Diabetes mellitus is a group of metabolic disorders distinguished by persistent hyperglycemia, stemming from defects in insulin secretion, insulin action, or both. This chronic hyperglycemia is associated with 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, ranging from autoimmune destruction of pancreatic β-cells leading to insulin deficiency, to conditions causing resistance to insulin action. At the core of metabolic abnormalities in diabetes—affecting carbohydrate, fat, and protein metabolism—is the insufficient action of insulin on target tissues. This deficiency arises from inadequate insulin secretion and/or reduced tissue responsiveness to insulin at different points in the hormone’s action pathways. Often, both impaired insulin secretion and defects in insulin action coexist within the same patient, making it difficult to pinpoint the primary cause of hyperglycemia.
Symptoms of pronounced hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unintentional weight loss, sometimes increased appetite (polyphagia), and blurred vision. Chronic hyperglycemia can also lead to impaired growth and increased susceptibility to infections. Acute, life-threatening complications of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.
Long-term complications of diabetes encompass retinopathy potentially causing vision loss, nephropathy leading 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 are at a higher risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and lipoprotein metabolism abnormalities are also commonly observed in diabetic individuals.
Most diabetes cases fall into two major categories. 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 the pancreatic islets and by genetic markers. Type 2 diabetes, the more prevalent form, results from a combination of insulin resistance and an insufficient compensatory insulin secretion. In type 2 diabetes, hyperglycemia sufficient to cause pathological changes in target tissues, but without noticeable clinical symptoms, may be present for a long period before diagnosis. During this asymptomatic phase, carbohydrate metabolism abnormalities can be detected by measuring plasma glucose levels in a fasting state or after an oral glucose load.
The severity of hyperglycemia can vary over time, depending on the underlying disease progression. A disease process might be present without causing hyperglycemia initially. The same process can lead to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without meeting full diabetes diagnostic criteria. Some individuals with diabetes can achieve glycemic control through lifestyle modifications like weight reduction, exercise, and/or oral glucose-lowering medications, thus not requiring insulin. Others might have some residual insulin secretion but need exogenous insulin for adequate control. Individuals with extensive β-cell destruction and no residual insulin secretion require insulin for survival. The degree of metabolic abnormality can progress, regress, or remain stable. Therefore, hyperglycemia levels reflect the severity of the metabolic process and its management rather than the process’s nature itself.
Classification of Diabetes Mellitus and Categories of Glucose Regulation
Assigning a specific diabetes type can depend on the circumstances at diagnosis, and many individuals do not fit neatly into one category. For example, gestational diabetes mellitus (GDM) may resolve after delivery or persist as type 2 diabetes. Similarly, diabetes induced by exogenous steroids might resolve upon discontinuation but reappear later due to other factors like pancreatitis. Thiazide-induced diabetes might actually be exacerbated type 2 diabetes. Therefore, understanding the pathogenesis of hyperglycemia and treating it effectively is more crucial than simply labeling the diabetes type.
Type 1 Diabetes: β-cell Destruction Leading to Insulin Deficiency
Type 1 diabetes is characterized by β-cell destruction, typically leading to absolute insulin deficiency. It is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
This form, accounting for 5–10% of diabetes cases, is caused by autoimmune destruction of pancreatic β-cells. Markers of this 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 85–90% of individuals at initial diagnosis with fasting hyperglycemia. The disease also shows strong HLA associations, particularly with DQA and DQB genes and influenced by DRB genes, with certain HLA-DR/DQ alleles being predisposing or protective.
The rate of β-cell destruction varies, being rapid in children and slower in adults. Some patients, especially children, may present with ketoacidosis as the first symptom. Others may have mild fasting hyperglycemia that quickly escalates to severe hyperglycemia or ketoacidosis under stress or infection. Adults may retain enough β-cell function to prevent ketoacidosis for years but eventually become insulin-dependent and at risk for ketoacidosis. At this stage, insulin secretion is minimal or absent, indicated by low plasma C-peptide levels. Immune-mediated diabetes is common in childhood and adolescence but can occur at any age.
