Diabetes mellitus represents a cluster of metabolic disorders characterized by persistent hyperglycemia. This condition arises from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes is linked to long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels.
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 action. The core issue in diabetes, concerning carbohydrate, fat, and protein metabolism, is the insufficient action of insulin on target tissues. This deficient insulin action 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 the same patient, making it challenging to pinpoint the primary cause of hyperglycemia.
Pronounced hyperglycemia manifests with symptoms like polyuria, polydipsia, unexplained weight loss (sometimes accompanied by polyphagia), and blurred vision. Chronic hyperglycemia may also hinder growth and increase susceptibility to certain infections. Acute, life-threatening consequences of uncontrolled diabetes include hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.
Long-term diabetes complications are extensive, including retinopathy with potential vision loss, nephropathy progressing to renal failure, peripheral neuropathy increasing risks of foot ulcers, amputations, and Charcot joints, and autonomic neuropathy causing gastrointestinal, genitourinary, cardiovascular problems, 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 etiopathogenesis. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion. Individuals at higher risk can often be identified through serological evidence of autoimmune processes in pancreatic islets and specific genetic markers. Type 2 diabetes, the more common form, results from a combination of insulin resistance and an inadequate compensatory insulin secretion. In type 2 diabetes, a level of hyperglycemia sufficient to cause pathological and functional changes in target tissues, but without overt clinical symptoms, can persist for a considerable time before diagnosis. During this asymptomatic phase, carbohydrate metabolism abnormalities can be detected by measuring plasma glucose in a fasting state or after an oral glucose load.
The severity of hyperglycemia can fluctuate over time, depending on the progression of the underlying disease and its management, as illustrated in (Fig. 1). A disease process may be present without causing immediate hyperglycemia. The same process can lead to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without meeting full diagnostic criteria for diabetes. Some individuals with diabetes can achieve adequate glycemic control through lifestyle modifications like weight reduction and exercise, or with oral glucose-lowering medications, thus avoiding insulin therapy. Others might have some residual insulin secretion but require exogenous insulin for optimal glycemic control, though they can survive without it. However, individuals with significant β-cell destruction and no residual insulin secretion depend on insulin for survival. The metabolic abnormality’s severity can progress, regress, or remain stable. Therefore, the degree of hyperglycemia is more reflective of the underlying metabolic process’s severity and its treatment rather than the process’s inherent nature.
Figure 1.
Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival.
CLASSIFICATION OF DIABETES MELLITUS AND OTHER GLYCEMIC CATEGORIES
Assigning a specific diabetes type can be context-dependent at the time of diagnosis, and many cases do not fit neatly into a single category. For example, gestational diabetes mellitus (GDM) might resolve post-delivery, or it could transition into type 2 diabetes. Similarly, diabetes induced by exogenous steroids may remit upon discontinuation but reappear years later, perhaps after pancreatitis episodes. Thiazide-induced diabetes is another complex scenario; while thiazides rarely cause severe hyperglycemia alone, they can exacerbate underlying type 2 diabetes. For clinicians and patients, understanding the pathogenesis of hyperglycemia and effectively treating it is more crucial than rigidly labeling the diabetes type.
Type 1 Diabetes: Beta-Cell Destruction and Insulin Deficiency
Type 1 diabetes is characterized by the destruction of pancreatic beta-cells, typically leading to a severe or absolute insulin deficiency. This form accounts for a minority, 5–10%, of all diabetes cases. Formerly termed insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, it arises from a cell-mediated autoimmune attack on pancreatic β-cells. 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 85–90% of individuals newly diagnosed with fasting hyperglycemia, one or more of these autoantibodies are detectable. Type 1 diabetes also shows strong associations with HLA genes, particularly the DQA and DQB genes, 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, especially children and adolescents, may present with diabetic ketoacidosis (DKA) as their initial symptom. Others might have mild fasting hyperglycemia that quickly escalates to severe hyperglycemia and/or DKA during infections or periods of stress. Adults, in particular, may retain enough residual β-cell function to prevent ketoacidosis for years. However, these individuals eventually become insulin-dependent for survival and remain at risk for ketoacidosis. At this advanced stage, insulin secretion is minimal or absent, reflected in low or undetectable plasma C-peptide levels. Immune-mediated diabetes is more common in childhood and adolescence but can occur at any age, including later decades of life.
