Prediabetes and screening

Prediabetes identifies a condition of impaired glucose homeostasis in which blood glucose or glycated hemoglobin values are above normal but not yet sufficient for a diagnosis of diabetes mellitus. It is not a clinically meaningless gray zone or merely an occasional laboratory abnormality, but a biological state in which reduced beta-cell reserve, increased hepatic glucose production, peripheral insulin resistance, and broader disruption of the cardiometabolic profile begin to become evident. Clinically, recognition is crucial because this phase often precedes type 2 diabetes mellitus, but may also accompany other pathological trajectories, including some early forms of autoimmune diabetes or secondary forms in predisposing contexts.

The purpose of screening is to identify asymptomatic individuals with undiagnosed dysglycemia, preventing the disease from being recognized only after overt hyperglycemia, microvascular complications, or established cardiovascular damage has developed. This principle is particularly important in type 2 diabetes mellitus, which may remain silent for years while hepatic steatosis, arterial hypertension, atherogenic dyslipidemia, albuminuria, early neuropathy, and vascular remodeling progress. On this page, prediabetes is treated as an autonomous clinical entity from diagnostic and prognostic perspectives, while screening is analyzed as a rational process of risk identification, selection of individuals to test, choice of the most appropriate test, and definition of follow-up for patients with normal, intermediate, or diabetes-range results.

Prediabetes occupies an intermediate position between normoglycemia and overt diabetes, but this simplified definition does not fully capture its biological meaning. It is actually a state of metabolic instability in which compensatory mechanisms that have maintained blood glucose within apparently normal limits for years begin to lose effectiveness. Pancreatic beta cells often continue to produce substantial absolute amounts of insulin, sometimes even elevated amounts, but secretion becomes inadequate relative to the degree of insulin resistance, loss of first-phase secretion, persistent hepatic gluconeogenesis, and altered incretin regulation. The individual is therefore not yet diabetic according to official criteria, but already has pathologically vulnerable glucose regulation.

This transition has major clinical significance because the risk associated with prediabetes is not limited to the future development of type 2 diabetes mellitus. Many patients already show marked clustering of cardiometabolic risk factors at this stage, including visceral obesity, hypertriglyceridemia, reduced high-density lipoprotein cholesterol, increased blood pressure, metabolic dysfunction-associated steatotic liver disease, a chronic low-grade proinflammatory state, and sometimes early signs of target-organ damage. Prediabetes should therefore not be interpreted merely as a chronological waiting room before diabetes, but as a pathological stage in which overall risk is already increased and active management is required.

Nosologically, the term prediabetes is widely used in clinical practice and guidelines, but includes different phenotypes. Some individuals predominantly have impaired fasting glucose, others impaired glucose tolerance, and still others an isolated increase in glycated hemoglobin. These patterns are not equivalent. Impaired fasting glucose more closely reflects dysfunction of hepatic control and basal insulin secretion, whereas impaired glucose tolerance more clearly reveals failure to manage a postprandial glucose load. HbA1c in the intermediate range integrates average glycemic burden over time, but may be influenced by hematological and biological conditions that limit its reliability. Prediabetes should therefore always be described specifically, clarifying which parameter is abnormal, to what extent, and in what clinical context.

Progression from normoglycemia to prediabetes and from prediabetes to diabetes does not occur as an abrupt leap, but as a slow pathological reorganization of energy homeostasis. In the early stages, the body compensates for insulin resistance by increasing insulin secretion. This response may maintain apparently normal glycemia for years, but at the cost of an increasing functional burden on beta cells. When secretory reserve begins to decline, dynamic abnormalities emerge first, particularly in postprandial metabolism, because loss of first-phase insulin secretion impairs containment of the initial glycemic peak after an oral load or mixed meal. Subsequently, increased fasting glucose and a progressive rise in glycated hemoglobin also become evident.

The liver plays a decisive role in this process. Reduced ability of insulin to suppress hepatic glucose production leads to excessive glucose output during overnight fasting and in the morning hours. At the same time, skeletal muscle becomes less efficient at utilizing postprandial glucose, while visceral adipose tissue increases release of free fatty acids, proinflammatory adipokines, and mediators that worsen systemic insulin resistance. Incretin dysfunction, inappropriate glucagon secretion, and reduced metabolic flexibility further amplify the regulatory defect.

