Diabetes mellitus is not a single disease but a group of metabolic disorders characterized by persistent hyperglycemia. This high blood sugar condition arises from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes leads to long-term damage and dysfunction of various organs, including the eyes, kidneys, nerves, heart, and blood vessels. Understanding the diagnosis and classification of diabetes is crucial for effective diabetes care and management. This article provides a detailed overview based on established guidelines for diabetes diagnosis and classification.
Understanding Diabetes Mellitus
The development of diabetes involves several complex pathogenic processes. These range from autoimmune destruction of pancreatic β-cells, leading to insulin deficiency, to abnormalities causing resistance to insulin’s action. The core issue in diabetes is the deficient action of insulin on target tissues, disrupting carbohydrate, fat, and protein metabolism. This deficient action can result from insufficient insulin secretion, reduced tissue responsiveness to insulin, or a combination of both. Often, it’s challenging to pinpoint whether impaired insulin secretion or insulin resistance is the primary cause of hyperglycemia.
Symptoms of significant hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes increased appetite (polyphagia), and blurred vision. Chronic hyperglycemia can also impair growth and increase susceptibility to infections. Acute, life-threatening complications of uncontrolled diabetes include hyperglycemia with ketoacidosis and the nonketotic hyperosmolar syndrome.
Long-term complications of diabetes are serious and include retinopathy (eye damage) that can lead to blindness, nephropathy (kidney disease) progressing to renal failure, peripheral neuropathy (nerve damage) causing foot ulcers, amputations, and Charcot joints, and autonomic neuropathy affecting gastrointestinal, genitourinary, and cardiovascular functions, as well as sexual health. Individuals with diabetes also have a higher risk of atherosclerotic cardiovascular disease, peripheral arterial disease, and cerebrovascular disease. Hypertension and abnormal lipid profiles are commonly observed in diabetic individuals.
The majority of diabetes cases fall into two main categories: type 1 and type 2 diabetes. In type 1 diabetes, the primary cause is an absolute deficiency of insulin secretion, often due to autoimmune destruction of pancreatic β-cells. Type 2 diabetes, the more prevalent form, results from a combination of insulin resistance and an inadequate compensatory insulin secretion. In type 2 diabetes, hyperglycemia may be present for a long time before diagnosis, often without noticeable clinical symptoms. During this asymptomatic phase, abnormalities in glucose metabolism can be detected through fasting plasma glucose measurements or oral glucose tolerance tests.
The severity of hyperglycemia can fluctuate over time, influenced by the underlying disease process and its management, as illustrated in Figure 1. A disease process may be present without causing immediate hyperglycemia. It can also manifest as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), conditions that don’t fully meet diabetes diagnostic criteria but indicate increased risk. Glycemic control in diabetes can sometimes be achieved through lifestyle modifications like weight reduction and exercise, or with oral glucose-lowering medications, potentially negating the need for insulin. However, individuals with severe β-cell destruction and minimal to no insulin secretion require insulin for survival. Therefore, the degree of hyperglycemia reflects the severity of the metabolic disturbance and the effectiveness of treatment, rather than solely the nature of the disease process itself.
Classification of Diabetes Mellitus
Classifying diabetes can be complex as individuals may not always fit neatly into a single category. The classification often depends on the circumstances at the time of diagnosis. For instance, gestational diabetes mellitus (GDM) may transition into type 2 diabetes after pregnancy. Similarly, diabetes induced by medications like steroids may resolve upon discontinuation but reappear later due to other factors like pancreatitis. Therefore, understanding the underlying pathogenesis of hyperglycemia is more critical for effective treatment than simply labeling the type of diabetes.
Type 1 Diabetes: β-cell Destruction and Insulin Deficiency
Type 1 diabetes is characterized by the destruction of pancreatic β-cells, typically leading to an absolute insulin deficiency.
