Using Time in Tight Glucose Range as a Health-Promoting Strategy in Preschoolers With Type 1 Diabetes

The purpose of insulin treatment in children with type 1 diabetes (T1D) is to promote health and quality of life (QOL) in the short- and long-term. To achieve sustainable health and freedom from complications, hyperglycemia needs to be avoided (1,2). Children who develop diabetes in their first years of life risk exposure to many decades of hyperglycemia, hence having a high risk of early complications and premature death (3). An additional age-dependent risk is that dysglycemia, especially hyperglycemia, negatively affects the developing brain (4). In estimating complication risk for current preschoolers with T1D, a 70-year perspective needs to be kept in mind—not only risk in the relatively short 30-year period, as has previously been reported as long-term follow-up (2,5).

In evaluating the outcome of insulin treatment at an individual and group level, cutoff thresholds for glucose values are needed. All of these targets are somewhat arbitrarily chosen. The choice of glucose cutoffs has many implications. Group-level recommendations are the basis for education of people with diabetes (PwD) and diabetes team staff and can also be used in designing algorithms for automated insulin delivery (AID) and to form a basis for reporting in quality registers. An individual treatment target is a matter of agreement between the diabetes team and PwD.

In Sweden, over the past two decades, many pediatric diabetes teams set glycemic targets to 70–140 mg/dL (3.9–7.8 mmol/L). In everyday conversations with families this was referred to as 4–8 mmol/L. The purpose of this was to maximize normoglycemia. This work was initiated prior to continuous glucose monitoring (CGM) access.

When CGM became available, there was no international consensus on CGM targets. Therefore, in 2017 the Swedish Association for Pediatric Endocrinology and Diabetes decided to use 70–140 mg/dL (3.9–7.8 mmol/L) as target range for all pediatric age-groups with the addition of CGM (real time or intermittently scanned) to treatment. In parallel with the development of the Swedish targets in 2017, the international consensus on time in range (TIR) (70–180 mg/dL, 3.9–10 mmol/L) was developed and published (6).

Then, in 2022, in its consensus guideline “Managing Diabetes in Preschoolers” (7), the International Society of Pediatric and Adolescent Diabetes (ISPAD) recommended that for preschoolers with T1D and access to diabetes care of high quality, either >70% of time with glucose in range 70–180 mg/dL (3.9–10 mmol/L) (TIR) or >50% of time in a tighter range, 70–140 mg/dL (TITR), can be used as a CGM target.

The purpose of this review is to share and discuss knowledge and experiences from working with TITR instead of TIR as a health-promoting strategy for preschoolers with T1D.

The core difference between the two concepts TIR and TITR is philosophical. While TIR was introduced as a CGM metric corresponding to HbA_1c (8), TITR (previously called time in target [9]) was defined to measure time in a state of normoglycemia; afterward, the correlation with HbA_1c was sought for estimation of what proportion of TITR to recommend (9). TITR was defined according to the percentage of time with CGM glucose readings within 70–140 mg/dL (3.9–7.8 mmol/mol) (10).

The basis for the suggested TIR target was that 70% of time in TIR corresponds to an HbA_1c of ∼7% (53 mmol/mol). For TITR, 50% of time correlates to HbA_1c 6.5% (48 mmol/mol) (9). However, an HbA_1c of 7% (53 mmol/mol) correlates to 56%–84% TIR and 38%–42% TITR, depending on coefficient of variation (CV) (11,12).

In a study in children and adolescents a cutoff of 72% TIR was identified in order to identify individuals who achieved a TITR of ≥50%. Both TITR and TIR correlate with the average glucose and the fluctuation in glucose levels (CV). The correlation between TITR and TIR is high (0.95) (13). TITR is on average 20%–25% lower than TIR (12). TIR correlates to TITR (in a nonlinear way) but depends also on CV.

Treatment targets have for decades been defined with HbA_1c. The American Diabetes Association recommends that HbA_1c goals be individualized and reassessed over time. HbA_1c <7% (53 mmol/mol) is appropriate for many children according to the American Diabetes Association. However, a more stringent HbA_1c goal of <6.5% (<48 mmol/mol) can be used if it can be achieved without hypoglycemia or too heavy a treatment burden (14). In contrast, as stated above, ISPAD suggests that preschool children with access to diabetes care of high quality can be treated with an aim of an HbA_1c target of <6.5% (48 mmol/mol) (7).

HbA_1c is easy and important to measure in the clinic, and the correlation between HbA_1c and complication risk is well-documented. Measured HbA_1c is a robust marker of glycemic quality of diabetes treatment. However, HbA_1c solely is not a reliable indicator of an individual’s glycemic control due to the wide range of mean glucose concentrations and glucose profiles that can be associated with a given HbA_1c level. Additionally, HbA_1c is not a tool for fine-tuning of insulin treatment in everyday life. There are many pros and cons with HbA_1c as a marker of glycemic control, but that goes beyond the scope of this review.