At the cellular and molecular levels, prediabetes is often accompanied by mild but persistent glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress, and mitochondrial abnormalities in beta cells. These phenomena accelerate loss of secretory function and transform initially effective compensation into a progressively inadequate response. Not all patients follow the same trajectory: in individuals with greater obesity and insulin resistance, a prolonged phase of compensatory hyperinsulinemia often predominates, whereas in others, particularly those with genetic predisposition or lower baseline beta-cell mass, secretory decline may occur relatively early. This heterogeneity explains why prediabetes is a unified clinical category but a pathophysiologically composite one.

Prediabetes is extremely common in adult populations and is now one of the main sources of future expansion of type 2 diabetes mellitus. Its prevalence increases in parallel with overweight, visceral obesity, physical inactivity, sleep deprivation, population aging, and social inequalities that influence diet, access to care, physical activity, and the quality of the living environment. From a public health perspective, prediabetes is therefore relevant not only because of the absolute number of people affected, but also because it represents the link between latent metabolic risk and the emergence of overt disease on a large scale.

Risk is not distributed uniformly. Older age increases the probability of dysglycemia, but the problem is increasingly common among younger adults with abdominal adiposity, a positive family history, previous gestational diabetes, polycystic ovary syndrome, physical inactivity, or membership in ethnic groups with greater metabolic vulnerability. Scientific societies also emphasize that in some Asian populations risk may emerge at lower body mass index values than those traditionally used to define overweight because of differences in body composition and ectopic fat distribution.

The epidemiological importance of prediabetes also derives from the fact that a substantial proportion of affected individuals are not identified in time. This occurs because the condition is often asymptomatic or minimally symptomatic and because many people do not undergo testing until overt hyperglycemia or associated complications appear. Organized or opportunistic screening is therefore crucial: it shifts diagnosis from a late stage to a stage in which lifestyle modification, weight loss, and, in selected cases, preventive pharmacological therapy can still substantially alter the natural history of disease.

Screening for prediabetes is not an indiscriminate procedure to be applied blindly, but a strategy that begins with risk identification. The central factors are overweight or obesity, particularly when accompanied by abdominal fat distribution, because visceral adiposity is the strongest driver of insulin resistance in type 2 diabetes mellitus. Risk is not limited to body weight, however. A first-degree family history of diabetes, increasing age, arterial hypertension, atherogenic dyslipidemia, physical inactivity, metabolic dysfunction-associated steatotic liver disease, previous hyperglycemia during pregnancy, and certain endocrine or gynecological syndromes substantially increase the probability of dysglycemia.

An important element of assessment is the integrated clinical context. A patient with acanthosis nigricans, increased waist circumference, hypertriglyceridemia, hyperuricemia, polycystic ovary syndrome, or a history of premature cardiovascular disease should not be considered merely as someone with a possible glucose abnormality, but as having an evolving metabolic syndrome in which dysglycemia is one of the central signals. In these circumstances, screening has broader prognostic significance than the diagnosis of prediabetes alone.

The absence of obesity does not exclude risk. Some apparently normal-weight individuals have disproportionate visceral adiposity, sarcopenia, reduced muscular oxidative capacity, or marked genetic susceptibility to beta-cell decline. Clinicians should therefore avoid a simplistic view of risk based solely on body mass index. Effective screening arises precisely from the ability to recognize the overall metabolic profile rather than mechanically applying a single number.

According to the most authoritative recommendations, screening for prediabetes and type 2 diabetes mellitus in asymptomatic adults should be risk based. In clinical practice, this means actively testing adults with overweight or obesity who have additional predisposing factors and, in many contemporary recommendations, all adults beginning at a specified age even in the absence of other particularly evident factors. The U.S. Preventive Services Task Force recommends screening adults aged 35 to 70 years with overweight or obesity, whereas the most recent diabetes standards support broad and earlier screening strategies in at-risk adults to detect disease during its preclinical phase.

In outpatient practice, screening is often most usefully initiated when an abnormal metabolic profile, progressive weight gain, a history of gestational diabetes, polycystic ovary syndrome, atherosclerotic cardiovascular disease, or hepatic steatosis is identified. In these cases, clinicians should not wait for cardinal symptoms of hyperglycemia because such symptoms often appear only when disease is already advanced. The objective of screening is exactly the opposite: to recognize dysglycemia while it is still silent.

