following volunteer members of the writing group for the updated sections on diagnosis and categories of increased risk: 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.