Autoimmune β-cell destruction is influenced by multiple genetic predispositions and environmental factors that are still not fully understood. Although patients are usually not obese at diagnosis, obesity does not rule out type 1 diabetes. These patients are also more susceptible to other autoimmune conditions like Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
Idiopathic Type 1 Diabetes
A subset of type 1 diabetes cases lacks identifiable causes, termed idiopathic type 1 diabetes. These patients experience permanent insulinopenia and are prone to ketoacidosis, but show no evidence of autoimmunity. While representing a small fraction of type 1 diabetes, it’s more prevalent among individuals of African or Asian descent. Idiopathic type 1 diabetes is characterized by episodic ketoacidosis with varying degrees of insulin deficiency between episodes. It has a strong hereditary component, lacks immunological markers of β-cell autoimmunity, and is not linked to 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 is the most prevalent form, accounting for approximately 90–95% of all diabetes cases. Previously known as non–insulin-dependent diabetes or adult-onset diabetes, type 2 diabetes includes individuals with insulin resistance and a relative insulin deficiency. Importantly, these individuals typically do not require insulin treatment for survival, especially at the outset and often throughout their lives. The etiology of type 2 diabetes is likely multifactorial, but autoimmune β-cell destruction is not involved, nor are the specific causes of diabetes listed in other categories.
Obesity is a major risk factor for type 2 diabetes, and it contributes to insulin resistance. Even non-obese individuals by standard criteria may have increased abdominal fat, a significant factor in insulin resistance. Spontaneous ketoacidosis is rare in type 2 diabetes; when it occurs, it’s usually triggered by the stress of another illness, such as infection. Type 2 diabetes often remains undiagnosed for years because hyperglycemia develops gradually and may not initially be severe enough to cause noticeable symptoms. However, these patients are still at increased risk for macrovascular and microvascular complications. While insulin levels in type 2 diabetes may appear normal or even elevated, they are inappropriately low relative to the degree of hyperglycemia, indicating defective β-cell function and insufficient compensation for insulin resistance. Insulin resistance can improve with weight loss and pharmacological interventions but rarely returns to normal. The risk of type 2 diabetes increases with age, obesity, physical inactivity, prior GDM, hypertension, and dyslipidemia, and varies across racial and ethnic groups. It exhibits a strong genetic predisposition, possibly stronger than autoimmune 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, each with distinct underlying causes.
Genetic Defects of Beta-Cell Function
Several diabetes forms are linked to monogenetic defects affecting β-cell function. These often manifest as hyperglycemia at a young age, typically before 25 years. Known as maturity-onset diabetes of the young (MODY), these are characterized by impaired insulin secretion with minimal insulin action defects. MODY is inherited in an autosomal dominant pattern. Mutations at multiple genetic loci on different chromosomes have been identified. The most common form involves mutations in the hepatocyte nuclear factor (HNF)-1α gene on chromosome 12. Another form is caused by mutations in the glucokinase gene on chromosome 7p, leading to a defective glucokinase enzyme. Glucokinase is crucial as it converts glucose to glucose-6-phosphate, a process that stimulates insulin secretion in β-cells, acting as the “glucose sensor.” Defects in glucokinase require higher glucose levels to trigger normal insulin secretion. Less common MODY forms result from mutations in other transcription factors like HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1.
Mitochondrial DNA point mutations are also associated with diabetes and deafness. The most frequent mutation is at position 3,243 in the tRNA leucine gene, an A-to-G transition. This same mutation is seen in MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome), but diabetes is not a core feature of MELAS, suggesting varied phenotypic expressions of this genetic defect.
Genetic abnormalities preventing the conversion of proinsulin to insulin have been identified in some families, inherited in an autosomal dominant manner, resulting in mild glucose intolerance. Similarly, mutant insulin molecules with impaired receptor binding have been found, also with autosomal inheritance, associated with mild or even normal glucose metabolism.
