Diabetes mellitus is not a singular disease, but rather a cluster of metabolic disorders all pointing towards a common outcome: hyperglycemia. This condition arises from issues in insulin production, insulin function, or often, a combination of both. The persistent high blood sugar levels characteristic of diabetes are the root cause of long-term damage and malfunction across various organs, with the eyes, kidneys, nerves, heart, and blood vessels being particularly vulnerable.
The development of diabetes is a complex process involving multiple pathways. At one end of the spectrum is the autoimmune destruction of pancreatic β-cells, leading to a stark deficiency in insulin. On the other end are abnormalities causing resistance to insulin’s action. Fundamentally, diabetes disrupts the body’s metabolism of carbohydrates, fats, and proteins due to ineffective insulin action in target tissues. This ineffectiveness can stem from insufficient insulin secretion or reduced tissue responsiveness to insulin, or a mix of both. In many patients, it’s hard to pinpoint whether impaired secretion or action is the primary culprit behind hyperglycemia.
Uncontrolled hyperglycemia manifests in noticeable symptoms such as excessive urination (polyuria), intense thirst (polydipsia), unexplained weight loss, sometimes increased appetite (polyphagia), and blurred vision. Chronic hyperglycemia can also hinder growth and increase susceptibility to infections. In acute scenarios, uncontrolled diabetes can lead to life-threatening conditions like ketoacidosis or hyperosmolar hyperglycemic state.
Over the long term, diabetes can result in serious complications. These include retinopathy, potentially causing blindness; nephropathy, which can progress to kidney failure; peripheral neuropathy, increasing risks of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy, leading to digestive, urological, cardiovascular issues, and sexual dysfunction. Furthermore, individuals with diabetes face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipid abnormalities are also commonly observed in diabetic populations.
Most diabetes cases fall into two major categories based on their underlying causes. Type 1 diabetes is marked by an absolute lack of insulin secretion. Individuals at risk for type 1 diabetes can often be identified through blood tests revealing autoimmune markers in pancreatic islets and specific genetic markers. Type 2 diabetes, the more prevalent form, results from insulin resistance coupled with an inadequate insulin response from the body. In type 2 diabetes, significant hyperglycemia capable of causing tissue damage can be present for years without noticeable symptoms. This asymptomatic phase can be detected by measuring blood glucose levels after fasting or after a glucose challenge, like the oral glucose tolerance test.
The severity of hyperglycemia in diabetes can fluctuate over time, influenced by the progression of the underlying disease and its management, as illustrated in Figure 1. A disease process might be present but not advanced enough to cause hyperglycemia initially. It can also manifest as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without meeting full diagnostic criteria for diabetes. Some individuals with diabetes can manage their blood sugar through lifestyle changes like weight loss and exercise, or with oral medications, avoiding the need for insulin. Others may still produce some insulin but require supplemental insulin to achieve adequate control. In contrast, those with extensive β-cell destruction and no insulin production are entirely dependent on external insulin for survival. The level of hyperglycemia, therefore, reflects the severity of the metabolic disturbance and the effectiveness of treatment, rather than the fundamental nature of the diabetic process itself.
Figure 1.
Figure 1: Spectrum of Glycemic Disorders: Etiologic Types and Stages. This diagram illustrates the progression of glycemia disorders, highlighting different stages and types of diabetes. *Note: Even after experiencing ketoacidosis, some patients may temporarily return to normal blood sugar levels without continuous therapy, known as the “honeymoon” remission phase. **Important exception: In rare cases, patients in these categories, such as those with Vacor toxicity or type 1 diabetes in pregnancy, might require insulin for survival.
Classifying Diabetes Mellitus and Glucose Regulation Disorders
Assigning a specific type of diabetes can be complex, often depending on the clinical context at diagnosis. Many individuals don’t neatly fit into a single category. For instance, gestational diabetes mellitus (GDM) diagnosed during pregnancy might persist as type 2 diabetes after delivery. Similarly, diabetes induced by high-dose steroid medication might resolve once steroids are stopped, only to potentially reappear years later due to other conditions like pancreatitis. Another scenario involves thiazide diuretics, which, while rarely causing severe hyperglycemia on their own, can unmask underlying type 2 diabetes. Therefore, for both clinicians and patients, understanding the mechanisms behind hyperglycemia and managing it effectively is more crucial than simply labeling the diabetes type.