Promoting health and QOL in children with diabetes (CwD) is not only a matter of delaying complications. One description of a health-promoting strategy to increase diabetes resilience is to support a high sense of coherence in the child and parents (15). For this, insulin treatment needs to be explained as meaningful (promotes health and growth), comprehensive (to as much as possible restore normoglycemia), and manageable (it is possible to estimate the prandial insulin need by carbohydrate counting) (Fig. 1).

It is likely that insulin treatment methods will improve further, and early adoption of a physiological target glucose for young children may reduce the challenges regarding the need for relearning in the future. Giving the growing child words for a meaningful treatment target from onset is a way to prepare for a healthy future with diabetes. Giving the parents a simple explanation, “We want your glucose level to be as much as possible as in any other child,” can contribute to a high sense of coherence.

Diabetes onset is the key time to introduce the target of maximizing normoglycemia. This needs to be done in a way that boosts the sense of diabetes resilience in the child and family.

One of the major benefits of using CGM data for fine-tuning insulin treatment is that it is instantly available for the user. Prior to CGM metrics, normoglycemia was hard to describe in a manner that was easily grasped by PwD, especially CwD and their families. When the concept of TIR was developed, health care professionals had a logical tool for these discussions (6). With reports of CGM data from individuals without diabetes at different ages (16,17), we now know that people without diabetes across different ages spend >90% of time within the range 70–140 mg/dL (3.9–7.8 mmol/L), and this can be used as a reference in discussing normoglycemia.

The term “time in tight range,” which includes the word “tight,” can send an unintentional signal, both to health care providers and to patients and their caregivers, that this range as a target is narrow, difficult to achieve, and accompanied by risk. However, this is a misinterpretation. TITR describes the normal physiological glucose range. Therefore, we argue that TITR could be renamed to “time in normal range.” There are several examples of use of normal range in interpreting results of procedures for evaluation of other conditions. An example is percentage of time with decreased oxygen saturation on polysomnography when obstructing sleep apnea is suspected. The use of the term “normal range” is easily understandable by everyone, and importantly, the use of the term “time in normal range” does not imply a more demanding treatment.

Glycemic control achieved early in the disease course with insulin treatment in childhood will affect glycemic outcomes for many years (18). This has been shown in tracking individuals, and in comparing trajectories in national diabetes registries (19). Hyperglycemia is the major risk factor for development of diabetes complications, and even a small glucose elevation during a long period constitutes an elevated risk (5).

TITR is a neutral description of time within normoglycemic range. As per any description of glycemic outcomes in diabetes treatment, its use needs to be discussed and agreed upon with parents and children in an individualized and noncondemning manner. Simultaneously, diabetes team professionals need to have a common clear message (20–23) of both what is reasonable to achieve and what represents a currently tolerable risk of complication development with insulin treatment in young children. Modern technology has facilitated the possibility to achieve and maintain a high percent TITR over time, but the importance of a well-educated CwD, and families and caregivers, in addition to a well-functioning diabetes team, should not be underestimated.

Swedish register data show that >50% of children <7 years old have >50% TITR (24) (Fig. 2). In 2018, before access to AID systems, the average TITR in Swedish preschoolers was 48%, with mean glucose 154 mg/dL (8.4 mmol/L) and average time with glucose levels below target (TBT) 7.8% (25).

Diabetes care can be improved by structural quality work by the diabetes teams in cooperation with national quality registers (Norway, Sweden) and initiatives by local diabetes teams (26). The first quality improvement project for pediatric diabetes teams started in Sweden in 2011. The project has been followed by similar projects in Sweden, as well as in other countries including Norway. The diabetes teams follow the same model for improving, using diabetes register data to follow up and compare openly available results. Both in Norway and Sweden, the intercenter variability in mean HbA_1c in pediatric patients with T1D is low (27). In Sweden, benchmarking within the Swedish National Diabetes Register (Swediabkids/NDR) has been open since 2005. This has, during almost two decades, fostered an open culture of intercollegial support among pediatric diabetes teams. Open benchmarking has the potential to provide for knowledge sharing (28–30).

One effect of these collaborations is also that new technology and strategies can be implemented nationwide as the teams communicate with each other and share their experiences. An example of the importance of both formal and informal networking is how the idea of pursuing insulin treatment to maximize normoglycemia spread over Sweden (Fig. 3). One local diabetes team independently started the process and developed local praxis. More and more teams followed, and a new standard developed. This resulted in a national decision in 2017 to follow the National Institute for Health and Care Excellence guidelines (31), and a national HbA_1c target of ≤6.5% (48 mmol/mol) was adopted. Figure 4 describes the development of HbA_1c in children aged 0–6 years with T1D in Sweden.