Genetic Defects in Insulin Action
Rare diabetes cases arise from genetically determined 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 present with acanthosis nigricans. Women might exhibit virilization and polycystic ovaries. Historically, this was termed type A insulin resistance. Leprechaunism and Rabson-Mendenhall syndrome are pediatric syndromes involving insulin receptor gene mutations, leading to extreme insulin resistance. Leprechaunism is characterized by distinct facial features and is typically fatal in infancy, while Rabson-Mendenhall syndrome includes dental and nail abnormalities and pineal gland hyperplasia.
In insulin-resistant lipoatrophic diabetes, structural and functional changes in the insulin receptor are not evident, suggesting defects in post-receptor signal transduction pathways.
Diseases of the Exocrine Pancreas
Conditions that broadly damage the pancreas can induce diabetes. Acquired conditions include pancreatitis, trauma, infection, pancreatectomy, and pancreatic cancer. Except for cancer-induced diabetes, significant pancreatic damage is usually required. Interestingly, even small pancreatic adenocarcinomas have been linked to diabetes, suggesting mechanisms beyond simple β-cell mass reduction. Cystic fibrosis and hemochromatosis, if extensive, can also damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may present with abdominal pain radiating to the back and pancreatic calcifications detectable on X-rays. Autopsies have revealed pancreatic fibrosis and calcium stones in exocrine ducts.
Endocrinopathies
Several hormones, including growth hormone, cortisol, glucagon, and epinephrine, counteract insulin action. Excess levels of these hormones, as seen in acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma, can cause diabetes. This typically occurs in individuals with pre-existing insulin secretion deficits, and hyperglycemia often resolves when the hormonal excess is corrected.
Somatostatinoma and aldosteronoma-induced hypokalemia can also lead to diabetes, partly by inhibiting insulin secretion. Hyperglycemia generally resolves after tumor removal.
Drug- or Chemical-Induced Diabetes
Numerous drugs can impair insulin secretion. These drugs might not cause diabetes independently but can precipitate it in individuals with insulin resistance. In such cases, classification is complex due to unclear sequences or relative importance of β-cell dysfunction and insulin resistance. Certain toxins like Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells, though such reactions are rare. Many drugs and hormones can also impair insulin action, such as nicotinic acid and glucocorticoids. α-interferon treatment has been linked to diabetes with islet cell antibodies and, in some cases, severe insulin deficiency. Table 1 lists common drug-, hormone-, and toxin-induced diabetes forms.
Table 1.
Etiologic classification of diabetes mellitus
| 1. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) 1. Immune mediated 2. Idiopathic 2. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) 3. Other specific types 1. A. 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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It’s important to note that insulin treatment can be necessary at some point in any diabetes form. Insulin use itself does not define the diabetes classification.
Infections
Certain viruses have been implicated in β-cell destruction. Congenital rubella infection is associated with diabetes, often showing HLA and immune markers typical of type 1 diabetes. Coxsackievirus B, cytomegalovirus, adenovirus, and mumps viruses have also been linked to certain diabetes cases.
Uncommon Forms of Immune-Mediated Diabetes
This category includes conditions like stiff-man syndrome, an autoimmune neurological disorder causing axial muscle stiffness and painful spasms. Patients often have high GAD autoantibody titers, and about one-third develop diabetes.
Anti-insulin receptor antibodies can cause diabetes by blocking insulin binding to its receptor in target tissues. Paradoxically, in some cases, these antibodies can act as insulin agonists, leading to hypoglycemia. Anti-insulin receptor antibodies are sometimes found in systemic lupus erythematosus and other autoimmune diseases. Similar to other extreme insulin resistance states, patients with these antibodies often have acanthosis nigricans. This condition was previously known as type B insulin resistance.
Other Genetic Syndromes Associated with Diabetes
Numerous genetic syndromes increase diabetes incidence, including chromosomal abnormalities like Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome, an autosomal recessive disorder, is characterized by insulin-deficient diabetes and β-cell absence at autopsy, along with diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1.
Gestational Diabetes Mellitus (GDM)
GDM has historically been defined as any degree of glucose intolerance first recognized during pregnancy. Although typically resolving after delivery, the definition applied regardless of postpartum persistence and included cases where glucose intolerance might have predated or begun with pregnancy. This definition provided a consistent approach to GDM detection and classification, but its limitations have been long acknowledged. The ongoing obesity and diabetes epidemics have increased type 2 diabetes prevalence among women of childbearing age, leading to more pregnant women with undiagnosed type 2 diabetes.
