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Type 1 diabetes mellitus: Disease prediction and screening

Type 1 diabetes mellitus: Disease prediction and screening
Literature review current through: Jan 2024.
This topic last updated: Jan 10, 2024.

INTRODUCTION — Type 1 diabetes is caused by immune-mediated destruction and dysfunction of insulin-producing pancreatic beta cells. Over time, overt insulin insufficiency develops, requiring exogenous insulin therapy. Historically, the diagnosis of type 1 diabetes was made at the onset of clinical signs and symptoms of hyperglycemia, often with diabetic ketoacidosis (DKA). However, with enhanced understanding of disease natural history, individuals with type 1 diabetes can be identified before the development of clinical disease. Type 1 diabetes develops on a background of genetic risk, but most individuals with genetic risk never develop type 1 diabetes. In contrast, virtually all individuals with ≥2 diabetes-related autoantibodies eventually develop clinical type 1 diabetes.

Screening for diabetes-related autoantibodies and metabolic monitoring can detect preclinical type 1 diabetes, identify candidates for disease-modifying therapy, provide early access to diabetes-related education and support, and reduce the severity of presentation at clinical diagnosis. This topic will review the natural history of type 1 diabetes, as well as strategies for autoantibody screening and metabolic monitoring for disease progression in individuals with high risk for clinical disease. The etiology and pathophysiology of type 1 diabetes are reviewed separately, as are therapies that target the underlying immune-mediated pathogenesis of the disease. (See "Pathogenesis of type 1 diabetes mellitus" and "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

STAGES OF TYPE 1 DIABETES — Virtually all individuals with two or more diabetes-related autoantibodies will eventually progress to clinical type 1 diabetes [1]. The cascade of events that leads from a background of genetic risk to immune activation and beta cell destruction is incompletely understood. Nonetheless, the presence of this immune response is readily detected with the measurement of diabetes-related autoantibodies. Thus, autoantibody status is the critical identifier of individuals who will develop clinical type 1 diabetes. Data supporting this concept derive from multiple longitudinal studies conducted in different countries over many decades. (See "Pathogenesis of type 1 diabetes mellitus".)

For example, in an analysis that combined data from three studies including 585 infants with multiple diabetes-related autoantibodies and either human leukocyte antigen (HLA) risk genes or a family history of type 1 diabetes, 50 percent of infants developed clinical disease within five years and 85 percent within 15 years [2]. Similarly, in a Diabetes TrialNet study of more than 2300 older children and young adults (median age 16.2 years) who had a relative with type 1 diabetes and also had multiple autoantibodies, 35 percent of individuals with normal glucose tolerance and 70 percent of those with abnormal glucose tolerance progressed to clinical disease within five years, while others progressed over a longer time period [1,3].

Based on the recognition that individuals with multiple diabetes-related autoantibodies almost invariably develop clinical disease, type 1 diabetes progression is classified into discrete stages (table 1).

Stage 1 diabetes – Individuals with multiple (≥2) diabetes-related autoantibodies have stage 1 (preclinical) type 1 diabetes. At this stage, individuals are asymptomatic with normal glucose tolerance, but they have impaired insulin (C-peptide) secretion compared with autoantibody-negative individuals. Specifically, first-phase or early insulin secretion is impaired in response to intravenous (IV) or oral glucose administration, whereas fasting insulin levels remain normal. Although significantly impaired, insulin secretion may remain stable over time in many individuals. For others, further loss of early insulin secretion can occur even while glucose levels remain in the normal range.

Stage 2 diabetes – Stage 2 type 1 diabetes also constitutes preclinical disease and is defined by progression to dysglycemia evident as abnormal glucose tolerance. Individuals with stage 2 diabetes are also asymptomatic. Impaired early phase insulin (C-peptide) secretion results in increasing postprandial glucose values, whereas fasting glucose has little or no change prior to clinical diagnosis. Glycated hemoglobin (A1C) remains below the threshold for diabetes diagnosis, as this threshold is typically not reached until fasting glucose rises.