Type 1 Diabetes: Immune-Mediated and Idiopathic Forms
Type 1 diabetes is characterized by β-cell destruction, typically leading to absolute insulin deficiency. It is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
This form constitutes 5–10% of all diabetes cases and was previously known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes. It is caused by an autoimmune attack that destroys the insulin-producing β-cells in the pancreas. 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 when fasting hyperglycemia is first detected. Genetically, immune-mediated diabetes is strongly linked to HLA genes, particularly DQA and DQB, and influenced by DRB genes. Specific HLA-DR/DQ alleles can either increase or decrease the risk of developing this condition.
The rate of β-cell destruction varies significantly. It can be rapid, especially in infants and children, or slower, mainly in adults. Some patients, particularly children and adolescents, may initially present with diabetic ketoacidosis. Others may have milder fasting hyperglycemia that can quickly escalate to severe hyperglycemia or ketoacidosis under stress, such as infection. Adults may maintain some residual β-cell function, preventing ketoacidosis for years, but eventually become insulin-dependent and prone to ketoacidosis. At this advanced stage, insulin secretion is minimal or absent, reflected in 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, which are still not fully understood. Although patients are typically not obese at diagnosis, obesity does not rule out this type of diabetes. These individuals are also at higher risk for 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
Some cases of type 1 diabetes lack a known cause (idiopathic). These patients experience permanent insulin deficiency and are prone to ketoacidosis but show no signs of autoimmunity. This category is less common, predominantly affecting individuals of African or Asian descent. Idiopathic diabetes is characterized by episodic ketoacidosis with varying degrees of insulin deficiency between episodes. It has a strong hereditary component but lacks immunological markers of β-cell autoimmunity and is not associated with HLA. The need for insulin replacement therapy in these patients can fluctuate.
Type 2 Diabetes: Insulin Resistance and Secretory Defects
Type 2 diabetes is the most common form, accounting for approximately 90–95% of all diabetes cases. Formerly known as non–insulin-dependent diabetes or adult-onset diabetes, it encompasses individuals with insulin resistance and a relative insulin deficiency. Importantly, these patients typically do not require insulin for survival, especially in the initial stages and often throughout their lives. The exact causes of type 2 diabetes are diverse and not fully understood, but it is not associated with autoimmune destruction of β-cells or other specific diabetes etiologies.
Obesity is a major contributing factor, with most type 2 diabetes patients being obese. Even those not conventionally obese may have increased abdominal fat, which is strongly linked to insulin resistance. 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 its gradual development and initially mild symptoms. However, even in these early stages, patients are at increased risk of macrovascular and microvascular complications. While insulin levels in type 2 diabetes may appear normal or even elevated, they are insufficient to overcome insulin resistance and maintain normal blood glucose levels. Weight loss and certain medications can improve insulin resistance but rarely restore it to normal. The risk of type 2 diabetes increases with age, obesity, lack of physical activity, prior gestational diabetes, hypertension, and dyslipidemia. It is also more prevalent in certain racial and ethnic groups and has a strong genetic component, though the genetics are complex and not fully defined.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several other specific types of diabetes exist, each with unique underlying mechanisms.
Genetic Defects of β-Cell Function
Several monogenic disorders lead to diabetes through defects in β-cell function. These often manifest as hyperglycemia at a young age, typically before 25. Known as maturity-onset diabetes of the young (MODY), these conditions are characterized by impaired insulin secretion with minimal insulin resistance. MODY is inherited in an autosomal dominant pattern. Mutations at multiple genetic loci have been identified. The most common form involves mutations in the hepatocyte nuclear factor (HNF)-1α gene on chromosome 12. Another form is linked to mutations in the glucokinase gene on chromosome 7p, affecting glucokinase, the enzyme that acts as the “glucose sensor” in 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 mutations are also associated with diabetes and deafness. The most common mutation is at position 3,243 in the tRNA leucine gene. Genetic defects preventing the conversion of proinsulin to insulin and mutations producing faulty insulin molecules with impaired receptor binding are rare genetic causes of mild diabetes.