Immune-Mediated Diabetes
This subtype, accounting for 5–10% of diabetes cases, is an autoimmune disease. It involves the body’s immune system mistakenly attacking and destroying the insulin-producing β-cells in the pancreas. Markers of this autoimmune destruction 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 the majority (85–90%) of individuals when fasting hyperglycemia is initially detected. Genetic factors, particularly HLA genes (DQA, DQB, and DRB), also play a significant role in susceptibility.
The rate of β-cell destruction varies, being rapid in children and slower in adults. Some individuals, especially children, may initially present with ketoacidosis. Others may have mild fasting hyperglycemia that can quickly worsen to severe hyperglycemia or ketoacidosis due to stress or infection. Adults may retain some β-cell function for longer periods, delaying insulin dependence but eventually requiring it for survival and remaining at risk for ketoacidosis. At advanced stages, 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 exact causes are multifactorial, involving genetic predispositions and environmental triggers that are not yet fully understood. Although patients are typically not obese at diagnosis, obesity does not rule out this type. These individuals are also more susceptible to other autoimmune disorders like Graves’ disease, Hashimoto’s thyroiditis, and Addison’s disease.
Idiopathic Diabetes
Idiopathic type 1 diabetes represents cases with no known cause. These patients experience permanent insulinopenia and are prone to ketoacidosis, but lack evidence of β-cell autoimmunity. This is a minority of type 1 diabetes cases, more common in individuals of African or Asian descent. Patients may have episodic ketoacidosis with varying degrees of insulin deficiency between episodes. This form has a strong genetic component but no HLA associations or immunological markers of β-cell autoimmunity. Insulin replacement therapy needs may fluctuate.
Type 2 Diabetes: Insulin Resistance and Relative Insulin Deficiency
Type 2 diabetes constitutes the vast majority of diabetes cases (90–95%). It is characterized by insulin resistance, where the body’s cells do not respond effectively to insulin, and a relative insulin deficiency, where the pancreas may not produce enough insulin to overcome this resistance. Initially, and often throughout life, individuals with type 2 diabetes do not require insulin for survival. The exact causes are diverse and not fully understood, but autoimmune β-cell destruction is not involved, and other specific causes of diabetes are absent.
Obesity is a major contributing factor, causing insulin resistance. Even non-obese individuals may have increased abdominal fat, contributing to insulin resistance. Spontaneous ketoacidosis is rare in type 2 diabetes, typically occurring under severe stress like infection. Type 2 diabetes often develops gradually and may remain undiagnosed for years due to subtle early symptoms. However, even in early stages, patients are at increased risk of macrovascular and microvascular complications. While insulin levels might appear normal or elevated, they are insufficient to compensate for the insulin resistance. Insulin resistance can improve with weight loss and medication but rarely returns to normal. Risk factors include age, obesity, physical inactivity, prior GDM, hypertension, dyslipidemia, and certain racial/ethnic backgrounds. Genetics play a strong role, although the genetic basis is complex and not fully defined.
Other Specific Types of Diabetes
Several less common forms of diabetes are attributed to specific underlying causes.
Genetic Defects of β-Cell Function
These monogenic forms of diabetes often manifest as hyperglycemia at a young age (typically before 25) and are known as maturity-onset diabetes of the young (MODY). They are characterized by impaired insulin secretion with minimal insulin resistance and are inherited in an autosomal dominant pattern. Mutations in several genes, including hepatic transcription factors like HNF-1α, HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1, as well as glucokinase, are implicated. Glucokinase mutations, for example, lead to a defective glucose sensor in β-cells, requiring higher glucose levels to stimulate insulin secretion.
Mitochondrial DNA mutations, particularly at position 3,243 in the tRNA leucine gene, have also been linked to diabetes and deafness. Genetic defects affecting proinsulin conversion to insulin or resulting in mutant insulin molecules with impaired receptor binding are rare autosomal dominant conditions causing mild glucose intolerance.