International benchmarking and networking with pediatric teams are also possible within the SWEET (better control in pediatric and adolescent diabeteS: Working to crEate CEnTers of reference) network. Through meeting other diabetes teams and comparing data both nationally and internationally knowledge and new treatment regimens are spread and implemented (28,29). Studies have shown almost identical increase of HbA_1c from the young to the older child between countries (19). Helping the preschool CwD to achieve a high proportion of TITR will have an effect over time on the HbA_1c of older age-groups.

Findings of high percent TITR in randomized control trial studies, especially with use of AID, are often suggested to be biased by the higher socioeconomic status and educational level of participants compared with the general population (32). National registers from Norway and Sweden have very high (>97% of national patient population) coverage regardless of factors such as immigrant status. For example, in 2023, 39% of all children <5 years old in Sweden were either born abroad or had at least one parent born abroad (33).

In adults in Sweden, it has been shown that lower income, but not level of education, correlates with glycemic outcome in T1D (34), even if all diabetes-related costs are reimbursed. In newly diagnosed children in Sweden, lower family income is associated with higher risk of ketoacidosis at diabetes onset (35). In Sweden and Norway, insulin and equipment for insulin treatment are of no cost to the user. This makes the report by Phelan et al. (26) important; it demonstrates outcomes from a diabetes team education program with a focus on lower glycemic targets in young children using either multiple daily injections or pump therapy. Phelan et al. show glycemic outcomes similar to those in Sweden from a center in Australia, a country with less generous reimbursement of treatment equipment and with fewer social support structures.

After initiation of insulin treatment, most preschool children regain some capacity to produce endogenous insulin that will increase the possibility of achieving high TITR. During this important period, the diabetes team needs to support the family to build confidence and resilience in the sense of being capable of taking care of their child with diabetes. During the remission period, many young children achieve far more TITR than 50% and the continual strategy of the diabetes team can be to encourage the family to identify strategies that work well and fit into their life. During this period, the diabetes team needs to deepen their understanding of the individual CwD and the family to be able to tailor insulin treatment further.

Glycemic control, measured as HbA_1c, established early in the disease course has a high propensity to follow the PwD for many years (36). Therefore, detection of children with early dysglycemia, hopefully before HbA_1c rises, and identification of necessary interventions are important. Practical advice to give to the family is to carefully watch TITR and to call the diabetes team if TITR decreases below a defined threshold, which early during remission can be 70% or 80%. Use of TITR, instead of mean glucose, for initiation of contact is a way to avoid accumulation of time below target as a “false friend” to lower mean glucose. The target is maximizing normoglycemia—not as low a mean as possible.

The underlying principle of any hormone replacement therapy, including insulin treatment, is restoration of physiology. In teaching parents of a newly diagnosed child with T1D, this can be framed as the necessity for estimation of how much insulin the child needs to remain normoglycemic. Insulin need and glucose levels vary from day to day and have a particular diurnal pattern in preschool children. Preschool children have a higher day-to-day variation in insulin need than older children (37). AID can be a useful tool for handling this (32). If AID not is available, flexible basal/bolus insulin dosing, with pump or multiple daily injections, is necessary (7). Access to technological tools for insulin treatment makes achieving targets easier, but only providing technology will not achieve glycemic targets (38).

Communication with parents is needed regarding awareness and acceptance of the constant need for changes and adaptation of insulin treatment. The child is growing and developing very fast during this period of life. Every meeting between the CwD and diabetes team needs to focus on proactive preparation for the upcoming period—not a focus on the previous period.

Even prior to CGM access, families in Sweden were taught to give extra insulin preprandially and 2 h postprandially if glucose levels where >144 mg/dL (8 mmol/L). There was also a national consensus on treating hypoglycemia, defined as glucose levels <70 mg/dL (<3.9 mmol/L), primarily only with dextrose 0.3 g/kg body wt.

Knowledge about typical insulin need in preschoolers is essential for having a realistic plan in starting insulin treatment. The need for basal insulin is very low after midnight/early morning and very high in the evening. Age-appropriate, individualized insulin-to-carbohydrate ratios need to be applied; a starting point can be ratios of providing approximately double the insulin dose of older children (150 rule at breakfast, 250 during the day, and 200 in evening). As a starting point, the insulin sensitivity factor can be 100 during the day, 70 in the late evening, and 150–200 after midnight until morning (7,39). However, these will need to be adjusted according to the individual CwD. In using an AID the settings also need to be adapted to the algorithm of the system. Underestimating the need of bolus insulin increases the risk of postprandial hyperglycemia.

