Diabetes mellitus represents a cluster of metabolic disorders marked by hyperglycemia. This condition arises from impairments in insulin secretion, insulin action, or both. Persistent hyperglycemia in diabetes is linked to long-term damage and dysfunction across various organs, notably the eyes, kidneys, nerves, heart, and blood vessels. This article delves into the diagnosis and classification of diabetes mellitus, aligning with the standards of diabetes care as understood in 2008.
The development of diabetes involves multiple pathogenic pathways, ranging from autoimmune destruction of pancreatic β-cells leading to insulin deficiency, to conditions causing resistance to insulin action. At the core of metabolic disruptions in diabetes—affecting carbohydrates, fats, and proteins—is the inadequate action of insulin on target tissues. This deficiency stems from insufficient insulin secretion and/or reduced tissue responsiveness to insulin at various stages of hormonal action. Often, both impaired insulin secretion and defects in insulin action coexist within a patient, making it difficult to pinpoint the primary cause of hyperglycemia.
Pronounced hyperglycemia manifests through symptoms like polyuria, polydipsia, unexplained weight loss, sometimes accompanied by polyphagia, and blurred vision. Chronic hyperglycemia may also hinder growth and increase susceptibility to infections. In acute settings, uncontrolled diabetes can lead to life-threatening conditions such as hyperglycemia with ketoacidosis or 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 issues, and sexual dysfunction. Individuals with diabetes also face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipoprotein metabolism abnormalities are frequently observed in diabetic populations.
Most diabetes cases fall into two main categories. 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 an insufficient compensatory insulin secretion. In type 2 diabetes, hyperglycemia may be present for a significant period without noticeable symptoms, yet still cause pathological changes. This asymptomatic phase can be detected through plasma glucose measurements in fasting states or post-glucose challenge.
The severity of hyperglycemia can fluctuate depending on the underlying disease progression and management (Fig. 1). A disease process might be present without causing immediate hyperglycemia, or it may lead to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), conditions that don’t fully meet diabetes diagnostic criteria. Some individuals with diabetes can achieve glycemic control through lifestyle modifications or oral medications, negating the need for insulin. Others may require exogenous insulin to manage blood glucose levels adequately. In cases of extensive β-cell destruction and no residual insulin secretion, insulin becomes essential for survival. The degree of hyperglycemia, therefore, reflects the intensity of the metabolic disturbance and the effectiveness of treatment, rather than the nature of the diabetes type itself.
Figure 1.
Disorders of glycemia: etiologic types and stages illustrating the progression from normoglycemia through impaired glucose tolerance and impaired fasting glucose to overt diabetes, showing the potential reversibility at early stages and the need for insulin in advanced stages of type 1 diabetes.
Classification of Diabetes Mellitus and Categories of Glucose Regulation
Diabetes classification at diagnosis can be complex, with many cases not fitting neatly into a single category. Gestational diabetes mellitus (GDM), for instance, may transition into type 2 diabetes postpartum. Similarly, steroid-induced diabetes might resolve upon cessation of glucocorticoids but reappear later due to other factors like pancreatitis. Thiazide-induced hyperglycemia, while rare in causing severe diabetes alone, may exacerbate underlying type 2 diabetes. For clinical practice, understanding the pathogenesis of hyperglycemia and effective treatment strategies is more critical than strictly labeling the diabetes type.
Type 1 Diabetes: Immune-Mediated and Idiopathic
Type 1 diabetes involves β-cell destruction, typically leading to absolute insulin deficiency. It’s further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
This form, accounting for 5–10% of diabetes cases, previously termed insulin-dependent or juvenile-onset diabetes, results from autoimmune destruction of pancreatic β-cells. Immune markers include islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and tyrosine phosphatases IA-2 and IA-2β autoantibodies. These are present in 85–90% of individuals at initial diagnosis of fasting hyperglycemia. HLA associations, particularly with DQA, DQB, and DRB genes, are also significant, influencing predisposition or protection.
The pace of β-cell destruction varies, being rapid in children and slower in adults. Ketoacidosis can be the initial presentation, especially in younger patients. Others may show mild hyperglycemia progressing to severe levels with stress or infection. Adults might maintain some β-cell function, preventing ketoacidosis for years but eventually requiring insulin and facing ketoacidosis risk. At advanced stages, insulin secretion is minimal, evidenced by low C-peptide levels. Immune-mediated diabetes is more common in childhood but can occur at any age.
Genetic predispositions and environmental factors, still under study, contribute to autoimmune β-cell destruction. Obesity at diagnosis is uncommon but not contradictory. These patients are also susceptible to other autoimmune disorders like Graves’ disease and Addison’s disease.
Idiopathic Diabetes
Some type 1 diabetes cases lack known causes, characterized by permanent insulinopenia and ketoacidosis without autoimmunity evidence. Predominantly seen in individuals of African or Asian descent, this form features episodic ketoacidosis and varying insulin deficiency. It shows strong inheritance, no autoimmune markers, and no HLA association. Insulin therapy needs may fluctuate.