Genetic Defects in Insulin Action
Rare forms of diabetes result from genetic abnormalities in insulin action, often due to mutations in the insulin receptor gene. These can range from hyperinsulinemia and mild hyperglycemia to severe diabetes. Syndromes like type A insulin resistance, leprechaunism, and Rabson-Mendenhall syndrome are associated with insulin receptor mutations and extreme insulin resistance. Lipoatrophic diabetes, another insulin-resistant condition, is believed to involve defects in postreceptor signal transduction pathways.
Diseases of the Exocrine Pancreas
Conditions that damage the pancreas diffusely, such as pancreatitis, trauma, pancreatectomy, and pancreatic carcinoma, can lead to diabetes. Significant pancreatic damage is usually required, except in cases of pancreatic cancer where other mechanisms may be involved. Cystic fibrosis and hemochromatosis, if extensive, can also impair insulin secretion. Fibrocalculous pancreatopathy is another pancreatic condition associated with diabetes.
Endocrinopathies
Excess hormones that counter insulin action, like growth hormone (acromegaly), cortisol (Cushing’s syndrome), glucagon (glucagonoma), and epinephrine (pheochromocytoma), can cause diabetes, particularly in individuals with pre-existing insulin secretion defects. Hyperglycemia typically resolves when the hormone excess is addressed. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion.
Drug- or Chemical-Induced Diabetes
Various drugs can impair insulin secretion or action. While some drugs may not cause diabetes alone, they can trigger it in individuals with insulin resistance. Toxins like Vacor and pentamidine can permanently damage β-cells. Drugs like nicotinic acid and glucocorticoids can impair insulin action. Alpha-interferon has been associated with diabetes and β-cell autoimmunity. Table 1 lists 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. A. Genetic defects of β-cell function |
| 2. Genetic defects in insulin action | |
| 3. Diseases of the exocrine pancreas | |
| 4. Endocrinopathies | |
| 5. Drug or chemical induced | |
| 6. Infections | |
| 7. Uncommon forms of immune-mediated diabetes | |
| 8. Other genetic syndromes sometimes associated with diabetes | |
| 4. Gestational diabetes mellitus |
Infections
Certain viruses, such as congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, have been implicated in β-cell destruction and the development of diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, an autoimmune neurological disorder, are associated with high GAD autoantibodies and an increased risk of diabetes. Anti-insulin receptor antibodies can also cause diabetes by blocking insulin binding to its receptor, leading to insulin resistance.
Other Genetic Syndromes
Several genetic syndromes, including Down syndrome, Klinefelter syndrome, Turner syndrome, and Wolfram syndrome, are associated with a higher incidence of diabetes.
Gestational Diabetes Mellitus (GDM)
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first detected during pregnancy. It may resolve after delivery but indicates an increased risk of developing type 2 diabetes later in life. With rising rates of obesity and type 2 diabetes in women of childbearing age, undiagnosed type 2 diabetes in pregnant women is becoming more common.
The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends that women with high risk factors for diabetes be screened at their initial prenatal visit using standard diabetes criteria (Table 3). If diabetes is diagnosed at this initial visit, it is classified as overt diabetes, not gestational diabetes. GDM complicates approximately 7% of pregnancies.
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
Recognizing individuals at increased risk for diabetes is essential for preventive strategies. The Expert Committee on Diagnosis and Classification of Diabetes Mellitus has identified an intermediate group with glucose levels higher than normal but not meeting diabetes criteria. This category includes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
Individuals with IFG [fasting plasma glucose (FPG) 100–125 mg/dl (5.6–6.9 mmol/l)] or IGT [2-h plasma glucose in a 75-g oral glucose tolerance test (OGTT) 140–199 mg/dl (7.8–11.0 mmol/l)] are considered to have pre-diabetes. Pre-diabetes signifies a high risk for developing diabetes and cardiovascular disease. IFG and IGT are not clinical entities themselves but rather risk factors associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions focusing on physical activity and modest weight loss, along with certain medications, can prevent or delay diabetes development in people with IGT.