During stage 2 diabetes, stimulated insulin secretion (measured as area under the curve [AUC] C-peptide from an oral glucose tolerance test [OGTT]) may increase [4,5]. This increase likely reflects a compensatory beta cell response to rising postprandial glucose. Within 6 to 12 months before clinical diagnosis, the insulin secretion pattern changes abruptly, with a marked drop in measures of beta cell function [6]. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

Stage 3 diabetes – Stage 3 type 1 diabetes marks the onset of clinical disease and is defined based on American Diabetes Association (ADA) diagnostic criteria (table 1). Glycemia rather than insulin deficiency defines stage 3 diabetes. The marked decline in insulin secretion that begins 6 to 12 months before the onset of stage 3 disease continues at approximately the same rate [6]. Thus, as an individual crosses the diagnostic thresholds for clinical type 1 diabetes, the rate of decline in insulin secretion remains relatively constant.

At the time of clinical diagnosis, almost all individuals with stage 3 diabetes continue to have significant insulin secretion [7-9], although the degree of preserved secretion varies across individuals. Therefore, C-peptide level is not helpful at the time of diagnosis for distinguishing between type 1 and type 2 diabetes. As a population, individuals with type 1 diabetes have lower C-peptide levels than those with type 2 diabetes at diagnosis, but only rare individuals with new-onset stage 3 type 1 diabetes will have undetectable C-peptide. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Distinguishing type 1 from type 2 diabetes'.)

Longstanding ("stage 4") diabetes – Though not part of the formally defined stages, the term "stage 4" type 1 diabetes is often used to designate longstanding clinical disease. Many people living with type 1 diabetes continue to secrete insulin, albeit at low levels, for decades after clinical diagnosis. The clinical benefits of continued insulin secretion and therapeutic strategies to preserve beta cell function in clinical type 1 diabetes are reviewed separately. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preserving insulin secretion in clinical disease'.)

SCREENING FOR DIABETES-RELATED AUTOANTIBODIES

Clinical benefit — Screening for diabetes-related autoantibodies, if followed by appropriate metabolic monitoring, reduces the likelihood of severe hyperglycemia or diabetic ketoacidosis (DKA) at the time of clinical type 1 diabetes diagnosis [10]. Identifying individuals with preclinical type 1 diabetes also creates an opportunity to provide early support and diabetes education. Finally, screening and monitoring facilitate timely access to disease-modifying therapy, either with commercially available agents or through participation in clinical trials. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

Severe hyperglycemia and DKA cause significant morbidity including possible long-term cognitive effects, and, rarely, even death. Under usual care, 20 to 70 percent of individuals with type 1 diabetes present with DKA at the time of initial clinical diagnosis, whereas in the context of research studies with established screening and monitoring programs, <5 percent of individuals present with DKA at diagnosis [10].

Autoantibody screening

Whom to screen — Three approaches to systematically identify autoantibody-positive individuals are used in research programs and, increasingly, in clinical care. In the clinical setting, most efforts focus on providing diabetes-related autoantibody screening to first- and second-degree relatives of individuals with type 1 diabetes.

Relatives of individuals with type 1 diabetes – We agree with the American Diabetes Association (ADA) recommendation that all first- and second-degree relatives of individuals with type 1 diabetes should be informed of their increased relative risk for the disease and offered autoantibody testing. Whenever possible, autoantibody screening should be performed through referral to or in consultation with experts in the early diagnosis and treatment of type 1 diabetes. (See 'How to screen' below.)

An important benefit of testing is that 95 percent of those tested will be autoantibody negative, thus providing reassurance for most individuals. Prior to autoantibody screening, however, clinicians should have a plan for education, counseling, and follow-up for autoantibody-positive individuals. All individuals with at least two confirmed diabetes-related autoantibodies require metabolic monitoring. In those relatives with no positive autoantibodies or a single positive autoantibody, repeat autoantibody testing is warranted. (See 'Test interpretation' below and 'Monitoring for disease progression' below and 'Repeat autoantibody testing' below.)

