Prediabetes
Prediabetes is a serious health condition characterized by blood glucose levels that are higher than normal but not elevated enough to meet the diagnostic threshold for type 2 diabetes mellitus.[1] It typically results from insulin resistance, where cells in the muscles, fat, and liver do not respond effectively to insulin, leading the pancreas to produce more insulin to compensate until it can no longer keep blood sugar levels in check.[2] As a precursor to type 2 diabetes, prediabetes significantly increases the risk of developing the full disease, as well as cardiovascular complications such as heart disease and stroke, if left unaddressed.[1] In the United States, prediabetes affects approximately 98 million adults—more than one in three—making it a widespread public health concern, with over 80% of those affected unaware of their condition.[3] The prevalence is higher among certain demographic groups, including older adults, racial and ethnic minorities such as African Americans, Hispanic/Latinos, American Indians, Alaska Natives, Pacific Islanders, and some Asian Americans, and those with a family history of diabetes.[1] Without intervention, people with prediabetes have a high risk of developing type 2 diabetes within five to ten years, underscoring the importance of early detection and lifestyle modifications to reverse or delay onset.[2] The exact causes of prediabetes remain incompletely understood but are closely linked to a combination of genetic and environmental factors, including obesity and sedentary behavior, which exacerbate insulin resistance.[4] Key risk factors include being overweight or obese (particularly with excess abdominal fat), physical inactivity, age 35 or older, history of gestational diabetes, polycystic ovary syndrome (PCOS), smoking, and certain medications like glucocorticoids or antipsychotics.[2] Most people with prediabetes experience no noticeable symptoms, though some may develop subtle signs such as increased thirst, frequent urination, fatigue, blurred vision, or darkened skin patches in areas like the neck or armpits (acanthosis nigricans).[4] Diagnosis of prediabetes is typically confirmed through blood tests, including an A1C test showing levels of 5.7% to 6.4%, a fasting plasma glucose (FPG) test of 100 to 125 mg/dL, or an oral glucose tolerance test (OGTT) result of 140 to 199 mg/dL.[2] Prevention and management focus on lifestyle interventions, such as losing 5% to 7% of body weight through a balanced diet and at least 150 minutes of moderate physical activity per week, which can reduce the risk of progressing to type 2 diabetes by up to 58% overall (and 71% in those over age 60).[1] In select cases, medication like metformin may be prescribed, particularly for individuals at higher risk, alongside regular screening to monitor blood glucose levels.[4]Clinical Overview
Definition
Prediabetes is defined as an intermediate stage of hyperglycemia in which blood glucose concentrations exceed normal levels but do not meet the diagnostic criteria for type 2 diabetes mellitus.[5][6] This condition represents a high-risk state for progression to overt diabetes and is characterized by impaired insulin secretion, action, or both.[7] According to the American Diabetes Association (ADA), prediabetes is diagnosed based on one or more of the following: fasting plasma glucose (FPG) of 100–125 mg/dL (5.6–6.9 mmol/L), 2-hour plasma glucose of 140–199 mg/dL (7.8–11.0 mmol/L during a 75-g oral glucose tolerance test (OGTT)), or hemoglobin A1c (HbA1c) of 5.7–6.4%.[5] The World Health Organization (WHO) defines prediabetes, referred to as intermediate hyperglycemia, through impaired fasting glucose (IFG) with FPG of 110–125 mg/dL (6.1–6.9 mmol/L) or impaired glucose tolerance (IGT) with 2-hour OGTT values of 140–199 mg/dL (7.8–11.0 mmol/L), but does not recommend HbA1c for this classification.[6] These thresholds distinguish prediabetes from normoglycemia—defined by ADA as FPG below 100 mg/dL (5.6 mmol/L), 2-hour OGTT below 140 mg/dL (7.8 mmol/L), and HbA1c below 5.7%—and from diabetes, which requires FPG of at least 126 mg/dL (7.0 mmol/L), 2-hour OGTT of at least 200 mg/dL (11.1 mmol/L), or HbA1c of at least 6.5%.[5][6] The term "prediabetes" was coined by the ADA in 2003 to unify and raise awareness of the previously separate categories of IFG and IGT, emphasizing its role as a precursor to diabetes.[8] Prediabetes is closely linked to metabolic syndrome, a cluster of conditions including central obesity, hypertension, dyslipidemia, and insulin resistance that collectively increase cardiovascular risk.[7] Individuals with prediabetes often exhibit features of this syndrome, highlighting the shared pathophysiology of impaired glucose regulation and cardiometabolic dysfunction.[9]Signs and Symptoms