Autoimmune β-cell destruction has genetic predispositions and is linked to poorly understood environmental factors. While patients are typically not obese at diagnosis, obesity doesn’t rule out this diagnosis. These patients are also prone to other autoimmune disorders like Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, and celiac disease.
Idiopathic Diabetes
Some type 1 diabetes cases have no known cause (idiopathic). These patients experience permanent insulinopenia and ketoacidosis but lack evidence of autoimmunity. Most affected individuals are of African or Asian descent. This form is characterized by episodic ketoacidosis and varying insulin deficiency between episodes. It is strongly inherited, lacks immunological markers of β-cell autoimmunity, and is not HLA-associated. Insulin replacement therapy needs can fluctuate in these patients.
Type 2 Diabetes: Insulin Resistance and Relative Insulin Deficiency
Type 2 diabetes, accounting for 90–95% of diabetes cases, involves insulin resistance and relative insulin deficiency. Initially and often throughout life, individuals do not require insulin for survival. The exact causes are varied and not fully understood, but autoimmune β-cell destruction is not involved, and other specific diabetes causes are excluded.
Most type 2 diabetes patients are obese, and obesity contributes to insulin resistance. Non-obese patients might have increased abdominal fat. Ketoacidosis is rare spontaneously, usually occurring with illnesses like infections. Type 2 diabetes often goes undiagnosed for years due to gradual hyperglycemia development and initially mild symptoms. However, these patients are at increased risk of macrovascular and microvascular complications. While insulin levels may appear normal or elevated, they are insufficient to compensate for insulin resistance. Insulin resistance can improve with weight loss or medication but is rarely fully reversed. Risk factors include age, obesity, inactivity, prior GDM, hypertension, dyslipidemia, and certain racial/ethnic backgrounds. It has a strong genetic predisposition, more so than autoimmune type 1 diabetes, though the genetics are complex and not fully defined.
Other Specific Types of Diabetes
This category includes diabetes forms with known specific causes, such as genetic defects, diseases of the exocrine pancreas, endocrinopathies, drug-induced diabetes, infections, and uncommon immune-mediated forms, and genetic syndromes.
Genetic Defects of the β-cell
Several monogenetic defects in β-cell function cause diabetes, often appearing before age 25, known as maturity-onset diabetes of the young (MODY). MODY is characterized by impaired insulin secretion with minimal insulin action defects, inherited in an autosomal dominant pattern. Mutations at six genetic loci on different chromosomes have been identified. Common forms involve mutations in hepatic transcription factors like HNF-1α (chromosome 12) and glucokinase gene mutations (chromosome 7p), affecting glucokinase’s role as the β-cell’s “glucose sensor”. Less common forms involve mutations in transcription factors like HNF-4α, HNF-1β, IPF-1, and NeuroD1.
Mitochondrial DNA point mutations are also linked to diabetes and deafness, particularly at position 3,243 in the tRNA leucine gene. Genetic abnormalities preventing proinsulin-to-insulin conversion and mutant insulin molecules with impaired receptor binding also exist, causing mild glucose intolerance, inherited in an autosomal dominant manner.
Genetic Defects in Insulin Action
Unusual diabetes forms result from genetically determined insulin action abnormalities. Insulin receptor mutations can cause a range from hyperinsulinemia and mild hyperglycemia to severe diabetes. Some patients may have acanthosis nigricans. Women may exhibit virilization and polycystic ovaries. Severe insulin resistance syndromes like leprechaunism and Rabson-Mendenhall syndrome are pediatric conditions with insulin receptor gene mutations, causing extreme insulin resistance. Leprechaunism is typically fatal in infancy, while Rabson-Mendenhall syndrome involves teeth, nail, and pineal gland abnormalities.
Insulin-resistant lipoatrophic diabetes is believed to involve postreceptor signal transduction pathway defects, rather than insulin receptor issues.
Diseases of the Exocrine Pancreas
Pancreatic damage from pancreatitis, trauma, infection, pancreatectomy, or pancreatic carcinoma can cause diabetes. Except for cancer, extensive damage is usually needed. Cystic fibrosis and hemochromatosis, if severe, can also damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may also lead to diabetes.