Individuals with known genetic risk – Human leukocyte antigen (HLA) genotyping is typically limited to research settings and currently plays no clinical role in the selection of individuals for diabetes-related autoantibody screening. Some individuals may know their HLA genotype (eg, through prior participation in a research study). Most individuals with genetic risk based on HLA genotype alone never develop type 1 diabetes. Therefore, in the absence of a family history, we typically do not measure autoantibodies in such individuals outside of research studies.

The declining cost of genotyping makes future, population-based genetic screening potentially more feasible, and this strategy has been implemented in a research setting. For example, the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) study [11] will use both genetic risk score and family history to identify infants with >10 percent genetic risk for type 1 diabetes, an estimated 1 percent of >300,000 infants tested. This study also promises valuable insights into discussing screening and disease risk with families during the newborn period, including those without a history of type 1 diabetes.

Population-wide screening – Population-wide screening strategies for type 1 diabetes risk have been proposed but have not been implemented in clinical practice. Some advocate for population-wide screening because a strategy that confines autoantibody testing to individuals with affected family members will miss most people who eventually develop type 1 diabetes. Indeed, approximately 85 percent of people with type 1 diabetes have no family member with the disease [12]. However, the primary challenge with autoantibody screening in the general population is the low incidence of type 1 diabetes (0.3 percent). Even with a very sensitive autoantibody test, such widespread screening would generate many false-positive results.

Most individuals who develop clinical type 1 diabetes prior to puberty have positive autoantibodies by age 5 [13], suggesting the potential utility of broad, population-based screening in very young children. Limited data support both the feasibility and clinical benefit of population-based autoantibody screening. In a primary care-based, four-year effort in Germany [14], >90,000 children (aged approximately 2 to 5 years) underwent screening for diabetes-related autoantibodies via a capillary blood sample. Those with multiple autoantibodies then underwent confirmatory testing using a venous blood sample. Participants with confirmed preclinical type 1 diabetes (n = 280; 0.31 percent) were offered metabolic monitoring for disease progression along with an educational program. Approximately 25 percent (n = 54) of those with preclinical type 1 diabetes progressed to clinical type 1 diabetes within three years, and only two individuals had DKA at diagnosis. Parents who were informed that their child had early type 1 diabetes had an increase in psychological stress that decreased over time. (See 'Psychosocial burden' below.)

When to screen — We offer periodic screening for diabetes-related autoantibodies to all first- and second-degree relatives of people living with type 1 diabetes through the age of 45 years. Autoantibody testing is most critical during early childhood, as the rate of progression from multiple autoantibodies to clinical disease is more rapid in younger individuals. Consequently, although type 1 diabetes can occur at any age, most research studies have focused on the optimal timing of autoantibody screening in children. In most children who develop type 1 diabetes by puberty, diabetes-related autoantibodies appear before age 5 years. In one analysis of data from five prospective cohorts, screening family members for antibodies at age 2 years and 3 to 5 years later had an estimated sensitivity of >80 percent for detecting diabetes before age 15 years [15]. Adopting this approach, however, would miss those who develop type 1 diabetes before 2 years of age.

Fewer data are available to inform the optimal timing of autoantibody screening to detect later-onset type 1 diabetes. Nonetheless, postpubertal children and adults constitute one-half of individuals diagnosed with type 1 diabetes, underscoring the importance of screening older individuals.

How to screen

Autoantibody selection — In individuals selected for type 1 diabetes screening, the following four diabetes-related autoantibodies ideally should be measured:

Insulin autoantibodies (IAA) [16].

Glutamic acid decarboxylase (GAD) autoantibodies.

Tyrosine phosphatase autoantibodies (IA2).

Zinc transporter (ZnT8) autoantibodies.

Islet cell autoantibodies (ICA) also may be measured but are generally available only in research laboratories; the other four, often termed "biochemical" autoantibodies, are widely available in both research and clinical laboratories. Depending on the clinical laboratory and specific assays used, reflex testing may provide the most cost-effective strategy. For example, one or two autoantibodies are measured initially (often GAD and IAA), and additional antibodies are measured only if at least one of the initial titers is positive. If any autoantibody titer is positive, all four biochemical autoantibodies should be measured because the number of positive autoantibodies is the key predictor of disease risk.