Prediabetes is typically asymptomatic, meaning most individuals do not experience noticeable signs or symptoms and remain unaware of their condition until it is detected through routine blood glucose screening.[4][10] This lack of overt manifestations contributes to the high prevalence of undiagnosed prediabetes, affecting an estimated 98 million adults in the United States alone.[3] In rare cases, subtle symptoms may emerge that overlap with those of early type 2 diabetes, such as increased thirst (polydipsia), frequent urination (polyuria), unexplained fatigue, and blurred vision.[4][11] These symptoms arise due to mild impairments in glucose regulation but are not specific to prediabetes and often go unrecognized or attributed to other causes like stress or dehydration.[10] Certain associated skin and oral conditions can also signal underlying insulin resistance in prediabetes. Acanthosis nigricans, characterized by darkened, velvety patches of skin typically appearing on the neck, armpits, or groin, serves as a visible marker of hyperinsulinemia.[10][11] Additionally, gingival inflammation and early periodontal disease may be linked to prediabetic states, with studies showing a strong association between impaired fasting glucose and increased bleeding on probing, an indicator of chronic oral inflammation.[12] However, prediabetes lacks unique symptoms exclusive to the condition; its discovery is primarily incidental through standard health evaluations rather than symptomatic presentation.[4]Etiology and Pathophysiology
Causes and Risk Factors
The primary causes of prediabetes involve a combination of insulin resistance and beta-cell dysfunction in the pancreas, which together impair the body's ability to regulate blood glucose levels effectively. Insulin resistance occurs when cells in muscle, fat, and liver do not respond appropriately to insulin, reducing glucose uptake, while beta-cell dysfunction limits the production and secretion of insulin in response to rising blood sugar. This interplay leads to elevated blood glucose concentrations that characterize prediabetes, often progressing from impaired fasting glucose or impaired glucose tolerance.[13][14][15] Non-modifiable risk factors play a significant role in prediabetes susceptibility. Age 35 years or older increases risk due to age-related declines in insulin sensitivity and beta-cell function.[16] A family history of diabetes, particularly type 2, elevates individual risk through shared genetic predispositions. Certain ethnic backgrounds confer higher susceptibility, including African American, Hispanic/Latino, American Indian, Alaska Native, Asian American, and Pacific Islander populations, who experience disproportionate rates compared to non-Hispanic White individuals. Additionally, a history of gestational diabetes during pregnancy substantially heightens the risk of developing prediabetes later in life. Certain medical conditions, such as polycystic ovary syndrome (PCOS), sleep apnea, and Cushing’s syndrome, also increase risk.[2][17][18][19] Modifiable risk factors are central to prediabetes prevention and include lifestyle and metabolic conditions that can be addressed. Overweight or obesity, defined as a body mass index (BMI) of 25 kg/m² or higher, promotes insulin resistance through excess adipose tissue, particularly visceral fat. Physical inactivity exacerbates this by further impairing glucose uptake in muscles. Poor dietary patterns, characterized by high intake of refined carbohydrates and saturated fats, contribute to weight gain and metabolic stress. Smoking is associated with increased oxidative stress and endothelial dysfunction, elevating prediabetes risk. Use of certain medications, such as glucocorticoids, antipsychotics, or HIV medications, can also contribute to risk. Hypertension and dyslipidemia, often co-occurring with obesity, compound insulin resistance through vascular and lipid abnormalities.[17][17][20][21][21][2] Genetic factors influence prediabetes vulnerability, with variants in genes such as TCF7L2 (transcription factor 7-like 2) being among the strongest predictors. The rs7903146 polymorphism in TCF7L2 is linked to impaired beta-cell function and increased susceptibility to impaired glucose tolerance, independent of body mass index. These genetic markers explain a portion of familial clustering and ethnic disparities in risk.[22][23] Environmental influences, particularly in low- and middle-income countries, contribute to rising prediabetes rates through rapid urbanization and associated sedentary lifestyles. Urban migration often leads to reduced physical activity, increased consumption of processed foods, and higher stress levels, amplifying metabolic risks in transitioning populations. Infrastructure limitations in these settings further hinder access to healthy environments, exacerbating the epidemic.[24][25]Pathophysiology
