Diabetes mellitus represents a cluster of metabolic disorders characterized by elevated blood sugar (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. This article provides a detailed overview of the diagnosis and classification of diabetes mellitus, drawing upon established guidelines and research in diabetes care.
Understanding the Pathophysiology of Diabetes
The development of diabetes involves multiple disease processes, ranging from autoimmune destruction of pancreatic β-cells leading to insulin deficiency, to abnormalities causing resistance to insulin’s action. At its core, diabetes involves deficient insulin action on target tissues, stemming from inadequate insulin secretion and/or reduced tissue responsiveness to insulin. Often, both impaired insulin secretion and defects in insulin action coexist, making it challenging to pinpoint the primary cause of hyperglycemia.
Key symptoms of significant hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes increased hunger (polyphagia), and blurred vision. Furthermore, chronic hyperglycemia can impair growth and increase susceptibility to infections. Acute, life-threatening complications include hyperglycemia with ketoacidosis and the nonketotic hyperosmolar syndrome.
Long-term diabetes complications are extensive and debilitating. These include retinopathy, potentially leading to blindness; nephropathy, progressing to kidney failure; peripheral neuropathy, increasing risks of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy, causing gastrointestinal, genitourinary, cardiovascular issues, and sexual dysfunction. Individuals with diabetes also face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipid abnormalities are frequently observed in diabetic patients.
The majority of diabetes cases fall into two main categories: type 1 and type 2. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion, often identifiable through autoimmune markers and genetic predispositions. Type 2 diabetes, far more common, involves a combination of insulin resistance and insufficient compensatory insulin secretion. In type 2 diabetes, prolonged periods of asymptomatic hyperglycemia may occur before diagnosis, during which metabolic abnormalities can be detected through blood glucose measurements.
The severity of hyperglycemia in diabetes can fluctuate over time, influenced by the underlying disease progression and treatment effectiveness, as illustrated in Fig. 1. A disease process might be present without causing immediate hyperglycemia, or it may manifest as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), not yet meeting full diabetes diagnostic criteria. Conversely, effective management through lifestyle changes or medications can improve glycemic control, sometimes to the point where insulin is not required. The degree of hyperglycemia, therefore, reflects the dynamic interplay of the disease process and its management rather than the fundamental nature of the disease itself.
Classification of Diabetes Mellitus: Types and Categories
Classifying diabetes can be complex, as individuals may not always fit neatly into a single category, and circumstances at diagnosis significantly influence classification. For instance, gestational diabetes mellitus (GDM) might evolve into type 2 diabetes post-delivery. Drug-induced diabetes, such as from steroids or thiazides, may resolve upon cessation of the medication, only to potentially re-emerge later due to underlying type 2 diabetes or other conditions like pancreatitis. Therefore, understanding the pathogenesis of hyperglycemia is paramount for effective treatment, often outweighing the precise labeling of diabetes type.
Type 1 Diabetes: β-cell Destruction and Insulin Deficiency
Type 1 diabetes, representing 5-10% of all diabetes cases, is characterized by β-cell destruction, typically leading to absolute insulin deficiency. It was previously known as insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes.
Immune-Mediated Diabetes
This subtype results from autoimmune destruction of pancreatic β-cells. Immune markers, including islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and tyrosine phosphatase autoantibodies IA-2 and IA-2β, are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Genetic factors, particularly HLA-DR/DQ genes, play a significant role, with certain alleles predisposing to or protecting against the disease.
The rate of β-cell destruction varies, being rapid in children and slower in adults. Presentation can range from ketoacidosis at onset, especially in children, to milder hyperglycemia that can quickly escalate with stress or infection. Adults may retain some β-cell function, delaying insulin dependence but eventually progressing to insulin deficiency and ketoacidosis risk, marked by low C-peptide levels. While commonly diagnosed in childhood, immune-mediated diabetes can occur at any age.
Genetic predisposition and poorly understood environmental factors contribute to autoimmune β-cell destruction. Although obesity is uncommon at diagnosis, it doesn’t exclude this type. These patients are also more susceptible to other autoimmune disorders like Graves’ disease and celiac sprue.
Idiopathic Diabetes
A smaller subset of type 1 diabetes lacks known etiologies or autoimmune markers. These individuals experience permanent insulinopenia and ketoacidosis proneness but without autoimmunity evidence. More prevalent in those of African or Asian descent, this form shows strong inheritance patterns, lacks HLA associations, and exhibits episodic ketoacidosis with variable insulin deficiency between episodes. Insulin replacement therapy needs may fluctuate.