Endocrinopathies
Excess hormones like growth hormone, cortisol, glucagon, and epinephrine can counter insulin action, potentially causing diabetes in individuals with pre-existing insulin secretion defects. Conditions like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma can induce diabetes, which often resolves when hormone excess is corrected. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion, generally resolving after tumor removal.
Drug- or Chemical-Induced Diabetes
Many drugs can impair insulin secretion or action, potentially precipitating diabetes, especially in those with insulin resistance. Toxins like Vacor and intravenous pentamidine can permanently damage β-cells. Drugs like nicotinic acid and glucocorticoids can impair insulin action. Alpha-interferon has been linked to diabetes with islet cell antibodies and severe insulin deficiency.
Insulin treatment might be necessary at some point for any diabetes form and does not determine the diabetes classification itself.
Infections
Certain viruses, like congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, have been implicated in β-cell destruction and diabetes development.
Uncommon Forms of Immune-Mediated Diabetes
Conditions like stiff-man syndrome, an autoimmune CNS disorder, are associated with GAD autoantibodies and diabetes. 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 systemic lupus erythematosus and other autoimmune diseases, often with acanthosis nigricans.
Other Genetic Syndromes
Several genetic syndromes, including Down syndrome, Klinefelter syndrome, and Turner syndrome, are associated with increased diabetes incidence. Wolfram syndrome, an autosomal recessive disorder, involves insulin-deficient diabetes and other manifestations like diabetes insipidus and optic atrophy.
Gestational Diabetes Mellitus (GDM)
GDM is defined as glucose intolerance first recognized during pregnancy. While usually resolving post-delivery, it can persist or indicate pre-existing undiagnosed diabetes. With rising obesity and type 2 diabetes among women of childbearing age, undiagnosed type 2 diabetes in pregnant women is increasing.
The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends diagnosing overt diabetes, not GDM, in high-risk pregnant women at their first prenatal visit if standard diabetes criteria are met. GDM complicates approximately 7% of pregnancies.
Categories of Increased Risk for Diabetes
In 1997 and 2003, expert committees recognized pre-diabetes, an intermediate category for individuals with glucose levels higher than normal but not meeting diabetes criteria. This includes impaired fasting glucose (IFG) with FPG levels of 100-125 mg/dl and impaired glucose tolerance (IGT) with 2-h OGTT values of 140-199 mg/dl.
IFG and IGT are not clinical entities but risk factors for diabetes and cardiovascular disease, seen as intermediate stages in various disease processes. They are linked to obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes development in IGT individuals.
As A1C testing becomes more common for diabetes diagnosis, it also identifies those at higher risk. The International Expert Committee noted a continuum of diabetes risk with glycemic measures but didn’t formally define an intermediate A1C category, though they observed increased risk at A1C levels of 6.0-6.4%. Research suggests an A1C range of 5.5-6.0% accurately identifies people with IFG or IGT, and preventive interventions are effective even below 5.9% A1C. An A1C range of 5.7-6.4% is considered to identify individuals at high risk for future diabetes, termed pre-diabetes.
Individuals with A1C 5.7-6.4% should be informed of increased risks and counseled on risk-reducing strategies. Risk increases disproportionately with A1C levels, necessitating more intensive interventions for those above 6.0%. However, even below 5.7% A1C, risk may still exist depending on other factors.
Evaluation should include a global risk factor assessment for diabetes and cardiovascular disease, considering comorbidities, life expectancy, and patient capacity for lifestyle change.
Diagnostic Criteria for Diabetes Mellitus
Diabetes diagnosis has long relied on glucose criteria, FPG or OGTT. In 1997, diagnostic criteria were revised using the association between FPG and retinopathy prevalence. Studies identified glycemic levels where retinopathy prevalence increased, informing new diagnostic cut points: ≥126 mg/dl for FPG and ≥200 mg/dl for 2-h PG.
A1C, reflecting average glucose over 2-3 months, is crucial in diabetes management, correlating with microvascular and macrovascular complications. Recent standardization of A1C assays led the International Expert Committee and ADA to recommend A1C for diabetes diagnosis, with a threshold of ≥6.5%, associated with an inflection point for 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 accurate enough for diagnosis.