A1C is also used to identify individuals at higher risk. While there isn’t a formally defined intermediate category for A1C, levels above the laboratory normal range but below the diabetes diagnostic cut point (5.7–6.4%) indicate increased risk. An A1C in the 5.7–6.4% range is associated with a significantly higher diabetes incidence. An A1C cut point of 5.7% has a good balance of sensitivity and specificity for identifying individuals at risk.
Table 2 summarizes the categories of increased risk for diabetes. Risk assessment should include a comprehensive evaluation of risk factors for both diabetes and cardiovascular disease, considering individual comorbidities, life expectancy, 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
The diagnosis of diabetes mellitus has traditionally relied on glucose criteria, specifically fasting plasma glucose (FPG) and the 75-g oral glucose tolerance test (OGTT). In 1997, diagnostic criteria were revised based on the association between FPG levels and retinopathy. Studies showed a glycemic threshold above which retinopathy prevalence increased significantly. This led to the adoption of ≥126 mg/dl (7.0 mmol/l) for FPG and ≥200 mg/dl (11.1 mmol/l) for 2-h PG as diagnostic cut points.
A1C, reflecting average blood glucose over 2-3 months, is a crucial marker in diabetes management. With advancements in A1C assay standardization, the International Expert Committee recommended A1C as a diagnostic tool for diabetes, with a threshold of ≥6.5%. This cut point correlates with retinopathy prevalence, similar to FPG and 2-h PG thresholds. Diagnostic A1C tests should be NGSP certified and standardized to the DCCT assay. Point-of-care A1C tests are not yet sufficiently accurate for diagnosis.
A1C offers advantages like convenience (no fasting required), greater preanalytical stability, and less variability during stress. However, it is more costly, less available in some regions, and may be affected by certain conditions like anemia and hemoglobinopathies. For patients with hemoglobinopathies, specific A1C assays without interference should be used. In conditions with abnormal red cell turnover, glucose criteria should be used exclusively.
Established glucose criteria (FPG and 2-h PG) remain valid. Random plasma glucose ≥200 mg/dl (11.1 mmol/l) in patients with classic hyperglycemia symptoms or hyperglycemic crisis can also diagnose diabetes. In rapidly developing diabetes, A1C may not be elevated initially.
There is not complete concordance between A1C and glucose-based tests. A1C ≥6.5% may identify fewer undiagnosed diabetes cases than FPG ≥126 mg/dl (7.0 mmol/l). However, the convenience of A1C testing may lead to wider application and potentially increase overall diagnoses.
Discordance between different tests may arise from measurement variability, time changes, or the fact that A1C, FPG, and postchallenge glucose measure different physiological processes. When tests are discordant, the test above the diagnostic cut point should be repeated for confirmation. If both tests are above the threshold, diabetes is confirmed.
When a repeated test falls below the diagnostic cut point, close patient follow-up and repeat testing in 3–6 months may be appropriate. The choice of diagnostic test should be at the healthcare professional’s discretion, considering test availability and practicality. Ensuring diabetes testing is performed when indicated is crucial, as many at-risk individuals still do not receive adequate screening and counseling. Table 3 summarizes the diagnostic criteria for diabetes.
Diagnosis of Gestational Diabetes Mellitus (GDM)
GDM poses risks to both mother and baby. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a continuous increase in adverse outcomes with maternal glycemia, even within previously considered normal ranges. This led to revised diagnostic criteria for GDM.
The IADPSG recommends a 75-g OGTT at 24–28 weeks of gestation for all pregnant women not previously diagnosed with diabetes. Diagnostic cut points for fasting, 1-h, and 2-h plasma glucose are set to identify women at increased risk of adverse outcomes (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. |
|---|
| 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 increase GDM prevalence as only one abnormal value is needed for diagnosis. The ADA acknowledges this increase and aims to optimize outcomes for mothers and babies in the context of rising obesity and diabetes rates. While data on therapeutic interventions for women diagnosed solely by these new criteria are limited, lifestyle therapy is often effective. Further research is needed to determine optimal monitoring and treatment intensity for GDM diagnosed by these new criteria.
References
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