Diabetes mellitus represents a cluster of metabolic disorders characterized by persistent hyperglycemia. This elevated blood sugar arises from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia is the hallmark of diabetes and is associated with long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart, and blood vessels. Understanding the Diagnosis And Classification Of Diabetes Mellitus is crucial for effective management and patient care.
Several underlying processes contribute to the development of diabetes. These range from the autoimmune destruction of pancreatic β-cells, leading to insulin deficiency, to conditions causing resistance to insulin’s effects. At the heart of metabolic abnormalities in diabetes is the insufficient action of insulin on target tissues. This deficiency can stem from inadequate insulin secretion, reduced tissue responsiveness to insulin, or a combination of both. Often, both impaired insulin secretion and insulin resistance coexist, making it challenging to pinpoint the primary cause of hyperglycemia.
The noticeable symptoms of significant hyperglycemia include increased urination (polyuria), excessive thirst (polydipsia), unexplained weight loss, sometimes accompanied by increased hunger (polyphagia), and blurred vision. Furthermore, chronic hyperglycemia can hinder growth and increase susceptibility to infections. Acute, life-threatening complications of uncontrolled diabetes include hyperglycemia with ketoacidosis and the nonketotic hyperosmolar syndrome.
Over time, diabetes can lead to severe complications, including retinopathy and potential vision loss, nephropathy progressing to renal failure, peripheral neuropathy 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 face a heightened risk of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. Hypertension and abnormal lipid profiles are frequently observed in diabetic populations.
The vast majority of diabetes cases fall into two main categories: type 1 and type 2 diabetes. Type 1 diabetes is characterized by an absolute deficiency in insulin secretion, often triggered by autoimmune destruction of pancreatic β-cells. Type 2 diabetes, the more prevalent form, results from a combination of insulin resistance and an insufficient compensatory insulin response. Importantly, individuals may experience a prolonged asymptomatic period with elevated blood glucose levels before diabetes is clinically detected. During this phase, impaired carbohydrate metabolism can be identified through fasting plasma glucose measurements or oral glucose tolerance tests.
The degree of hyperglycemia in diabetes can fluctuate over time, influenced by the progression of the underlying disease and the effectiveness of treatment, 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 do not fully meet the diagnostic criteria for diabetes but indicate increased risk. Glycemic control in diabetes can be achieved through lifestyle modifications like weight reduction and exercise, oral glucose-lowering medications, or insulin therapy, depending on individual needs and disease severity. The severity of hyperglycemia reflects the underlying metabolic disturbance and its management rather than the nature of the disease process itself.
CLASSIFICATION OF DIABETES MELLITUS
Classifying diabetes type is often context-dependent at the time of diagnosis, and many individuals do not fit neatly into a single category. For instance, gestational diabetes mellitus (GDM) may transition into type 2 diabetes post-delivery. Conversely, steroid-induced diabetes might resolve upon discontinuation of glucocorticoids but reappear later due to other factors like pancreatitis. Similarly, thiazide diuretics can exacerbate underlying type 2 diabetes. Therefore, understanding the underlying mechanisms of hyperglycemia and effective treatment strategies is more critical for clinicians and patients than simply labeling the diabetes type.
Type 1 Diabetes: β-cell Destruction and Insulin Deficiency
Type 1 diabetes is marked by the destruction of pancreatic β-cells, typically leading to a complete lack of insulin. It is further divided into immune-mediated and idiopathic forms.
Immune-Mediated Diabetes
This form, previously known as insulin-dependent diabetes or juvenile-onset diabetes, accounts for 5–10% of diabetes cases. It is an autoimmune condition where the body’s immune system mistakenly attacks and destroys pancreatic β-cells. Markers of this autoimmune process 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 at the onset of fasting hyperglycemia. Genetic predisposition plays a significant role, with associations to HLA genes (DQA, DQB, and DRB).