Genetic Defects in Insulin Action
Rare forms of diabetes result from genetic abnormalities in insulin action. Mutations in the insulin receptor gene can cause a spectrum of metabolic issues, from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some individuals may exhibit acanthosis nigricans. Women might experience virilization and polycystic ovaries. Syndromes like Leprechaunism and Rabson-Mendenhall syndrome, both pediatric conditions with insulin receptor gene mutations, lead to extreme insulin resistance, with Leprechaunism typically fatal in infancy and Rabson-Mendenhall syndrome associated with dental and nail abnormalities and pineal hyperplasia. Insulin-resistant lipoatrophic diabetes is another condition where post-receptor defects are suspected.
Diseases of the Exocrine Pancreas
Damage to the pancreas from conditions like pancreatitis, trauma, infection, pancreatectomy, and pancreatic cancer can cause diabetes. Except for cancer-related diabetes, substantial pancreatic damage is usually required. Cystic fibrosis and hemochromatosis, if extensive, can also impair insulin secretion. Fibrocalculous pancreatopathy, characterized by abdominal pain, pancreatic calcifications, fibrosis, and ductal stones, can also lead to diabetes.
Endocrinopathies
Excess hormones that counter insulin action, such as growth hormone, cortisol, glucagon, and epinephrine, can induce diabetes. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can lead to diabetes, usually in individuals with pre-existing insulin secretion issues. Hyperglycemia often resolves when the hormonal excess is addressed. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion, typically resolving after tumor removal.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action, potentially triggering diabetes, especially in those with insulin resistance. Toxins like Vacor and intravenous pentamidine can permanently damage β-cells. Drugs like nicotinic acid and glucocorticoids impair insulin action. Alpha-interferon has been linked to diabetes with islet cell antibodies and severe insulin deficiency. Table 1 lists common 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 |
Table 1: Etiologic Classification of Diabetes Mellitus. This table provides a detailed classification of diabetes mellitus based on etiology, including type 1, type 2, other specific types, and gestational diabetes. It further breaks down ‘other specific types’ into genetic defects, exocrine pancreas diseases, endocrinopathies, drug-induced diabetes, infections, uncommon immune forms, and associated genetic syndromes.
Insulin use doesn’t define diabetes type; patients with any diabetes form may require insulin at some point.
Infections
Certain viruses, such as congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, have been linked to β-cell destruction and diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, an autoimmune neurological disorder, are associated with diabetes. Patients with stiff-man syndrome often have GAD autoantibodies, and about a third develop diabetes. Anti-insulin receptor antibodies can also cause diabetes by blocking insulin binding, though paradoxically, they can sometimes mimic insulin and cause hypoglycemia. These antibodies are seen in conditions like systemic lupus erythematosus and are associated with acanthosis nigricans, formerly termed type B insulin resistance.
Other Genetic Syndromes
Several genetic syndromes, including Down syndrome, Klinefelter syndrome, Turner syndrome, and Wolfram syndrome, increase diabetes risk. Wolfram syndrome, for example, is characterized by insulin-deficient diabetes, diabetes insipidus, optic atrophy, and deafness. Table 1 lists other associated syndromes.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first detected during pregnancy. While typically resolving after delivery, it may persist or indicate pre-existing undiagnosed diabetes. The increasing prevalence of obesity and type 2 diabetes in women of childbearing age has led to a rise in pregnant women with undiagnosed type 2 diabetes.
The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends diagnosing overt diabetes, not GDM, in high-risk pregnant women at their first prenatal visit if they meet standard diabetes criteria (Table 3). GDM complicates approximately 7% of pregnancies.
Table 3.
Criteria for the Diagnosis of Diabetes
| 1. A1C ≥6.5%. This test must be performed in a laboratory using an NGSP certified method 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 hours.* |
| OR |
| 3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should follow WHO guidelines, using a glucose load of 75g anhydrous glucose in water.* |
| OR |
| 4. In patients with classic hyperglycemia symptoms or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l). |
Table 3: Diagnostic Criteria for Diabetes. This table outlines the criteria for diagnosing diabetes mellitus, including A1C levels, Fasting Plasma Glucose (FPG), 2-hour plasma glucose during an Oral Glucose Tolerance Test (OGTT), and random plasma glucose in symptomatic patients. *Note: Criteria 1–3 should be confirmed by repeat testing unless unequivocal hyperglycemia is present.