In the United States and Canada, individuals with a relative with type 1 diabetes can undergo autoantibody screening free of charge through Diabetes TrialNet, a clinical trial research network sponsored by the National Institutes of Health.

Test interpretation

Confirm positive autoantibodies – Although a variety of autoantibody assays are available, any clinically qualified laboratory test may be used. However, regardless of the utilized test, we confirm any autoantibody-positive result with a second sample. Result confirmation is particularly important if the initial test was not performed with a serum sample.

All individuals with at least two confirmed diabetes-related autoantibodies require metabolic monitoring. In those with no positive autoantibodies or a single positive autoantibody, repeat autoantibody testing is warranted. (See 'Monitoring for disease progression' below and 'Repeat autoantibody testing' below.)

Assay variability – Antibody standardization programs and workshops evaluate assay performance in samples from people with diabetes and healthy controls. In general, clinically available autoantibody assays that use serum samples are highly reproducible. Nonetheless, although assay sensitivity and specificity are generally quite high across all laboratories, assay performance may differ, and not all autoantibody assay results will be concordant. Indeed, discordant results between laboratories for the same individual and autoantibody are not uncommon. However, irrespective of this discordance, evolving evidence suggests the predictive utility of the presence of ≥2 confirmed autoantibodies does not differ across laboratories.

Assay methods – The field of autoantibody testing for type 1 diabetes is rapidly evolving [17]. The current standard for IAA measurement is the micro-insulin autoantibody (mIAA) test using radioimmune assay technology. However, other assays for IAA are increasingly available. These include an electrochemiluminescence (ECL) assay, the Luciferase Immune Precipitation System (LIPS), and the multiplex Antibody Detection by Agglutination PCR (ADAP). None of these assays distinguishes between insulin autoantibodies and anti-insulin antibodies that form in response to exogenous insulin administration. Thus, a positive IAA test in someone with insulin-treated diabetes or other prior insulin exposure (eg, during a hospital admission) is insufficient to indicate autoimmunity. This issue has greater relevance for individuals with clinical diabetes in whom autoantibody testing is intended to discriminate between type 1 and other forms of diabetes. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Distinguishing type 1 from type 2 diabetes'.)

Most clinical laboratories also use radioimmune assay technology to test for GAD, IA2, and ZnT8 autoantibodies, which alternatively can be measured by ECL, LIPS, and ADAP methods. In contrast, ICA testing involves immunofluorescent staining of frozen pancreas sections. Serial dilutions are performed to determine the ICA titer, given as standardized Juvenile Diabetes Foundation (JDF) units. Autoantibody testing that employs multiplexing, high throughput assays, or use of capillary and/or dried blood spot samples are potential approaches to increase convenience and reduce costs. These testing strategies may be particularly important for implementing general, population-based screening programs in routine clinical care. (See 'Whom to screen' above.)

Repeat autoantibody testing

No positive autoantibodies — For individuals with no positive diabetes-related autoantibodies on initial testing, but with a family member with type 1 diabetes, no consensus guidance exists. Repeat autoantibody testing at two- to five-year intervals is reasonable.

Single positive autoantibody — Individuals with a confirmed, single positive diabetes-related autoantibody are at risk for disease progression. In such individuals, repeat autoantibody testing should be performed to assess for interim development of multiple autoantibodies. The frequency of testing depends on the individual's age and family history of type 1 diabetes. We follow the same approach to repeat testing irrespective of which diabetes-related autoantibody is positive.

Some people with a single autoantibody progress to clinical type 1 diabetes without prior detection of multiple autoantibodies; therefore, in addition to repeat autoantibody testing, such individuals should receive ongoing diabetes education and assessment for hyperglycemic signs and symptoms (eg, polyuria, polydipsia, weight loss).

Relative with type 1 diabetes and age ≤45 years

Children aged ≤5 years – In very young children with a single, confirmed positive autoantibody, repeat autoantibody testing should be performed every six months.