Following deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), a global consensus group including representatives from the American Diabetes Association (ADA) and other organizations, recommended that women identified with diabetes at their first prenatal visit using standard criteria (Table 3) be diagnosed with overt diabetes, not GDM. GDM complicates approximately 7% of pregnancies (ranging from 1 to 14% depending on population and diagnostic tests), accounting for over 200,000 cases annually.
Table 3.
Criteria for the diagnosis of diabetes
| 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 |
| FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* |
| OR |
| 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 |
| 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 category of individuals with glucose levels above normal but not meeting diabetes criteria (1,2). These individuals were classified as having impaired fasting glucose (IFG) [fasting plasma glucose (FPG) 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)] or impaired glucose tolerance (IGT) [2-h values in the oral glucose tolerance test (OGTT) 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)].
Individuals with IFG and/or IGT are considered to have pre-diabetes, indicating a 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 listed in Table 1. IFG and IGT are associated with obesity (especially abdominal obesity), dyslipidemia (high triglycerides and/or low HDL cholesterol), and hypertension. Structured lifestyle interventions focusing on increased physical activity and 5–10% weight loss, along with certain medications, have been shown to prevent or delay diabetes onset in people with IGT. However, the impact of these interventions on mortality or cardiovascular disease incidence is yet to be fully demonstrated. The 2003 ADA Expert Committee lowered the IFG threshold from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l) to align IFG prevalence with IGT prevalence. However, the World Health Organization (WHO) and many other diabetes organizations did not adopt this IFG definition change.
With the increasing use of A1C for diabetes diagnosis in at-risk individuals, it also serves to identify those at higher future diabetes risk. In its 2009 report recommending A1C for diabetes diagnosis, the International Expert Committee (3) emphasized the continuous risk spectrum for diabetes across all glycemic measures and did not formally define an intermediate A1C category. However, they noted that individuals with A1C levels above the laboratory “normal” range but below the diabetes diagnostic cut point (6.0 to 6.5%) have an elevated diabetes incidence (6–12% per year), significantly higher than the general U.S. population incidence (8). NHANES data analysis indicates that A1C values between 5.5 and 6.0% most accurately identify people with IFG or IGT. Linear regression analysis correlates an FPG of 110 mg/dl (6.1 mmol/l) with an A1C of 5.6%, and an FPG of 100 mg/dl (5.6 mmol/l) with an A1C of 5.4% (R.T. Ackerman, personal communication). The Diabetes Prevention Program (DPP) showed that preventive interventions are effective in people with A1C levels both below and above 5.9% (mean A1C in DPP was 5.9%, SD 0.5%) (9). These findings suggest that an A1C level around 5.5–6% is a reasonable threshold for initiating preventive measures.
Defining a lower limit for an intermediate A1C category is somewhat arbitrary, as diabetes risk is a continuum across all glycemia measures, even into normal ranges. An A1C cut point for intervention should balance the costs of false negatives (missing those who will develop diabetes) against false positives (unnecessarily intervening in those who would not).
Compared to the 100 mg/dl (5.6 mmol/l) fasting glucose cut point, an A1C cut point of 5.7% is less sensitive but more specific, with a higher positive predictive value for identifying individuals at risk of future diabetes. A large prospective study found that a 5.7% A1C cut point has a 66% sensitivity and 88% specificity for predicting 6-year diabetes incidence (10). NHANES 1999-2006 data analysis indicates that an A1C of 5.7% has moderate sensitivity (39-45%) but high specificity (81-91%) for identifying IFP (FPG >100 mg/dl) or IGT (2-h glucose > 140 mg/dl) cases (R.T. Ackerman, personal communication). Other analyses suggest that an A1C of 5.7% is associated with a diabetes risk comparable to high-risk DPP participants (R.T. Ackerman, personal communication). Therefore, an A1C range of 5.7 to 6.4% can reasonably identify individuals at high risk for future diabetes, termed pre-diabetes if preferred.