Categories of Increased Risk for Diabetes
The Expert Committee on Diagnosis and Classification of Diabetes Mellitus recognized an intermediate category of individuals with glucose levels higher than normal but not meeting diabetes criteria. These individuals are classified as having 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 IGT, often termed pre-diabetes, indicate a high risk of developing diabetes and cardiovascular disease. They are not clinical conditions themselves but rather risk factors, potentially observed in various disease processes listed in Table 1. IFG and IGT are linked to obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes onset in people with IGT, though their impact on mortality and cardiovascular disease is still under investigation. The ADA lowered the IFG threshold to 100 mg/dl (5.6 mmol/l), while WHO and other organizations maintain a higher threshold.
A1C is increasingly used to identify individuals at risk. While no formal intermediate A1C category was initially defined, it’s noted that A1C levels between 6.0 and 6.4% indicate a significantly higher diabetes incidence. Data suggest that an A1C between 5.5 and 6.0% accurately identifies people with IFG or IGT. An FPG of 110 mg/dl (6.1 mmol/l) corresponds to an A1C of 5.6%, and 100 mg/dl (5.6 mmol/l) to 5.4%. Preventive interventions are effective even in those with A1C below 5.9%. Thus, an A1C range of 5.5–6% is a reasonable threshold for initiating preventive measures.
Defining a lower limit for intermediate A1C is somewhat arbitrary, as diabetes risk is a continuum. A 5.7% A1C cut-off is less sensitive but more specific than the 100 mg/dl fasting glucose cut-off and has a higher positive predictive value for future diabetes. Studies show a 5.7% cut-off has 66% sensitivity and 88% specificity for predicting 6-year diabetes incidence. An A1C of 5.7% is associated with diabetes risk similar to high-risk groups in prevention programs. Therefore, an A1C range of 5.7–6.4% is considered to identify individuals at high risk, termed pre-diabetes.
Individuals with A1C 5.7–6.4% should be informed of their increased risks and counseled on lifestyle modifications. Risk increases disproportionately with A1C levels, making interventions and follow-up particularly crucial for those above 6.0%. However, even those with A1C below 5.7% may still be at risk depending on other factors.
Table 2 summarizes categories of increased diabetes risk. Risk assessment should include a comprehensive evaluation of diabetes and cardiovascular risk factors, considering comorbidities, life expectancy, lifestyle 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% |
Table 2: Categories of Increased Risk for Diabetes. This table lists the criteria for identifying individuals at increased risk for diabetes, including Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), and elevated A1C levels. *Note: Risk is continuous across all three tests, increasing disproportionately at the higher ends of the ranges and extending below the lower limits.
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has long relied on glucose criteria, FPG or OGTT. In 1997, diagnostic criteria were revised based on the link between FPG levels and retinopathy. Studies showed a glycemic threshold above which retinopathy prevalence increased linearly. This led to the diagnostic cut-off of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed ≥200 mg/dl (11.1 mmol/l) for 2-h PG.
A1C, reflecting average glucose over 2–3 months, is crucial in diabetes management, correlating with microvascular and macrovascular complications. While prior committees hesitated to use A1C for diagnosis due to standardization issues, A1C assays are now highly standardized. An International Expert Committee recommended A1C for diagnosis with a threshold of ≥6.5%, which ADA supports. This A1C cut-off aligns with retinopathy prevalence inflection points, similar to FPG and 2-h PG thresholds. Diagnostic A1C tests must be NGSP certified and standardized to the DCCT assay. Point-of-care A1C tests are not yet accurate enough for diagnosis.
Using A1C offers advantages over FPG, including convenience (no fasting), greater stability, and less variability during stress. However, A1C is more costly and less available in some regions, with incomplete correlation with average glucose in certain individuals. It can also be misleading in anemias and hemoglobinopathies. For these conditions, glucose criteria must be used. For hemoglobinopathies with normal red cell turnover, specific A1C assays are available.