A1C offers convenience over FPG as fasting isn’t required and has greater preanalytical stability. However, it’s more expensive, less available globally, and correlation with average glucose is incomplete in some individuals. A1C can be misleading in certain anemias and hemoglobinopathies. For these patients, glucose criteria remain the primary diagnostic method.
Established glucose criteria (FPG and 2-h PG) remain valid. Random plasma glucose ≥200 mg/dl in patients with classic hyperglycemia symptoms or hyperglycemic crisis also remains diagnostic. While A1C might be measured in these cases, it may not always be elevated in rapidly evolving diabetes, like type 1 in children.
There is not full concordance between A1C and glucose-based tests. A1C ≥6.5% identifies fewer undiagnosed diabetes cases than FPG ≥126 mg/dl. However, A1C’s practicality might lead to wider testing and increased diagnoses.
Discordant results between different tests (e.g., FPG and A1C) require repeating the test above the diagnostic threshold for confirmation. If both tests are above thresholds, diagnosis is confirmed. If results are discordant, the test above threshold is repeated, and diagnosis is based on the confirmed test. If a repeated test falls below the threshold, close monitoring and repeat testing in 3-6 months are advised.
Test choice depends on healthcare professional discretion, considering patient practicality and test availability. Crucially, diabetes testing should be performed when indicated, as many at-risk patients still lack adequate testing and counseling.
Diagnosis of GDM
GDM diagnosis currently uses Carpenter and Coustan criteria. ADA’s Fourth International Workshop-Conference on Gestational Diabetes Mellitus supports Carpenter/Coustan criteria and alternative 75-g 2-h OGTT criteria.
Testing for Gestational Diabetes
Previous recommendations included universal GDM screening. However, low-risk women meeting all criteria below may not need screening:
- Age <25 years
- Normal weight pre-pregnancy
- No family history of diabetes in first-degree relatives
- No history of abnormal glucose metabolism
- No history of poor obstetric outcomes
- Not from a high-risk ethnic/racial group (Hispanic American, Native American, Asian American, African American, Pacific Islander)
Risk assessment for GDM should occur at the first prenatal visit. High-risk women (obesity, prior GDM, glycosuria, strong family history) should be tested early. If initial screening is negative, retesting is needed at 24-28 weeks gestation. Average-risk women should be tested at 24-28 weeks.
FPG >126 mg/dl or random glucose >200 mg/dl is diagnostic for diabetes. Confirmation is needed on a subsequent day unless unequivocal hyperglycemia is present, precluding a glucose challenge test. For average or high-risk women without this level of hyperglycemia, GDM evaluation follows one of two approaches:
One-Step Approach
Diagnostic OGTT without prior screening, potentially cost-effective in high-risk populations.
Two-Step Approach
Initial screening with a 50-g glucose challenge test (GCT). Diagnostic OGTT for women exceeding the GCT glucose threshold (typically >140 mg/dl or >130 mg/dl for higher sensitivity).
GDM diagnosis in either approach is based on OGTT. Diagnostic criteria for 100-g OGTT (Carpenter and Coustan) and 75-g OGTT are in Table 4.
For 100-g OGTT, two or more venous plasma glucose concentrations must be met or exceeded. Testing should be done in the morning after an 8-14 hour overnight fast, following at least 3 days of unrestricted diet (≥150 g carbohydrate/day) and normal physical activity. Subjects should remain seated and not smoke during the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study showed a continuous increase in adverse pregnancy outcomes with rising maternal glycemia, even within previously considered normal ranges. The IADPSG recommends a 75-g OGTT for all women at 24-28 weeks gestation, using fasting, 1-h, and 2-h plasma glucose cut points associated with an odds ratio of ≥1.75 for adverse outcomes compared to women with mean glucose levels in the HAPO study. ADA is considering adopting IADPSG diagnostic criteria, which will significantly increase GDM prevalence, but evidence suggests treating even mild GDM reduces morbidity for mothers and babies.
Acknowledgments
The American Diabetes Association acknowledges the volunteer writing group members for the updated sections on diagnosis and risk categories.
References
1,2,3,8,9,10,11,12,13,14 (Note: Full references would be listed here in a complete document, but were not provided in the original extract).