Type 2 Diabetes: Insulin Resistance and Relative Insulin Deficiency
Type 2 diabetes constitutes the vast majority (90-95%) of diabetes cases, formerly termed non-insulin-dependent diabetes or adult-onset diabetes. It involves insulin resistance coupled with relative insulin deficiency. Patients often do not require insulin for survival, especially initially. The exact causes are diverse, but autoimmune β-cell destruction is not involved, and other specific diabetes causes are excluded.
Obesity is a major risk factor, causing insulin resistance. Even non-obese individuals may have increased abdominal fat, contributing to insulin resistance. Ketoacidosis is rare spontaneously, usually occurring with illness-related stress. Type 2 diabetes often remains undiagnosed for years due to gradual hyperglycemia development and initially subtle symptoms. However, these individuals are at increased risk for macrovascular and microvascular complications. Despite seemingly normal or elevated insulin levels, β-cell function is insufficient to overcome insulin resistance. Weight loss and medication can improve insulin resistance but rarely normalize it. Risk factors include age, obesity, inactivity, prior GDM, hypertension, dyslipidemia, and racial/ethnic background. Genetic predisposition is stronger than in autoimmune type 1 diabetes but genetically complex.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several specific diabetes types exist due to genetic defects, diseases, endocrinopathies, drugs, infections, and uncommon immune-mediated mechanisms.
Genetic Defects of β-Cell Function
Monogenic defects in β-cell function can cause diabetes, often with onset before age 25, known as maturity-onset diabetes of the young (MODY). These are characterized by impaired insulin secretion with minimal insulin action defects, inherited autosomal dominantly. Mutations at multiple genetic loci are identified, including:
- HNF-1α mutations (MODY3): Most common form, affecting a hepatic transcription factor.
- Glucokinase gene mutations (MODY2): Resulting in defective glucokinase, impairing glucose sensing by β-cells.
- Other transcription factor mutations: HNF-4α, HNF-1β, IPF-1, and NeuroD1.
- Mitochondrial DNA mutations: Like the A-to-G transition at position 3,243 in the tRNA leucine gene, also linked to deafness.
- Proinsulin conversion defects: Genetic abnormalities impairing proinsulin-to-insulin conversion, leading to mild glucose intolerance.
- Mutant insulin molecules: Production of impaired insulin molecules with reduced receptor binding, also causing mild glucose intolerance.
Genetic Defects in Insulin Action
Rare diabetes forms result from genetically determined insulin action abnormalities. Insulin receptor mutations can cause a spectrum of metabolic issues from hyperinsulinemia to severe diabetes. Syndromes like type A insulin resistance, leprechaunism, and Rabson-Mendenhall syndrome are examples. Insulin-resistant lipoatrophic diabetes likely involves postreceptor signal transduction pathway defects.
Diseases of the Exocrine Pancreas
Pancreatic damage from pancreatitis, trauma, infection, pancreatectomy, or pancreatic carcinoma can cause diabetes, requiring extensive damage except in cancer cases, suggesting other mechanisms beyond β-cell mass reduction. Cystic fibrosis and hemochromatosis, if severe, can also impair insulin secretion. Fibrocalculous pancreatopathy is another pancreatic condition linked to diabetes.
Endocrinopathies
Excess hormones like growth hormone, cortisol, glucagon, and epinephrine can counteract insulin action, potentially causing diabetes, particularly in individuals with pre-existing insulin secretion defects. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma are examples. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion. Hyperglycemia often resolves with hormone excess correction.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action, potentially precipitating diabetes in susceptible individuals. Toxins like Vacor and pentamidine can permanently damage β-cells. Drugs like nicotinic acid and glucocorticoids impair insulin action. α-interferon has been linked to diabetes with islet cell antibodies and insulin deficiency. Table 1 lists more examples of drug-, hormone-, and toxin-induced 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 |
Infections
Certain viruses like congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been linked to β-cell destruction and diabetes. Congenital rubella-related diabetes often shares HLA and immune markers with type 1 diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, an autoimmune CNS disorder with GAD autoantibodies, are associated with diabetes development in about one-third of patients. Anti-insulin receptor antibodies can also cause diabetes by blocking insulin binding or, paradoxically, hypoglycemia by acting as insulin agonists. These antibodies are sometimes found in autoimmune diseases like lupus and are associated with acanthosis nigricans.
Other Genetic Syndromes
Several genetic syndromes, including Down syndrome, Klinefelter syndrome, Turner syndrome, and Wolfram syndrome, are associated with increased diabetes incidence. Wolfram syndrome, for example, is characterized by insulin-deficient diabetes and other endocrine and neurological issues.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first recognized during pregnancy. While usually resolving after delivery, it may persist or indicate pre-existing undiagnosed diabetes. With rising obesity and type 2 diabetes in women of childbearing age, undiagnosed type 2 diabetes in pregnancy is increasing.