Type 2 Diabetes: Insulin Resistance and Secretory Defects
Type 2 diabetes, representing 90–95% of diabetes cases, previously known as non–insulin-dependent or adult-onset diabetes, involves insulin resistance and relative insulin deficiency. Initially, and often throughout life, insulin treatment for survival is not needed. The exact causes are varied and not fully understood, but autoimmune β-cell destruction is absent.
Obesity is a major risk factor, causing insulin resistance. Non-obese individuals may have increased abdominal fat. Spontaneous ketoacidosis is rare, usually occurring with illness-related stress. Type 2 diabetes often goes undiagnosed for years due to gradual hyperglycemia development and initially mild symptoms. However, risks of macrovascular and microvascular complications are increased. While insulin levels might appear normal or elevated, they are insufficient to overcome insulin resistance, indicating defective β-cell function. Insulin resistance can improve with weight loss and medication but rarely normalizes. Risk factors include age, obesity, inactivity, prior GDM, hypertension, dyslipidemia, and racial/ethnic background. Genetic predisposition is strong but complex.
Other Specific Types of Diabetes
Specific diabetes types include those due to genetic defects, exocrine pancreas diseases, endocrinopathies, drugs, chemicals, infections, uncommon immune forms, and genetic syndromes.
Genetic Defects of β-Cell Function
Monogenetic defects in β-cell function lead to several diabetes forms, often with early-onset hyperglycemia (before 25 years), known as maturity-onset diabetes of the young (MODY). These are characterized by impaired insulin secretion with minimal insulin action defects, inherited in an autosomal dominant pattern. Mutations at six genetic loci are identified, including HNF-1α, glucokinase, HNF-4α, HNF-1β, IPF-1, and NeuroD1.
Mitochondrial DNA mutations, like the 3,243 A-to-G transition in the tRNA leucine gene, are linked to diabetes and deafness. Genetic defects affecting proinsulin to insulin conversion or mutant insulin molecules with impaired receptor binding also exist, causing mild glucose intolerance.
Genetic Defects in Insulin Action
Rare diabetes forms result from genetic abnormalities in insulin action, with insulin receptor mutations causing a spectrum from hyperinsulinemia to severe diabetes. Acanthosis nigricans may be present. Type A insulin resistance, leprechaunism, and Rabson-Mendenhall syndrome are examples, involving insulin receptor gene mutations and extreme insulin resistance.
Insulin-resistant lipoatrophic diabetes likely involves postreceptor signal transduction pathway defects.
Diseases of the Exocrine Pancreas
Pancreatic injury from pancreatitis, trauma, infection, pancreatectomy, or cancer can cause diabetes. Extensive damage is usually required, except in some cancer cases, suggesting mechanisms beyond β-cell mass reduction. Cystic fibrosis and hemochromatosis, if severe, can also impair insulin secretion. Fibrocalculous pancreatopathy and pancreatic fibrosis are other conditions.
Endocrinopathies
Hormone excesses (growth hormone, cortisol, glucagon, epinephrine) from conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can induce diabetes, typically in those with pre-existing insulin secretion defects. Hyperglycemia usually resolves with hormone level normalization. Somatostatinoma and aldosteronoma can cause diabetes via hypokalemia and insulin secretion inhibition.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action, potentially causing diabetes, especially in those with insulin resistance. Toxins like Vacor and pentamidine can permanently damage β-cells. Drugs like nicotinic acid and glucocorticoids impair insulin action. Alpha-interferon and other medications listed in Table 1 are also implicated.
Table 1.
Etiologic classification of diabetes mellitus, detailing type 1, type 2, other specific types including genetic defects, exocrine pancreas diseases, endocrinopathies, drug-induced, infections, uncommon immune forms, other genetic syndromes, and gestational diabetes mellitus.
Insulin treatment at any stage does not reclassify the diabetes type.
Infections
Certain viruses, including congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, are associated with β-cell destruction and diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, with GAD autoantibodies, and anti-insulin receptor antibodies can cause diabetes. Anti-insulin receptor antibodies may block insulin binding or paradoxically cause hypoglycemia. Type B insulin resistance is associated with these antibodies and acanthosis nigricans.
Other Genetic Syndromes
Genetic syndromes such as Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, and others listed in Table 1 are associated with increased diabetes incidence. Wolfram’s syndrome, for example, involves insulin-deficient diabetes and other conditions like diabetes insipidus.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first recognized during pregnancy. It may resolve post-delivery but can indicate underlying diabetes. Undiagnosed type 2 diabetes in pregnant women is increasing.
The International Association of Diabetes and Pregnancy Study Groups (IADPSG) in 2008–2009 recommended diagnosing overt diabetes, not GDM, at the first prenatal visit for high-risk women meeting standard diabetes criteria (Table 3). GDM complicates about 7% of pregnancies.
Table 3.
Criteria for the diagnosis of diabetes including A1C level, fasting plasma glucose, 2-hour plasma glucose during OGTT, and random plasma glucose in patients with classic hyperglycemia symptoms.