In a study of high genetic risk, autoantibody-positive children tested from ages 3 months to 3 years, 82 percent had only a single autoantibody [18]. The risk of progression from single to multiple autoantibodies over eight years was 33 percent, but this conversion happened most frequently within two years of initial screening. Further, among those who initially had a single autoantibody and developed multiple autoantibodies before age 5 years, 60 percent developed clinical disease within eight years.

Individuals aged >5 and ≤45 years – In individuals aged >5 and ≤45 years with a single, confirmed positive autoantibody, expert opinion generally supports repeat autoantibody testing annually. In the Diabetes TrialNet cohort of almost 1000 single autoantibody-positive individuals aged 3 to 45 years (median age 16.2 years) with a relative with type 1 diabetes, the risk of progression from single to multiple autoantibodies over five years was 22 percent [19]. Over the same period, the risk of progression to clinical diabetes was 6.6 percent [19].

No family history of type 1 diabetes or age >45 years – Few data exist on the predictive value of a single confirmed autoantibody in individuals without a family history of type 1 diabetes or in those over age 45 years. Since the rate of progression to clinical disease slows with age, many experts endorse repeat autoantibody testing at five-year intervals.

MONITORING FOR DISEASE PROGRESSION

Type 1 diabetes progression — While essentially everyone with multiple autoantibodies will eventually develop clinical type 1 diabetes, the rate of progression from preclinical to clinical disease is heterogeneous. The most important factors for predicting the rate of progression are age, the number of diabetes-related autoantibodies, and glucose tolerance status. In contrast, family history, genotype, and other demographic and clinical variables have little impact on progression once multiple autoantibodies are present. For example, in one study, school-aged children with a family history of type 1 diabetes had a higher relative risk of having multiple diabetes-related autoantibodies than children without a family history of type 1 diabetes [3.69 (95% CI 2.51-5.24)] [11]. However, among children with multiple autoantibodies, neither family history nor human leukocyte antigen (HLA) type impacted the rate of progression to clinical type 1 diabetes. Accordingly, monitoring strategies for autoantibody-positive individuals vary based on age, number of autoantibodies, and glucose tolerance status. (See 'Monitoring for disease progression' above.)

Among individuals with multiple autoantibodies, age strongly influences the rate of diabetes progression; nonetheless, in all age groups, the incidence of clinical diabetes increases over time. Thus, in the presence of multiple autoantibodies, age has no impact on who will get type 1 diabetes but strongly influences when it will occur.

Metabolic monitoring (all individuals with multiple diabetes-related autoantibodies) — All individuals with ≥2 confirmed diabetes-related autoantibodies should undergo baseline and longitudinal metabolic testing. Although no formal consensus exists, we typically do not remeasure autoantibodies after initial confirmation of multiple antibody status, as developing more antibodies or reverting to a single antibody (which occurs in <4 percent of individuals) does not alter the metabolic monitoring strategy.

Whenever possible, individuals with multiple autoantibodies should be referred to (or have their care coordinated with) experts in the early diagnosis and treatment of type 1 diabetes. In the United States and Canada, such expertise is available to antibody-positive individuals who enroll in the type 1 diabetes research network Diabetes TrialNet. Provider experience and expertise are critical, as decisions about the type and frequency of monitoring should involve an informed discussion of options. The specific monitoring strategy is individualized based on patient and family goals and preferences, and choices about monitoring strategy may evolve over time. Critically, for everyone with multiple autoantibodies, a clear plan is needed for rapid evaluation by expert providers when clinical (stage 3) diabetes develops.

The classic presentation of type 1 diabetes includes symptoms such as weight loss, polyuria, and polydipsia due to marked hyperglycemia. However, when those at early stages of disease cross the diagnostic threshold for stage 3 disease, symptoms are frequently absent (table 1), and symptoms are not required for defining stage 3 diabetes in clinical trials. (See 'Stages of type 1 diabetes' above.)