Individuals with an A1C of 5.7–6.4% should be informed of their increased diabetes and cardiovascular disease risk and counseled on effective risk-reduction strategies, like weight loss and physical activity. As diabetes risk increases disproportionately with rising A1C levels (curvilinear relationship), interventions and follow-up should be more intensive for those with A1C levels above 6.0%, who are at very high risk. However, even individuals with A1C 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 categories of increased diabetes risk. Risk evaluation should include a global risk factor assessment for both diabetes and cardiovascular disease. Diabetes risk screening and counseling should always 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 long relied on glucose criteria, either FPG or the 75-g OGTT. In 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus updated diagnostic criteria, using the correlation between FPG levels and retinopathy prevalence to define a glucose threshold. The Committee analyzed data from three cross-sectional epidemiological studies assessing retinopathy via fundus photography or direct ophthalmoscopy and measuring glycemia as FPG, 2-h PG, and A1C. These studies showed glycemic levels below which retinopathy was rare and above which retinopathy prevalence increased linearly. The glycemic deciles at which retinopathy onset began were consistent across measures and populations. The glycemic values above which retinopathy increased were also similar across populations. This analysis supported a new diagnostic FPG cut point of ≥126 mg/dl (7.0 mmol/l) and confirmed the established 2-h PG diagnostic value of ≥200 mg/dl (11.1 mmol/l).
A1C is a widely used marker of chronic glycemia, reflecting average blood glucose over 2–3 months. It is crucial in diabetes management as it correlates well with microvascular and, to a lesser extent, macrovascular complications, serving as a standard biomarker for glycemic control. Previous Expert Committees had not recommended A1C for diabetes diagnosis due to assay standardization concerns. However, A1C assays are now highly standardized, ensuring consistent results across time and populations. In their recent report (3), an International Expert Committee, after extensive review of epidemiological evidence, recommended A1C for diabetes diagnosis, with a threshold of ≥6.5%, a decision endorsed by the ADA. This diagnostic A1C cut point of 6.5%, like FPG and 2-h PG thresholds, aligns with an inflection point for retinopathy prevalence (3). Diagnostic A1C testing should use methods certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial reference assay. Point-of-care A1C assays are not currently accurate enough for diagnostic purposes.
Using a chronic marker like A1C versus acute glucose measures offers inherent logic, especially given A1C’s familiarity to clinicians for glycemic control. A1C offers advantages over FPG, including convenience (no fasting), greater preanalytical stability, and less variability during stress or illness. However, these benefits must be balanced against higher costs, limited A1C testing availability in some developing regions, and incomplete correlation between A1C and average glucose in some individuals. A1C can also be misleading in patients with certain anemias and hemoglobinopathies, which can have specific ethnic or geographic distributions. For patients with hemoglobinopathies but normal red cell turnover, like sickle cell trait, A1C assays without interference from abnormal hemoglobins should be used (updated lists at www.ngsp.org/prog/index3.html). For conditions with abnormal red cell turnover, such as anemias from hemolysis and iron deficiency, diabetes diagnosis must rely solely on glucose criteria.
Established glucose criteria for diabetes diagnosis (FPG and 2-h PG) remain valid. Additionally, patients with severe hyperglycemia, such as those with classic hyperglycemic symptoms or hyperglycemic crisis, can be diagnosed with a random (casual) plasma glucose ≥200 mg/dl (11.1 mmol/l). In such cases, A1C is likely also measured as part of the initial assessment and would usually be above the diagnostic cut point. However, in rapidly developing diabetes, like type 1 diabetes in children, A1C might not be significantly elevated despite overt diabetes.
Concordance between FPG and 2-h PG tests is not 100%, and neither is the concordance between A1C and glucose-based tests. NHANES data analysis indicates that, assuming universal screening, an A1C cut point of ≥6.5% identifies about one-third fewer undiagnosed diabetes cases than an FPG cut point of ≥126 mg/dl (7.0 mmol/l) (cdc website tbd). However, many type 2 diabetes cases remain undiagnosed. The lower sensitivity of A1C might be offset by its greater practicality, potentially increasing overall diagnoses through wider application of a more convenient test.
