LEARNING OBJECTIVES

After completing Module 8, the learner should be able to:

1. Name factors which contribute to the determination of monitoring intensity in islet autoantibody positive individuals.
2. Name methods for evaluating for dysglycemia in early-stage (presymptomatic) T1D.
3. Name symptoms of hyperglycemia and identify the symptoms that should prompt the person to access care immediately.

Monitoring and Managing Islet Autoantibody Positive Patients

08 |

Module Authors: Kimberly Bautista, Flor Sepulveda, Iman Taki, Brigitte Frohnert, Andrea Steck

Monitoring for Symptoms or Evidence of Dysglycemia

All patients with confirmed islet autoantibodies should be assessed at follow-up visits for dysglycemia or development of symptomatic (Stage 3) T1D:

Measurement of A1c and random blood glucose (RBG)
Evaluate for symptoms of hyperglycemia

– Polydipsia

– Polyuria (new bed wetting in previously dry child)

– Weight loss/poor weight gain in growing child

– Fatigue

Teach individuals/families regarding symptoms that should trigger expeditious evaluation: lethargy/confusion, vomiting, rapid breathing
If symptoms or glycemic measures (A1c, RBG) raise concerns, teach use of glucometer

(see Figure 2 and Home Glucose Testing section below)

FIGURE 1 Timeline and characteristics of the stages of type 1 diabetes. See Module 1 for details of ADA staging criteria including normoglycemia and dysglycemia.

Monitoring Guidelines Based on Stages of T1D

Individuals with confirmed positive islet autoantibody results should be monitored on a regular schedule. The monitoring regimen will vary depending on the stage of T1D as well as the age of the patient.(1) To engage the individual in active monitoring at home and in clinics, it is important to provide educational materials regarding the disease process, stages of T1D, how to monitor, and the importance of monitoring.

The following monitoring recommendations are based on expert experience and opinion (see the interactive Screening and Monitoring algorithm, also viewable under the RESOURCES menu above).
As monitoring recommendations are continually evolving it is important to visit the STOP T1D website for updates on monitoring guidelines.

Current recommendations based on confirmed islet autoantibody status are as follows:

Single Low Affinity Autoantibody and Normoglycemic

Individuals with a single low-affinity autoantibody are at low risk. In the absence of symptoms or abnormal glycemic measurements, it is recommended to follow up for repeat assessment in one year (including measurement of autoantibodies to determine whether the individual has become multiple IAb positive).

Confirmed for a Single High Affinity Autoantibody and Normoglycemic

If the results of the symptom review, A1c and BG are unremarkable, the recommendation is for follow-up assessment every 6 months. They should also receive a glucometer and be taught how to do home glucose testing (Figure 2).

Confirmed for a Single High Affinity Autoantibody and Evidence of Dysglycemia (Stage 2 T1D)

If the results of the symptoms review, A1c and BG show that the person is dysglycemic, meaning a BG of 140-199 or an A1C of 5.7-6.4, they should follow the recommendations listed under Stage 2 T1D.

Confirmed Multiple Autoantibody Positive (Stage 1 T1D)

In the absence of evidence of dysglycemia, the recommendation is for monitoring every 3-6 months depending on age. The patient/family should also receive a glucometer and instruction on home glucose testing (see Figure 2 and Home Glucose Testing section below) and may benefit from intermittent CGM wear.

FIGURE 2 Front of Patient Information Card available at AsktheExpers.org

FIGURE 3 Reverse side of Information Card

Confirmed Islet Autoantibody Positivity and Evidence of Dysglycemia (Stage 2 T1D)

An individual in Stage 2 T1D should be evaluated every 3-6 months depending on age to ensure medical safety and to determine metabolic staging. This will also allow for opportunities to discuss eligibility for therapeutic options with the goal of delaying progression to Stage 3 T1D. The patient/family should also receive a glucometer and instruction on home glucose testing (see Figure 2) or intermittent CGM wear. A home glucose testing card can guide when to test and what to do based on the glucose result (Figure 2 and 3).(2)

Use of Home Monitoring

It should be noted that ONLY serum glucose values (during OGTT or random) and A1c results are approved ADA criteria for staging of type 1 diabetes (in conjunction with islet autoantibody status).