Baseline testing — In individuals with ≥2 diabetes autoantibodies, baseline metabolic testing distinguishes between stage 1 and stage 2 type 1 diabetes and helps determine eligibility for disease-modifying therapy. Variable options exist for metabolic testing, and the selection of a specific strategy should be informed by resource availability and patient and family preferences. Oral glucose tolerance testing (OGTT) is the "gold-standard" for monitoring disease progression.

The American Diabetes Association (ADA) criteria for stage 2 type 1 diabetes include A1C ≥5.7 and ≤6.4 percent and a 2-hour postprandial glucose between 140 to 199 mg/dL (7.8 to 11.1 mmol/L) during an OGTT (table 1) [20]. While controversy persists, others have suggested that stage 2 diabetes can be identified with random glucose values or a percentage of time spent with glucose values ≥140 mg/dL (7.8 mmol/L) based on continuous glucose monitoring (CGM) [21,22]. The sensitivity and specificity of these measures has not been fully evaluated, and the role of CGM use in preclinical type 1 diabetes is not yet clear [23]. Efforts are underway to harmonize these approaches and better inform clinical practice.

Metabolic criteria that determine eligibility for disease-modifying therapy have not yet been clearly established; whereas stage 2 diabetes was defined initially based on OGTT data, postprandial glucose testing, CGM, or A1C eventually may become widely accepted alternatives for identifying stage 2 disease. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

Subsequent testing — Several approaches similarly exist for subsequent metabolic monitoring. For the goals of early diagnosis of clinical disease and preventing severe hyperglycemia or diabetic ketoacidosis (DKA), any of the strategies below is likely effective. The choice of strategy should be informed by resource availability and patient and family preferences. Metabolic monitoring must be accompanied by diabetes education and psychologic support. As glucose values often fluctuate, any abnormal result should be confirmed, particularly if treatment with disease-modifying therapy is considered. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

OGTT – In research studies, monitoring is generally performed with a standard 75 g OGTT. OGTT requires an office or laboratory visit and multiple venipunctures or intravenous (IV) catheter placement for obtaining blood. Individuals are required to fast prior to testing. This test is well tolerated and widely available clinically. When individuals identified through autoantibody screening are carefully monitored for disease progression, OGTT almost uniformly identifies clinical (stage 3) diabetes before hyperglycemic symptoms develop or A1C reaches the diagnostic threshold for diabetes.

A1C – A1C measurement requires only a single, nonfasting blood draw. However, the A1C value typically will not reach the diagnostic threshold for diabetes (>6.5 percent) until later in disease progression, well after OGTT establishes the onset of clinical type 1 diabetes. Therefore, A1C monitoring is less sensitive for detecting early disease progression. By the time the A1C value exceeds this diagnostic threshold, individuals will have clinical symptoms from hyperglycemia and thus potentially lose the benefit of early diagnosis of stage 3 disease. Nonetheless, one study in young, multiple autoantibody-positive children suggested that sequential A1C testing can be informative. In that study, a 10 percent increase in A1C, even within the normal range, indicated diabetes progression [24].

Other – Among alternatives to OGTT, urine glucose testing is the least costly and least invasive method. While this approach has not been formally tested, the renal threshold for glucosuria is approximately 180 mg/dL (10 mmol/L); thus, monitoring for glucosuria should allow for early diagnosis of stage 3 diabetes and help prevent severe hyperglycemia or DKA, provided further assessment and treatment are readily available if glucosuria is detected.

Other metabolic monitoring options include random or postprandial blood glucose testing. Glucose testing performed two hours after a carbohydrate-rich meal (eg, pancakes with syrup) can be done at home or a clinical laboratory. As noted above, whereas some evidence suggests that CGM could prove a useful monitoring strategy, we favor alternative strategies until more data are available to support its use in this setting.

Frequency of testing — For individuals with multiple, confirmed diabetes-related autoantibodies, the frequency of metabolic monitoring is more critical than the choice of specific metabolic test. For very young children (aged ≤5 years), some form of monitoring at three- to six-month intervals is reasonable given the possibility of rapid progression in this group.