The rate of β-cell destruction varies significantly. Children and infants may experience rapid destruction, while adults may have a slower progression. Ketoacidosis can be the initial presentation, especially in children and adolescents. Others may have mild hyperglycemia that quickly worsens with stress or infection. Adults may retain some β-cell function for years, delaying ketoacidosis but eventually requiring insulin for survival. At advanced stages, insulin secretion is minimal or absent, indicated by low plasma C-peptide levels. Immune-mediated diabetes is more common in younger populations but can occur at any age.
Genetic and environmental factors, still not fully understood, contribute to autoimmune β-cell destruction. While patients are often not obese at diagnosis, obesity does not rule out this type. These individuals are also susceptible to other autoimmune disorders like Graves’ disease, Hashimoto’s thyroiditis, and Addison’s disease.
Idiopathic Diabetes
Some cases of type 1 diabetes lack identifiable causes (idiopathic). These individuals experience permanent insulin deficiency and ketoacidosis but show no evidence of autoimmunity. This category is less common, predominantly affecting individuals of African or Asian descent. Episodic ketoacidosis and varying degrees of insulin deficiency characterize this form. It has a strong hereditary component but lacks autoimmune markers and HLA associations. Insulin therapy needs may fluctuate in affected individuals.
Type 2 Diabetes: Insulin Resistance and Relative Insulin Deficiency
Type 2 diabetes, formerly known as non-insulin-dependent or adult-onset diabetes, comprises 90–95% of diabetes cases. It is characterized by insulin resistance combined with a relative (not absolute) insulin deficiency. 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, nor are the specific causes listed for other diabetes types.
Obesity is a major contributing factor, causing insulin resistance. Even non-obese individuals may have increased abdominal fat, exacerbating insulin resistance. Spontaneous ketoacidosis is rare in type 2 diabetes, typically occurring under severe stress like infection. This type often remains undiagnosed for years due to gradual hyperglycemia development and initially subtle symptoms. However, even mild hyperglycemia increases the risk of macrovascular and microvascular complications. While insulin levels might appear normal or elevated, they are insufficient to overcome insulin resistance, indicating defective β-cell function. Weight loss and medication can improve insulin resistance but rarely restore it to normal. Risk factors include age, obesity, inactivity, prior GDM, hypertension, dyslipidemia, and ethnicity. Genetic predisposition is strong but complex and not well-defined.
Other Specific Types of Diabetes
Beyond type 1 and type 2, several other specific types of diabetes exist, often linked to genetic defects, diseases, or external factors.
Genetic Defects of β-cell Function
Several monogenic defects in β-cell function lead to diabetes, often appearing before age 25. These are known as maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion with minimal insulin resistance. MODY is inherited in an autosomal dominant pattern. Mutations in various genes, including hepatocyte nuclear factor (HNF)-1α (chromosome 12), glucokinase (chromosome 7p), HNF-4α (chromosome 20), HNF-1β (chromosome 17), insulin promoter factor (IPF)-1 (chromosome 13), and NeuroD1 (chromosome 2), have been identified. Glucokinase, crucial for glucose sensing in β-cells, is affected in one common form. Mitochondrial DNA mutations, particularly at position 3,243 in the tRNA leucine gene, are also linked to diabetes and deafness. Rarely, genetic defects impairing proinsulin-to-insulin conversion or producing mutant insulin molecules with reduced receptor binding can cause mild glucose intolerance.
Genetic Defects in Insulin Action
Rare genetic abnormalities affecting insulin action can cause diabetes. Mutations in the insulin receptor gene can result in a spectrum of metabolic issues, from hyperinsulinemia to severe diabetes. Acanthosis nigricans and virilization in women may be present. Leprechaunism and Rabson-Mendenhall syndrome are pediatric syndromes with insulin receptor gene mutations and extreme insulin resistance, often with severe outcomes. Insulin-resistant lipoatrophic diabetes likely involves defects in postreceptor signaling pathways.
Diseases of the Exocrine Pancreas
Diffuse pancreatic damage from pancreatitis, trauma, infection, pancreatectomy, or pancreatic cancer can lead to diabetes. Except for cancer-related diabetes, extensive damage is usually required. Cystic fibrosis and hemochromatosis, if severe enough, can also impair insulin secretion. Fibrocalculous pancreatopathy, characterized by abdominal pain and pancreatic calcifications, can also cause diabetes.