Established glucose criteria (FPG, 2-h PG) remain valid. Random plasma glucose ≥200 mg/dl (11.1 mmol/l) in symptomatic patients can also diagnose diabetes. While A1C is often measured in such cases and likely elevated, in rapidly developing diabetes like type 1 in children, A1C may not be significantly high initially.
A1C and glucose-based tests don’t always fully agree. A ≥6.5% A1C cut-off identifies fewer undiagnosed diabetes cases than a ≥126 mg/dl FPG cut-off. However, A1C’s greater practicality may lead to wider testing and potentially more diagnoses.
Further research is needed to understand discrepancies between A1C and glucose tests. Discordance may arise from measurement variability, time changes, or different physiological processes measured by each test. Elevated A1C with non-diabetic FPG might indicate higher postprandial glucose or glycation rates. High FPG with non-diabetic A1C could suggest increased hepatic glucose production or reduced glycation rates.
Diabetes diagnosis should be confirmed by repeat testing, preferably using the same test, unless clinical presentation is clear. If different tests are used and both are diagnostic, diabetes is confirmed. If discordant, repeat the test that was above the diagnostic threshold; diagnosis is based on the confirmed test.
If a repeat test falls below the diagnostic threshold, close patient monitoring and repeat testing in 3–6 months may be necessary.
Healthcare professionals should choose the most appropriate test based on patient needs and test availability. The most critical aspect is ensuring diabetes testing is performed when indicated, as many at-risk individuals are still not adequately tested or counseled. Table 3 summarizes current diagnostic criteria.
Diagnosis of GDM
GDM diagnosis currently uses Carpenter and Coustan criteria. ADA’s Fourth International Workshop-Conference on Gestational Diabetes Mellitus supports these criteria and the alternative 75-g 2-h OGTT.
Testing for Gestational Diabetes
Routine GDM screening is generally recommended. However, women meeting all low-risk criteria may not need screening. Low-risk criteria include being under 25, normal weight, no family history of diabetes, no history of abnormal glucose metabolism or poor obstetric outcomes, and not belonging to a high-risk ethnic/racial group.
Risk assessment should occur at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should be tested immediately. If initial screening is negative, retesting should occur at 24–28 weeks. Average-risk women should be tested at 24–28 weeks.
FPG >126 mg/dl (7.0 mmol/l) or random glucose >200 mg/dl (11.1 mmol/l) is diagnostic for diabetes. Confirmation is required on a subsequent day unless unequivocal hyperglycemia is present, precluding a glucose challenge. For other women, GDM evaluation follows one of two approaches:
One-Step Approach
Perform a diagnostic OGTT without initial screening, potentially cost-effective in high-risk groups.
Two-Step Approach
Initial screening with a 50-g glucose challenge test (GCT). If the 1-hour glucose level exceeds a threshold (e.g., >140 mg/dl or >130 mg/dl), a diagnostic OGTT is performed.
GDM diagnosis is based on OGTT results. Table 4 shows diagnostic criteria for 100-g OGTT (Carpenter/Coustan) and 75-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 |
Table 4: GDM Diagnosis with Glucose Load Tests. This table presents the diagnostic thresholds for Gestational Diabetes Mellitus using both 100-g and 75-g glucose load Oral Glucose Tolerance Tests (OGTT). Two or more venous plasma concentration values must be met or exceeded for a positive GDM diagnosis.
For a positive GDM diagnosis, two or more venous plasma glucose concentrations must meet or exceed the thresholds. The OGTT should be performed in the morning after an 8–14 hour fast, following at least 3 days of unrestricted diet (≥150 g carbohydrate/day) and normal physical activity. Subjects should remain seated and not smoke during the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a continuous increase in adverse pregnancy outcomes with rising maternal glycemia, even within previously normal ranges. IADPSG recommends a 75-g OGTT for all women at 24–28 weeks and established diagnostic cut-offs based on odds ratios for adverse outcomes from the HAPO study.
ADA is considering adopting IADPSG diagnostic criteria, which will significantly increase GDM prevalence. However, evidence suggests treating even mild GDM reduces maternal and infant morbidity.
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.