If the screening result is normal, reassessment should not be indefinite but scheduled. Major guidelines suggest periodic repeat testing, often every 3 years in individuals with normal results and sooner if risk increases, weight gain occurs, new comorbidities emerge, or values are near the upper limit of normal. When prediabetes is documented, follow-up should become more frequent and directed not only toward glycemic surveillance, but also structured prevention of progression.

Screening for prediabetes and type 2 diabetes mellitus in children and adolescents requires a different approach from that used in adults because risk depends not only on body weight, but also on puberty, growth rate, fat distribution, family history, and ethnic and socioenvironmental context. The problem has become more relevant with the increase in childhood obesity and the emergence of increasingly early forms of type 2 diabetes, often characterized by rapid loss of beta-cell function.

International pediatric recommendations propose targeted, rather than universal, screening in children and adolescents with overweight or obesity who have additional risk factors. Screening is generally considered after the onset of puberty or after 10 years of age because puberty itself is a physiological phase of reduced insulin sensitivity and can unmask pre-existing metabolic vulnerability. Identifying at-risk young people is particularly important because youth-onset type 2 diabetes tends to follow a more aggressive course than adult-onset disease.

In pediatric practice, it is also essential to avoid classification errors. An adolescent with obesity and hyperglycemia should not automatically be considered to have type 2 diabetes because the differential diagnosis includes autoimmune diabetes, monogenic diabetes, and other specific forms. Screening in young people must therefore form part of broader clinical reasoning that considers family pattern, autoimmunity, history of ketosis, metabolic phenotype, and features at onset.

The main tests for identifying prediabetes and diabetes are the same as those used to diagnose diabetes in nonpregnant individuals: fasting plasma glucose, glycated hemoglobin, and an oral glucose tolerance test with 75 g of glucose. These tools are not equivalent pathophysiologically or practically. Fasting plasma glucose is simple, inexpensive, and widely available, but may be less sensitive in the early stages of postprandial dysglycemia. Glycated hemoglobin is convenient because it does not require fasting and reflects average glycemic exposure over the preceding weeks, but may be unreliable with hemoglobinopathies, anemia, advanced kidney failure, pregnancy, hemolysis, transfusions, or altered red blood cell turnover. The oral glucose tolerance test is more sensitive for detecting dynamic abnormalities, particularly impaired glucose tolerance, but is less practical and more burdensome.

In prediabetes, incomplete overlap among tests is a crucial issue. An individual may have fasting glucose in the intermediate range but a normal oral glucose load, or still-normal fasting glucose with an already abnormal 2-hour response. Similarly, an HbA1c between 5.7% and 6.4% may identify people who do not yet meet glycemic criteria for impaired fasting glucose or impaired glucose tolerance, and vice versa. This does not mean that one test is “right” and another “wrong,” but that each captures a different aspect of the metabolic disorder.

Test selection should therefore integrate the purpose of screening, laboratory availability, patient characteristics, and pretest probability. For broad outpatient screening programs, fasting plasma glucose and/or glycated hemoglobin is often the most practical approach. When clinical suspicion remains high despite inconclusive values, or when a more precise assessment of the ability to handle a glucose load is needed, the oral glucose tolerance test retains superior diagnostic value. In special contexts such as cystic fibrosis or transplantation, the importance of the oral glucose tolerance test increases further.

Thresholds defining prediabetes

• Fasting plasma glucose between 100 and 125 mg/dL
• 2-hour plasma glucose after an oral glucose tolerance test between 140 and 199 mg/dL
• Glycated hemoglobin between 5.7% and 6.4%

These thresholds identify increased risk but do not all correspond to the same pathophysiological profile. Whenever possible, the patient description should therefore specify whether prediabetes is defined by impaired fasting glucose, impaired glucose tolerance, increased glycated hemoglobin, or a combination of several parameters.

In clinical practice, effective screening begins with the history and risk assessment, not with the blood draw itself. The physician should identify age, weight, weight trajectory, family history, obstetric history, physical activity, blood pressure, lipid profile, hepatic steatosis, medications, and associated conditions such as polycystic ovary syndrome or cardiovascular disease. Only after this assessment is the test selected rationally. In asymptomatic outpatients, first-line assessment often consists of fasting plasma glucose and glycated hemoglobin; if both are normal and risk is not high, later reassessment is scheduled; if they are in the intermediate range, follow-up and prevention begin; if they are diagnostic of diabetes, confirmation and etiological classification follow.