For individuals aged >5 years, initial assessment of metabolic status can guide the subsequent frequency of testing. For those with normoglycemia, annual metabolic monitoring is likely sufficient for safety. For those with dysglycemia or rising A1C, many experts recommend that testing should be performed every six months.

Intervention for stage 3 disease — All individuals identified with stage 3 diabetes require diabetes education and initiation of glucose monitoring, irrespective of whether clinical symptoms are apparent. Glucose monitoring enables initiation of treatment prior to metabolic deterioration. Strategies for glucose monitoring should be individualized. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Type 1 diabetes'.)

An unresolved clinical question is whether asymptomatic individuals who have crossed the OGTT diagnostic threshold for clinical type 1 diabetes should begin insulin therapy. The decision to implement insulin therapy should be individualized and informed by factors including the individual's readiness to engage in diabetes management and behaviors that increase risk of hyperglycemia (eg, high carbohydrate intake) or hypoglycemia (eg, vigorous aerobic exercise, low carbohydrate diet). (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preserving insulin secretion in clinical disease'.)

For asymptomatic individuals in whom insulin therapy is initiated, low doses of basal insulin at bedtime may protect against DKA without causing hypoglycemia; an alternative approach is to initiate low-dose prandial insulin. A challenge is that insulin treatment for clinical type 1 diabetes is typically tailored to achieve a specific A1C or CGM-based (eg, time-in-range) target, but such parameters often remain in the normal or target range when type 1 diabetes is diagnosed based on OGTT alone.

RISKS AND CONCERNS — Despite the clear benefits of screening and monitoring programs, such programs also introduce new challenges to individuals, their families, clinicians, and health care systems. Concerns include the following:

Psychosocial burden on the individual and their families of anticipating clinical type 1 diabetes

Logistical demands of metabolic monitoring for both the individual and healthcare systems

Lack of sufficient infrastructure to provide expert education, support, and treatment

Costs of screening and monitoring efforts

Psychosocial burden — Screening for type 1 diabetes can elicit a range of emotional responses from both the individual and family members. For many with a family history, prescreening counseling provides new information about elevated type 1 diabetes risk. Some may believe that knowledge of this risk alone is sufficient and prefer to self-monitor for symptoms rather than undergo autoantibody testing. Nonetheless, severe hyperglycemia at clinical diagnosis appears equally common in individuals with a first-degree relative with type 1 diabetes and those with no prior knowledge of their increased risk, suggesting that self-monitoring alone is inadequate to reduce the risk of severe presentation at clinical diagnosis. In others, learning of increased diabetes risk can lead to hypervigilance and unnecessary or even potentially harmful behavioral changes (eg, restrictive diets, taking unwarranted medications or supplements). Anxiety also can arise for an individual and family members after they learn of an autoantibody-positive status [25]. In the setting of clinical research studies, such anxiety decreases over time, but the question remains whether a clinical care setting can provide adequate support to similarly mitigate psychosocial stress. In individuals without a family history of type 1 diabetes, the potential risk for psychological stress from screening programs may be even higher given unfamiliarity with the disease and initial absence of any perceived risk. Thus, if screening programs are integrated into routine clinical care, significant resources for education and support will be essential.

These emotional risks are like those for other unexpected diagnoses and can be reduced through thoughtful clinical care. Moreover, potential psychological benefit can result from screening. Individuals and their family members can be better prepared and less overwhelmed by the evolution of clinical (stage 3) disease. Family members can be reassured that their absolute risk of type 1 diabetes is low (approximately 5 percent) and undergo screening through structured and supportive care. With proper support and education, early identification of asymptomatic type 1 diabetes may provide individuals with time to gather resources and move towards acceptance of the disease before metabolic decompensation occurs. Finally, the expanded array of treatment options for both preclinical and clinical type 1 diabetes affords individuals unprecedented choices and underscores the value of early diabetes detection and patient education. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