While home glucose testing and CGM monitoring are NOT included in the ADA criteria for Stage 2 or Stage 3 T1D, they can be very helpful to identify changes in glycemic profile as they can be performed easily at home and do not require a blood draw or clinic visit. Individuals with evidence of dysglycemia by home glucose testing or continuous glucose monitoring (CGM) should be considered at higher risk. These individuals may be targeted for additional testing by OGTT, A1c or serum glucose in order to determine whether they meet criteria for Stage 2 or Stage 3 T1D.

Methods for Monitoring of Glycemic Changes

Hemoglobin A1c (A1c)

The hemoglobin A1c test result reflects a person's average blood sugar level over the past three months. Specifically, the hemoglobin A1c (also called the glycated hemoglobin, glycosylated hemoglobin, hemoglobin A1C or HbA1c test) measures what percentage of hemoglobin proteins in the blood are coated with sugar (glycated). As discussed above, measurement of A1c is a cornerstone of monitoring. Both elevation (5.7 to 6.4%) as well as increase of 10% or more from previous measurement are amongst the criteria for Stage 2 T1D. However, while an abnormal A1c is informative, it can miss acute evolution of dysglycemia and is not as sensitive in children who may progress quickly. Further, abnormalities in A1c occur relatively late in disease progression. Finally, the A1c can be less accurate in those with anemia or disorders which impact red blood cell production and destruction.

Oral Glucose Tolerance Test (OGTT)

OGTTs are part of the gold standard for staging and diagnosing T1D. For people in Stage 1 or Stage 2 it is recommended to obtain an OGTT every 6-12 months to determine metabolic staging. However, OGTT may not be feasible in all people. Some patients may be averse to OGTTs, due to need for fasting, testing over multiple hours, or the needle sticks involved in multiple blood draws or IV placement. Standard testing involves drinking a solution containing glucose (1.75 g per kg of body weight up to a maximum of 75 g) followed by blood plasma sampling at 6 time points (-10, 0, 30, 60, 90, and 120 minutes); however, a 2-point OGTT (samples at 0 and 120 minutes) may suffice. OGTTs used in the clinical setting often do not include measurement of c-peptide as it is not a component of clinical criteria; however, these measures are often utilized in research studies (see “Monitoring in Research Studies” below).

Home Glucose Testing

Home glucose testing (HGT) is easy and inexpensive and should use glucometers which meet FDA guidelines.(3) While HGT is NOT an accepted ADA criteria for staging of T1D, patients are empowered to participate in their own monitoring and can obtain instant feedback when concerning symptoms arise. There is a long history of intermittent home glucose testing for high-risk participants in prospective studies and routine home glucose assessment is often a key component of early recognition of progression to Stage 3 T1D. Limitations include the logistics involved in the communication of results or frequency of testing. Many individuals require reminders to test at home. As post-prandial hyperglycemia is typically the first apparent abnormality, this is the preferred testing time. Intermittent testing is typically recommended; however, if there are significant concerns that transition to stage 3 T1D may be imminent, the person/family can be instructed to test daily for five days and contact the healthcare provider with the results.

Typical instructions for home glucose testing:

Baseline testing frequency by stage:
- Stage 1 T1D: Test one to two times per month.
- Stage 2 T1D: Test weekly.
Test daily if ill or experiencing symptoms of hyperglycemia.
Testing 2 hours after the biggest meal is preferred, but testing before breakfast or at any convenient time is also acceptable.
Remember to always wash hands with soap and water before testing to prevent any false readings.
Use glucose testing information card to guide response to testing results (Figure 2).

TABLE 1 Home Glucose and CGM Testing Ranges Guidelines
NOTE: Neither home glucose testing nor CGM values are accepted criteria for staging of T1D by ADA or ISPAD guidelines.