The oral glucose tolerance test is generally used as a second-level examination when initial data are discordant, when clinical suspicion is high despite nondiagnostic fasting glucose and HbA1c, or when the clinical context suggests that postprandial dysglycemia may precede fasting abnormalities. Screening is therefore not a rigid block but a reasoned sequence of investigations that increases in complexity only when necessary.

Communication of the result is an often overlooked aspect. Telling the patient that they “only have slightly high sugar” trivializes a condition that requires intervention. Conversely, presenting prediabetes as a disease inevitably destined to become overt diabetes is equally incorrect. The appropriate message is that prediabetes represents a real but potentially modifiable risk, provided it is recognized and treated consistently.

Screening does not eliminate all clinical uncertainty. In some patients, tests are discordant; in others, values close to the threshold fluctuate between normal and intermediate ranges; and in still others, a test appears falsely reassuring for biological or analytical reasons. A classic situation is the person with apparently normal glycated hemoglobin but high clinical suspicion, marked visceral obesity, and elevated postprandial peaks. In such cases, relying on HbA1c alone may miss a substantial proportion of metabolic abnormalities.

Particular attention is also needed when the context suggests atypical forms of diabetes. In a young, lean patient with an autosomal dominant family history, the issue may not be prediabetes preceding type 2 diabetes, but a monogenic form. In a patient with weight loss, autoimmunity, or rapid progression, apparently mild dysglycemia may represent the early phase of autoimmune diabetes. In a patient with chronic pancreatitis, cystic fibrosis, steroid therapy, or oncological immunotherapy, screening should be tailored to the specific risk and may require dedicated pathways.

Finally, no screening program is useful unless it is followed by intervention. Identifying prediabetes without initiating weight reduction, increased physical activity, clinical monitoring, and treatment of associated risk factors reduces screening to a mere label. The value of screening instead lies in its ability to change the patient's clinical trajectory.

Once prediabetes is identified, the patient enters a phase of active surveillance. The objective is not merely to document whether and when diabetes develops, but to monitor the evolution of the entire cardiometabolic profile. Progression may be slow, rapid, or nonlinear. Some individuals return to normoglycemia after weight loss and increased physical activity, some remain stable for years, and others progress rapidly because of the combined effects of visceral obesity, genetic predisposition, reduced beta-cell reserve, or new diabetogenic exposures.

Follow-up should therefore include periodic reassessment of blood glucose and/or glycated hemoglobin, weight, waist circumference, blood pressure, lipid profile, liver function, and comorbidities. In individuals with documented prediabetes, annual reassessment is often clinically reasonable, particularly when risk is high, values are close to the diabetic threshold, or hepatic steatosis, polycystic ovary syndrome, cardiovascular disease, or severe obesity coexist. The most recent standards also emphasize the need to monitor progression from prediabetes to all forms of diabetes, not only type 2 diabetes, when the clinical context makes this plausible.

The true quality of follow-up is not measured by the frequency of blood tests, but by the ability to use each visit to determine whether risk is decreasing or becoming entrenched. A patient who loses weight, increases physical activity, reduces hepatic steatosis, and improves blood pressure may also lower the risk of glycemic progression. Conversely, a patient with stable glucose values but progressively worsening visceral adiposity and lipid profile is not truly stable, even if blood glucose has not yet crossed the diabetic threshold.

Screening is worthwhile because prediabetes is a treatable condition. The strongest evidence shows that intensive lifestyle interventions, particularly weight loss, regular physical activity, and improved dietary quality, significantly reduce the risk of progression to diabetes. The benefit does not arise from a single mechanism, but from coordinated improvements in insulin sensitivity, relative beta-cell function, lipotoxicity, adipose tissue inflammation, and hepatic steatosis. The ADA 2026 Standards continue to place weight loss and weight maintenance among the central goals for diabetes prevention in high-risk adults with overweight or obesity.

In selected patients, particularly those at high risk with a high probability of progression, preventive pharmacological strategies may also be considered, with the rationale varying according to the clinical profile. The foundation, however, remains a structured intervention on behavior and body weight. This is essential because prediabetes is often managed too passively, with generic advice and sporadic monitoring, whereas the literature shows that meaningful effects are achieved when intervention is organized, measurable, and continuous.

A positive screening result therefore does not conclude the diagnostic process, but opens a therapeutic window. This window is precisely what justifies active case finding: identifying the patient early, while the metabolic trajectory can still be substantially modified.