Categories of Increased Risk for Diabetes
In 1997 and 2003, expert committees identified pre-diabetes categories: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), indicating glucose levels higher than normal but not meeting diabetes criteria. IFG is defined as FPG levels 100–125 mg/dl (5.6–6.9 mmol/l), and IGT as 2-h OGTT values 140–199 mg/dl (7.8–11.0 mmol/l).
Pre-diabetes indicates a high risk for future diabetes and cardiovascular disease, often associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions and some medications can prevent or delay diabetes onset in IGT individuals. In 2003, the ADA lowered the IFG threshold from 110 mg/dl to 100 mg/dl.
A1C is increasingly used to identify diabetes risk. While no formal intermediate A1C category was initially defined, levels above the normal range but below the diagnostic cut point (6.0–6.4%) indicate increased risk. An A1C of 5.7–6.4% is now considered to identify individuals at high risk, termed pre-diabetes. This range balances sensitivity and specificity for identifying future diabetes risk.
Individuals with A1C 5.7–6.4% should be informed of their increased risks and counseled on preventive strategies. Risk increases disproportionately with A1C levels, making intensive interventions crucial for those above 6.0%. However, risk is continuous, and even lower A1C levels may pose some risk depending on other factors.
Table 2 summarizes increased diabetes risk categories. Risk evaluation should include a comprehensive assessment for both diabetes and cardiovascular disease, considering comorbidities, life expectancy, and patient capacity for lifestyle changes.
Table 2.
Categories of increased risk for diabetes, listing impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and elevated A1C levels.
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has traditionally relied on glucose criteria, FPG, or OGTT. In 1997, revised criteria used retinopathy prevalence to establish glucose thresholds, setting FPG ≥126 mg/dl (7.0 mmol/l) and 2-h PG ≥200 mg/dl (11.1 mmol/l).
A1C, reflecting 2–3 month average glucose levels, is vital in diabetes management and correlates with complications. Standardized A1C assays led to its recommendation for diabetes diagnosis by an International Expert Committee in 2009, with a threshold of ≥6.5%, affirmed by ADA. This A1C cut point aligns with retinopathy prevalence inflection points, similar to FPG and 2-h PG thresholds. NGSP-certified and DCCT-standardized methods are required for diagnostic A1C testing.
A1C offers advantages over FPG, including no fasting requirement and greater stability, but is more costly and may be less available globally. It can be misleading in certain anemias and hemoglobinopathies. For these conditions, glucose criteria remain essential.
Established glucose criteria (FPG, 2-h PG) and random glucose ≥200 mg/dl (11.1 mmol/l) in hyperglycemic crisis remain valid. A1C may not always be elevated in rapidly developing diabetes, like type 1 in children.
Discordance between A1C and glucose tests can occur due to measurement variability or different physiological processes measured. Repeat testing is recommended to confirm diagnosis, preferably using the same test. If discordant results persist, the test above the diagnostic threshold should be repeated for confirmation.
Test selection should be at the healthcare professional’s discretion, considering test availability and practicality. Ensuring diabetes testing is performed when indicated is crucial. Table 3 summarizes current diagnostic criteria.
Diagnosis of GDM
GDM diagnosis follows Carpenter and Coustan criteria or the 75-g 2-h OGTT.
Testing for Gestational Diabetes
Risk assessment at the first prenatal visit is key. Low-risk women (younger than 25, normal weight, no family history of diabetes, no history of glucose intolerance or poor obstetric outcomes, not in a high-risk ethnic group) may not need screening. High-risk women should be tested early; if negative, retest at 24–28 weeks gestation. Average-risk women test at 24–28 weeks.
FPG >126 mg/dl or casual glucose >200 mg/dl indicates diabetes. If not meeting these, GDM evaluation follows one-step or two-step approaches.
One-Step Approach
Diagnostic OGTT without prior screening, potentially cost-effective in high-risk groups.
Two-Step Approach
Initial 50-g glucose challenge test (GCT). If threshold is exceeded (e.g., >140 mg/dl), proceed to diagnostic OGTT. Lower thresholds (e.g., >130 mg/dl) increase detection rates.
GDM diagnosis relies on OGTT. 100-g OGTT criteria from Carpenter and Coustan or 75-g glucose load criteria (Table 4) are used.
Table 4.
Diagnosis of GDM with a 100-g or 75-g glucose load, outlining glucose concentration thresholds at fasting, 1-hour, 2-hour, and 3-hour marks for both glucose load tests.
Two or more venous plasma concentrations must meet or exceed thresholds for a positive GDM diagnosis. Testing requires overnight fasting, unrestricted diet, and physical activity.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study highlighted continuous risk increase with maternal glycemia, even within normal pregnancy ranges, prompting criteria reconsideration. IADPSG recommends 75-g OGTT for all pregnant women at 24–28 weeks, with diagnostic cut points set to indicate increased adverse outcome risks. ADA is considering adopting IADPSG criteria, which will likely increase GDM prevalence, but evidence suggests treating even mild GDM benefits both mother and baby.
Acknowledgments
The American Diabetes Association credits the writing group members for updates on diagnosis and risk categories.