Elevated or high values should ONLY be used to prompt further evaluation. Those who have elevated or high values be instructed to wash hands well, test finger stick glucose (to validate CGM value or repeat test of initial glucometer result) and then contact health care team for further evaluation. Any “HI” result on the glucometer should prompt immediate evaluation.

Normal values may miss intermittent elevations and can underestimate progressive loss of beta cell function in individuals who eat low carbohydrate diets. While “normal” values do not rule out progression of disease, they can be somewhat reassuring

Continuous Glucose Monitors (CGM)

While CGM data is NOT an accepted ADA criteria for staging of T1D, CGMs are easy to wear, and patients can be taught to place them on themselves, giving patients an opportunity to participate in monitoring and to feel empowered. Many patients find CGM monitoring more acceptable than OGTTs or intermittent home glucose testing. Another benefit of CGM assessment is the ability to share results with the patient/family and to obtain detailed information about blood glucose variation while the person is eating their usual diet and participating in their normal daily activities. Sometimes, evidence of increasing glucose levels on CGM can encourage patients to undergo an OGTT. CGMs have the potential to identify important glycemic changes earlier than the less sensitive A1c or OGTTs which are not practical for frequent assessments.

Historically, CGMs used for monitoring of early-stage T1D have been worn in a blinded state. Unblinded CGMs provide patients/families with a constant input of data which many individuals are not equipped to interpret unless provided with education and support. Some individuals can experience psychological distress due to this constant ambiguous information and may become anxious if they see what they perceive to be abnormally low or high

blood sugars. Post-measurement discussion of blinded CGM findings allows sharing of information in the context of education regarding its meaning and an opportunity to answer questions and provide support.
It is recommended that unblinded CGM wear is used only in the context of education by experienced providers and availability of psychological support. This approach was piloted in individuals with Stage 2 T1D as part of The Early Start Study (TESS) at our center. Initial participant feedback to this approach was overall positive, and patients were able to gain an understanding of factors that impacted glycemic patterns. It is debatable whether unblinded CGM is as useful in individuals in Stage 1 T1D. In people with normal beta cell function, CGM tracings are typically very stable, thus opportunities to benefit from education during unblinded CGM wear are more limited. Ask the Experts has CGM guidance cards, which were adapted from the TESS study. These reference cards give the patient and family guidance on how to respond to both high and low values on their CGM (Figure 4).

FIGURE 4

Monitoring in Research Studies

A variety of indicators are used in research studies of early-stage T1D. There is as yet no consensus for their use in the clinical sphere; however, future work may incorporate these and other measures into both risk assessment as well as patient selection for clinical intervention.

Islet autoantibody pattern

Both the pattern of positive autoantibodies, including the appearance or disappearance of autoantibodies over time, as well as the antibody titers have been analyzed in those participating in prospective studies of islet autoimmunity. There is evidence that both pattern and titer of autoantibodies may be useful in prognosis of progression to Stage 3 T1D.

Risk scores

A variety of risk scores encompassing demographic characteristics as well as anthropomorphic, genetic, and metabolic measures have been developed for use in prognosis and tracking of progression in the context of clinical trials. Measures of pro-insulin and c-peptide and their ratios are often components of these risk scores as well as monitoring during intervention studies. Genetic risk scores are being incorporated into some screening strategies to identify high-risk children who are then targeted for autoantibody screening (see Module 2).

M2-References

REFERENCES

1. Simmons K, Frohnert B, O’Donnell H, et al. Historical Insights and Current Perspectives on the Diagnosis and Management of Pre-Symptomatic Type 1

Diabetes. Diabetes Technol Ther. 2023 Nov;25(11):790-799.

2. Home | Ask the Experts – Early T1D Answers and Guidance [Internet]. AsktheExperts. [cited 2023 Dec 9]; Available from: https://www.asktheexperts.org

3. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/self-monitoring-blood-glucose-test-systems-over-counter-use

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