The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends diagnosing overt diabetes, not GDM, at the first prenatal visit if standard diabetes criteria (Table 3) are met. GDM complicates approximately 7% of pregnancies.
Table 3. Criteria for the diagnosis of diabetes
| 1. A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* |
|---|
| OR |
| 2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* |
| OR |
| 3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* |
| OR |
| 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l). |
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
Categories of Increased Risk for Diabetes (Prediabetes)
Individuals with glucose levels not meeting diabetes criteria but higher than normal are categorized as having increased risk. This includes impaired fasting glucose (IFG) with FPG 100-125 mg/dl and impaired glucose tolerance (IGT) with 2-h OGTT values of 140-199 mg/dl.
IFG and IGT, often termed prediabetes, indicate a high risk of future diabetes and cardiovascular disease, not clinical entities themselves. They are associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes development in IGT individuals.
A1C is also used to identify individuals at higher diabetes risk. While no formal intermediate A1C category was initially defined, levels between 5.7-6.4% are now recognized as indicating increased risk. This range balances sensitivity and specificity for identifying future diabetes risk. Table 2 summarizes these risk categories. Risk assessment should incorporate global cardiovascular risk factors, considering individual patient context and health goals.
Table 2. Categories of increased risk for diabetes*
| FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) [IFG] |
|---|
| 2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT] |
| A1C 5.7–6.4% |
*For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has traditionally relied on glucose criteria like FPG and OGTT. The 1997 Expert Committee revised criteria based on retinopathy risk association with glucose levels. Studies showed a correlation between retinopathy prevalence and FPG, 2-h PG, and A1C levels, leading to diagnostic cut points of ≥126 mg/dl for FPG and ≥200 mg/dl for 2-h PG.
A1C, reflecting average glycemia over 2-3 months, is crucial in diabetes management. Standardized A1C assays now allow for its diagnostic use. An International Expert Committee recommended A1C ≥6.5% as a diagnostic threshold, affirmed by the ADA. This cut point, like glucose thresholds, correlates with retinopathy prevalence. Diagnostic A1C tests must be NGSP certified and standardized to the DCCT assay; point-of-care assays are not yet sufficiently accurate.
A1C offers convenience (no fasting), stability, and less variability compared to FPG. However, it’s more costly, less available in some regions, and can be misleading in certain anemias or hemoglobinopathies. In such cases, glucose criteria remain essential. Established glucose criteria (FPG, 2-h PG) and random glucose ≥200 mg/dl in symptomatic patients remain valid diagnostic tools.
A1C diagnoses fewer undiagnosed diabetes cases than FPG, but its practicality may lead to wider application and increased overall diagnoses. Discordance between A1C and glucose tests may arise due to measurement variability or differing physiological processes measured.
A positive diabetes diagnostic test should be repeated to rule out errors, preferably using the same test. If different tests are used and both are above diagnostic thresholds, diabetes is confirmed. In discordant cases, the test above the threshold should be repeated, and diagnosis is based on the confirmed test. If a repeat test falls below the threshold, close monitoring and repeat testing in 3-6 months are advised.
The choice of diagnostic test is at the healthcare professional’s discretion, considering practicality and patient factors. Crucially, diabetes testing should be performed when indicated, as under-testing and counseling remain concerning issues. Table 3 summarizes current diagnostic criteria.
Diagnosis of Gestational Diabetes Mellitus (GDM)
GDM diagnosis uses Carpenter-Coustan criteria or a 75-g 2-h OGTT. Low-risk pregnant women meeting specific criteria may not require GDM screening. Risk assessment at the first prenatal visit is crucial. High-risk women should be tested early, with repeat testing at 24-28 weeks if initial tests are negative. Average-risk women are tested at 24-28 weeks.
FPG >126 mg/dl or random glucose >200 mg/dl diagnoses diabetes, precluding further GDM testing. Otherwise, GDM evaluation uses a one-step (diagnostic OGTT directly) or two-step approach (glucose challenge test followed by OGTT if threshold is exceeded). A glucose threshold >140 mg/dl on GCT identifies ~80% of GDM cases.
GDM diagnosis is based on OGTT. Table 4 shows diagnostic criteria for 100-g and 75-g OGTTs. Two or more venous plasma glucose values must meet or exceed thresholds for a positive GDM diagnosis. Testing requires overnight fasting and adequate carbohydrate intake beforehand.
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 |
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. The IADPSG recommends a 75-g OGTT for all pregnant women at 24-28 weeks, with specific diagnostic cut points for fasting, 1-h, and 2-h glucose levels associated with increased adverse outcome risk. Adoption of IADPSG criteria is under consideration, potentially increasing GDM prevalence but also enabling intervention to reduce maternal and infant morbidity.