Prediabetes is characterized by peripheral insulin resistance, primarily in skeletal muscle and adipose tissue, which impairs glucose uptake and disposal in response to insulin stimulation. This resistance arises from defects in insulin signaling pathways, such as reduced phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt, leading to decreased translocation of glucose transporter 4 (GLUT4) to the cell membrane.[26] In the early stages, pancreatic beta cells compensate for this resistance by increasing insulin secretion, resulting in hyperinsulinemia that helps maintain euglycemia despite elevated postprandial glucose levels.[14] Over time, sustained hyperinsulinemia and chronic exposure to elevated glucose and free fatty acids lead to beta-cell exhaustion and dysfunction, marked by impaired glucose-stimulated insulin secretion and progressive loss of beta-cell mass. This exhaustion is exacerbated by glucolipotoxicity, which induces oxidative stress and endoplasmic reticulum stress in beta cells, ultimately reducing their ability to respond adequately to glucose challenges.[27] Concurrently, alpha-cell dysregulation contributes to the pathophysiology, with inappropriate postprandial glucagon secretion that fails to suppress, promoting excessive hepatic glucose production and further elevating blood glucose levels.[28] Chronic low-grade inflammation plays a key role in worsening insulin resistance, driven by proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 secreted from adipose tissue, which interfere with insulin signaling and promote endothelial dysfunction.[29] Alterations in the gut microbiome, including reduced abundance of beneficial genera like Akkermansia and Clostridium, are associated with increased intestinal permeability and low-grade systemic inflammation, further impairing metabolic homeostasis.[30] Defects in incretin hormones, particularly reduced secretion of glucagon-like peptide-1 (GLP-1) in response to oral glucose, diminish glucose-dependent insulin secretion and contribute to postprandial hyperglycemia.[31] The progression of prediabetes follows a continuum from normal glucose tolerance, through stages of impaired fasting glucose (IFG) characterized by hepatic insulin resistance, to impaired glucose tolerance (IGT) involving peripheral defects, and ultimately to overt type 2 diabetes upon beta-cell failure.[14] Risk factors such as obesity can intensify peripheral insulin resistance by increasing ectopic lipid accumulation in muscle and liver.[29]Diagnosis and Screening
Diagnostic Criteria
Prediabetes is diagnosed based on specific thresholds for blood glucose levels or glycated hemoglobin, as established by major health organizations. The American Diabetes Association (ADA) defines prediabetes using three primary tests: fasting plasma glucose (FPG) of 100–125 mg/dL (5.6–6.9 mmol/L), 2-hour plasma glucose of 140–199 mg/dL (7.8–11.0 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or HbA1c of 5.7–6.4% (39–47 mmol/mol).[32] These criteria remain consistent in the 2025 ADA Standards of Care, which emphasize HbA1c testing for its convenience—no fasting is required—and its reflection of average glycemia over 2–3 months, though with caveats for populations affected by conditions like anemia or hemoglobinopathies where accuracy may be compromised.[32] In contrast, the World Health Organization (WHO) criteria focus on impaired fasting glucose (IFG) with FPG of 110–125 mg/dL (6.1–6.9 mmol/L) or impaired glucose tolerance (IGT) with 2-hour plasma glucose of 140–199 mg/dL (7.8–11.0 mmol/L) during OGTT, but exclude HbA1c for prediabetes diagnosis due to insufficient evidence for its prognostic value in this context.[33] The following table summarizes the key differences:| Test | ADA Criteria | WHO Criteria |
|---|---|---|
| Fasting Plasma Glucose (FPG) | 100–125 mg/dL (5.6–6.9 mmol/L) | 110–125 mg/dL (6.1–6.9 mmol/L) |
| 2-hour OGTT | 140–199 mg/dL (7.8–11.0 mmol/L) | 140–199 mg/dL (7.8–11.0 mmol/L) |
| HbA1c | 5.7–6.4% (39–47 mmol/mol) | Not used for diagnosis |