Cost — The cost of screening and monitoring programs is considerable, and insurance coverage for such programs remains variable. Although effective programs will reduce hospitalizations for diabetic ketoacidosis (DKA) at diagnosis of stage 3 disease, these savings are too low to fully offset the costs of screening and monitoring. Potential longer-term financial savings are possible due to improved glycemia and reduced diabetes-related complications, but these are difficult to predict or quantify. Thus, widespread implementation of effective screening and monitoring programs within the context of clinical care will incur substantial cost to health care systems.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Type 1 diabetes (The Basics)")

Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Stages of diabetes – Essentially all individuals with multiple diabetes-related autoantibodies will eventually develop clinical type 1 diabetes. This understanding has led to the definition of preclinical stages of type 1 diabetes (table 1). The rate of progression from preclinical (stage 1 or stage 2) to clinical (stage 3) disease is heterogeneous. (See 'Stages of type 1 diabetes' above.)

Screening for diabetes-related autoantibodies

Clinical benefit – Screening for diabetes-related autoantibodies, if followed by appropriate metabolic monitoring for disease progression, reduces the likelihood of severe hyperglycemia or diabetic ketoacidosis (DKA) at the time of clinical type 1 diabetes diagnosis. Identifying individuals with preclinical type 1 diabetes also creates an opportunity to provide early support and diabetes education. Finally, screening and monitoring facilitate timely access to disease-modifying therapy. (See 'Clinical benefit' above and "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Preventing or delaying clinical disease in high-risk individuals'.)

Autoantibody screening

-Whom to screen – All first- or second-degree relatives of people living with type 1 diabetes should be informed of their 15-fold increased relative risk of developing diabetes and should be offered screening through diabetes-related autoantibody testing. (See 'Whom to screen' above.)

-When to screen – We offer periodic screening for diabetes-related autoantibodies to all first- and second-degree relatives of people living with type 1 diabetes through the age of 45 years. Autoantibody testing is most critical during early childhood, as the rate of progression from multiple autoantibodies to clinical disease is more rapid in the very young. In most children who develop type 1 diabetes by puberty, diabetes-related autoantibodies appear before age 5 years. (See 'When to screen' above.)

-How to screen – Four biochemical diabetes-related autoantibodies ideally should be measured, and all autoantibody-positive tests should be confirmed with a repeat sample. (See 'How to screen' above.)

In the United States and Canada, individuals with a relative with type 1 diabetes can undergo autoantibody screening through Diabetes TrialNet, a clinical trial research network sponsored by the National Institutes of Health.

Repeat autoantibody testing – In individuals with a family history of type 1 diabetes and no positive autoantibodies or a single positive autoantibody, repeat autoantibody testing is warranted. (See 'Repeat autoantibody testing' above.)

Monitoring for disease progression – All autoantibody-positive individuals should be provided diabetes education and support. (See 'Monitoring for disease progression' above.)

Type 1 diabetes progression – While essentially everyone with multiple diabetes-related autoantibodies will eventually develop clinical type 1 diabetes, the rate of progression from preclinical to clinical disease is heterogeneous. The most important factors for predicting the rate of progression are age, the number of autoantibodies, and glucose tolerance status. (See 'Type 1 diabetes progression' above.)

Metabolic monitoring All individuals with ≥2 diabetes-related autoantibodies should undergo baseline and longitudinal metabolic testing. Whenever possible, metabolic monitoring plans should be individualized and developed under the care of (or in consultation with) providers with expertise in the early diagnosis and treatment of type 1 diabetes. (See 'Metabolic monitoring (all individuals with multiple diabetes-related autoantibodies)' above.)

Variable options exist for metabolic testing, including oral glucose tolerance testing (OGTT) or serial measurement of glycated hemoglobin (A1C). For very young children (aged ≤5 years), some form of monitoring at three- to six-month intervals is reasonable given the possibility of rapid progression in this group. For those aged >5 years, initial assessment of metabolic status can guide the subsequent frequency of testing. (See 'Metabolic monitoring (all individuals with multiple diabetes-related autoantibodies)' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges Massimo Pietropaolo, MD (deceased), who contributed to earlier versions of this topic.

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Topic 1791 Version 18.0

References

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