Endocrinopathies
Excess hormones that counter insulin action, such as growth hormone, cortisol, glucagon, and epinephrine (in acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, respectively), can induce diabetes, especially in individuals with pre-existing insulin secretion defects. Hyperglycemia typically resolves when hormone excess is corrected. Somatostatinoma and aldosteronoma-induced hypokalemia can also cause diabetes by inhibiting insulin secretion.
Drug- or Chemical-Induced Diabetes
Numerous drugs can impair insulin secretion or action, potentially triggering diabetes in susceptible individuals. Toxins like Vacor and pentamidine can permanently destroy β-cells. Drugs like nicotinic acid and glucocorticoids impair insulin action. Alpha-interferon has been linked to diabetes with islet cell antibodies. Table 1 provides a list of common drug, hormone, or toxin-induced diabetes forms.
Infections
Certain viruses, including congenital rubella, coxsackievirus B, cytomegalovirus, adenovirus, and mumps, have been associated with β-cell destruction and diabetes.
Uncommon Forms of Immune-Mediated Diabetes
Rare immune conditions like stiff-man syndrome and anti-insulin receptor antibodies can cause diabetes. Stiff-man syndrome, an autoimmune neurological disorder, often presents with GAD autoantibodies and diabetes. Anti-insulin receptor antibodies can block insulin binding, causing insulin resistance and sometimes hypoglycemia.
Other Genetic Syndromes
Several genetic syndromes, such as Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, and Prader-Willi syndrome, are associated with increased diabetes risk.
It’s important to note that insulin use at any stage of diabetes does not define the diabetes type itself.
Gestational Diabetes Mellitus (GDM)
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first recognized during pregnancy. While usually resolving after delivery, the definition applies regardless of persistence post-pregnancy and includes cases where glucose intolerance may have pre-dated pregnancy. With increasing obesity and type 2 diabetes among women of childbearing age, undiagnosed type 2 diabetes in pregnancy is rising.
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 in high-risk women. GDM complicates approximately 7% of pregnancies.
CATEGORIES OF INCREASED RISK FOR DIABETES
Individuals with glucose levels above normal but not meeting diabetes criteria are considered at increased risk. These categories include impaired fasting glucose (IFG) with FPG levels of 100–125 mg/dl (5.6–6.9 mmol/l), impaired glucose tolerance (IGT) with 2-hour OGTT values of 140–199 mg/dl (7.8–11.0 mmol/l), and elevated A1C (5.7–6.4%). These conditions are often termed “pre-diabetes,” signifying a heightened risk of developing diabetes and cardiovascular disease. They are not clinical entities themselves but rather risk indicators associated with obesity, dyslipidemia, and hypertension. Lifestyle interventions and certain medications can prevent or delay diabetes onset in individuals with IGT.
A1C is increasingly used for diabetes risk assessment. While no formal intermediate A1C category was initially defined, levels between 5.7% and 6.4% are now recognized as indicating increased risk. This range identifies individuals with a significantly higher risk of developing diabetes. An A1C of 5.7% shows good specificity for identifying future diabetes risk. Individuals with A1C in the 5.7–6.4% range should be informed of their increased risk and counseled on risk-reduction strategies. Higher A1C levels within this range signify disproportionately greater risk, warranting more intensive interventions.
Table 2 summarizes the categories of increased diabetes risk. Risk evaluation should include a comprehensive assessment for both diabetes and cardiovascular disease, considering patient comorbidities, life expectancy, and personal health goals.
DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS
Diabetes diagnosis has historically relied on glucose criteria, specifically FPG and the 75-g OGTT. In 1997, diagnostic criteria were revised based on the association between FPG levels and retinopathy. Studies identified glycemic thresholds above which retinopathy prevalence increased. These analyses led to the FPG diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) and confirmed the 2-hour PG value of ≥200 mg/dl (11.1 mmol/l).