Further research is needed to better understand patients with discordant glycemic status based on different tests (e.g., FPG and A1C) performed close in time. Discordance may arise from measurement variability, temporal changes, or because A1C, FPG, and post-challenge glucose each measure distinct physiological processes. Elevated A1C with “nondiabetic” FPG might suggest higher postprandial glucose levels or increased glycation rates. Conversely, high FPG with A1C below the diabetes cut point might indicate augmented hepatic glucose production or reduced glycation rates.
Like most diagnostic tests, a diabetes-diagnostic test result should be repeated to rule out lab errors, unless clinically obvious (e.g., classic hyperglycemia symptoms or crisis). Repeating the same test is preferable for confirmation. For example, if initial A1C is 7.0% and repeat is 6.8%, diabetes diagnosis is confirmed. When two different tests are available and both exceed diagnostic thresholds, diabetes is confirmed.
However, if two different tests yield discordant results, the test above the diagnostic cut point should be repeated, and diagnosis is based on the confirmed test. For example, if A1C criteria for diabetes are met (two results ≥6.5%) but not FPG criteria (<126mg/dL), repeat A1C to confirm diagnosis.
Given preanalytical and analytical variability in all tests, repeating a test initially above the diagnostic threshold might yield a second value below the cut point. This is least likely for A1C, more likely for FPG, and most likely for 2-h PG. Barring lab error, such patients likely have test results near diagnostic thresholds. Close monitoring and repeat testing in 3–6 months may be appropriate.
The choice of diagnostic test should be at the health care professional’s discretion, considering test availability and practicality for individual patients or groups. More critical than the specific test used is ensuring diabetes testing is performed when indicated. Evidence suggests inadequate testing and counseling for at-risk patients and their cardiovascular risk factors remains a concern. Current diagnostic criteria for diabetes are summarized in Table 3.
Diagnosis of Gestational Diabetes Mellitus (GDM)
GDM poses risks for both mother and neonate. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (11), a large multinational study of ~25,000 pregnant women, demonstrated a continuous increase in adverse maternal, fetal, and neonatal outcomes with increasing maternal glycemia at 24-28 weeks, even within previously considered normal pregnancy ranges. For most complications, no risk threshold was identified. These findings led to a re-evaluation of GDM diagnostic criteria. Following 2008-2009 deliberations, the IADPSG developed revised GDM diagnostic recommendations. They recommended a 75-g OGTT for all women not previously diagnosed with diabetes at 24-28 weeks gestation. They also established diagnostic cut points for fasting, 1-h, and 2-h plasma glucose measurements associated with an odds ratio for adverse outcomes of at least 1.75 compared to women with mean glucose levels in the HAPO study. Current GDM screening and diagnostic strategies, based on the IADPSG statement (12), are outlined in Table 4.
Table 4.
Screening for and diagnosis of GDM
| Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24-28 of weeks gestation in women not previously diagnosed with overt diabetes. |
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| The OGTT should be performed in the morning after an overnight fast of at least 8 h. |
| The diagnosis of GDM is made when any of the following plasma glucose values are exceeded – Fasting: ≥92 mg/dl (5.1 mmol/l) – 1 h: ≥180 mg/dl (10.0 mmol/l) – 2 h: ≥153 mg/dl (8.5 mmol/l) |
These new criteria will significantly increase GDM prevalence, primarily because only one abnormal value, not two, is sufficient for diagnosis. The ADA acknowledges the anticipated GDM incidence increase and is mindful of concerns about “medicalizing” previously normal pregnancies. These diagnostic criteria changes are made in the context of rising global obesity and diabetes rates, aiming to optimize gestational outcomes for mothers and their babies.
Data from randomized clinical trials on therapeutic interventions for women diagnosed with GDM based on only one elevated glucose value (compared to older criteria requiring two) are limited. Expected benefits are inferred from intervention trials in women with milder hyperglycemia than identified by older GDM criteria, which showed modest benefits (13,14). The frequency of follow-up and blood glucose monitoring for these newly diagnosed GDM cases is still being determined but is likely to be less intensive than for women diagnosed by older criteria. Further well-designed clinical studies are needed to determine optimal monitoring and treatment intensity for women with GDM diagnosed by the new criteria, who would not have met prior GDM definitions. Importantly, 80-90% of women in mild GDM studies (with glucose values overlapping with recommended thresholds) could be managed with lifestyle therapy alone.