A1C, reflecting average glucose over 2-3 months, is crucial for diabetes management and correlates with microvascular and macrovascular complications. Standardized A1C assays are now recommended for diabetes diagnosis with a threshold of ≥6.5%. This cut point aligns with retinopathy prevalence inflection points, similar to FPG and 2-hour PG thresholds. Diagnostic A1C testing must be NGSP certified and standardized to the DCCT assay. Point-of-care A1C tests are not yet accurate enough for diagnosis.
A1C offers advantages like convenience (no fasting) and stability compared to FPG. However, it has limitations in cost, availability in developing regions, and potential inaccuracies in certain anemias and hemoglobinopathies. In such cases, glucose criteria remain the primary diagnostic tools. Established glucose criteria (FPG, 2-hour PG) and random glucose ≥200 mg/dl (11.1 mmol/l) in patients with hyperglycemic symptoms remain valid diagnostic options.
Discordance between A1C and glucose-based tests can occur due to measurement variability or different physiological processes measured by each test. A diagnostic test result should be repeated to rule out lab errors, ideally 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 for confirmation. If a repeated test falls below the diagnostic cut point after an initial elevated result, close monitoring and repeat testing in 3–6 months are recommended.
The choice of diagnostic test is at the healthcare professional’s discretion, considering test availability and practicality. Crucially, diabetes testing should be performed when indicated, as many at-risk individuals still lack adequate screening and counseling. Table 3 summarizes current diagnostic criteria.
DIAGNOSIS OF GDM
GDM diagnosis relies on specific criteria outlined by Carpenter and Coustan or the use of a diagnostic 75-g 2-hour OGTT.
Testing for Gestational Diabetes
Universal GDM screening in all pregnancies was previously recommended. However, low-risk women meeting all of the following criteria may not require screening: age <25 years, normal weight, no family history of diabetes, no history of abnormal glucose metabolism or poor obstetric outcomes, and not belonging to a high-risk ethnic/racial group.
Risk assessment should occur at the first prenatal visit. High-risk women (marked obesity, prior GDM, glycosuria, strong family history) should be tested immediately. If initial testing is negative, retesting should occur at 24–28 weeks. Average-risk women should be tested at 24–28 weeks.
FPG >126 mg/dl (7.0 mmol/l) or random glucose >200 mg/dl (11.1 mmol/l) is diagnostic for diabetes. Confirmation is needed on a subsequent day if unequivocal hyperglycemia is absent, precluding further glucose challenge. In other cases, GDM evaluation involves one-step or two-step approaches.
One-Step Approach
A diagnostic OGTT is performed without prior screening, potentially cost-effective in high-risk populations.
Two-Step Approach
Initial screening involves a 50-g glucose challenge test (GCT). If the 1-hour glucose level exceeds a threshold (typically >140 mg/dl or >130 mg/dl for higher sensitivity), a diagnostic OGTT is performed.
Both approaches rely on OGTT for GDM diagnosis. Criteria for the 100-g OGTT (Carpenter/Coustan) and 75-g OGTT are shown in Table 4.
For a positive GDM diagnosis using the 100-g OGTT, two or more venous plasma glucose concentrations must meet or exceed the thresholds. Testing should be done in the morning after an 8–14 hour fast, following at least 3 days of unrestricted diet and activity. The subject should remain seated and refrain from smoking during the test.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a continuous increase in adverse pregnancy outcomes with rising maternal glycemia, even within previously considered normal ranges. This has led to a re-evaluation of GDM diagnostic criteria. The IADPSG recommends a 75-g OGTT at 24–28 weeks for all women without known prior diabetes, establishing diagnostic cut points based on odds ratios for adverse outcomes from the HAPO study. While these new criteria may increase GDM prevalence, evidence suggests treating even mild GDM benefits both mother and baby.
Acknowledgments
The American Diabetes Association acknowledges the contributions of Silvio Inzucchi, MD; Richard Bergenstal, MD; Vivian Fonseca, MD; Edward Gregg, PhD; Beth Mayer-Davis, MSPH, PhD, RD; Geralyn Spollett, MSN, CDE, ANP; and Richard Wender, MD, for their work on updating the sections on diagnosis and risk categories.