Glucose levels cannot be the only tool for evaluation of the child’s insulin doses. Weight, height (or length in children <18–24 months according to national recommendations), and BMI need to be monitored every third month to evaluate the caloric balance of the child. Overweight and obesity are early markers of cardiovascular risk.

For further practical aspects of insulin treatment of preschool children we refer to ISPAD guidelines “Managing Diabetes in Preschoolers” (7).

Eating and mealtime behavior is a common concern in many families with young children. This is even more common in CwD when insulin treatment complicates the situation (40).

The team should assume that all families and children can establish food routines and believe that irrespective of cultural or socioeconomic status all can learn carbohydrate counting. Education needs to be tailored and individualized and presented with a positive can-do approach.

To maximize normoglycemia, caregivers must be empowered to follow key dietary principles: administration of preprandial bolus insulin 15 min before the meal even in the most unpredictable eaters, carbohydrate counting from onset, routine meal structure, and appropriate hypoglycemia treatment. To enable this, common team messages are required with behavioral management and emotional support. CGM reports can be used to reinforce messages about insulin timing and to discern whether carers require targeted nutrition interventions from the team. Educating caregivers about what is a normal glucose rise after food is key to addressing potential anxiety that has been reported with CGM use in young children (41).

To maintain high TITR, reasonable accuracy in matching the insulin dose to the anticipated carbohydrate intake is required (within 10 g of estimated meal content, if feasible) (42). It is important to educate families about appropriate food amounts for age to lessen the risk of large uneaten carbohydrate amounts (26). Miscalculations of carbohydrate content <5–7 g rarely affect the postprandial glucose levels (42), and this knowledge can be used to increase the confidence of families around mealtimes.

Guidance regarding carbohydrate amounts at meals and snacks based on the child’s previous intake and estimated energy intake is helpful to establish consistency, which alongside balanced meals, optimizes TITR (43,44). If the child is hungry or asking for food between mealtimes, it is necessary to divert the child, and caregivers should be reassured that offering food every 2–3 h over the day is sufficient. This assists both the child and the parent, as the entire day does not become about eating.

At breakfast, many young children have some degree of insulin resistance, and it is common to experience a sharp glucose peak despite an adequate insulin dose taken before the meal. Healthier carbohydrate choices such as whole grains and lower glycemic index–foods should, where possible, be encouraged.

Structured meals are important across all insulin therapy regimens to optimize TITR (40,43). Eating patterns such as continual snacking or consuming a bedtime snack due to fear of overnight hypoglycemia result in lower TITR. A routine eating pattern facilitates prandial insulin administration, as the child is hungry at the mealtime. It is important that mealtimes are limited to 20–30 min and that caregivers do not pressure their child to eat or offer too many food alternatives at one meal (40).

It is caregivers’ fear of hypoglycemia, associated with food refusal or unpredictable dietary patterns, that may result in force-feeding, grazing continually over the day, and postprandial insulin administration, causing prolonged periods of hyperglycemia. It is vital that these issues are addressed from diabetes onset with reinforcement at each clinic visit (45).

Technical devices such as AID and CGM are important tools in diabetes treatment in toddlers and preschoolers. As children <7 years old constitute a small minority of CwD (∼10% of children <18 years old), equipment for insulin treatment is rarely designed to fit the special needs of this group of users. There is also a lack of formally approved devices for insulin treatment, especially for children <2 years old. When using technical devices as insulin pumps, especially AID, it is important that the diabetes team knows in detail the benefits and challenges of the devices. There are substantial differences in dosing precision, dosing speed, dosing increments, and algorithm designs that have to be considered in choosing a pump system with the family of a CwD.

In the very youngest children, especially those weighing <10–15 kg, it is sometimes helpful to dilute the insulin with specific dilutant (7). Insulin can be diluted to 10 unit/mL. If this is to be done, the caregivers of the child need to be well-informed about the benefits and risks of the use of a different insulin strength than the pump system is designed for. Case reports and some studies are published regarding diluted insulin (46–48). Inclusion of relatively “old” (median age 5 years) children with relatively high insulin doses (mean 13.2 units/day) might contribute to absence of significant differences in interpreting the results (47).

The UN Convention on the Rights of the Child Article 24 (49) states, “States Parties recognize the right of the child to the enjoyment of the highest attainable standard of health and to facilities for the treatment of illness and rehabilitation of health. States Parties shall strive to ensure that no child is deprived of his or her right of access to such health care services.” From the perspective of a preschool child with T1D this means that the target needs to be to maximize normoglycemia regardless of socioeconomic status, education of parents, or family situation. The diabetes team needs to adapt the care, education, and support given to the family but not a priori the glycemic target setting. Adaption of care demands skill and prioritization of resources of the diabetes team. Time, patience, confidence building, and tailoring of strategies are needed. If a care strategy does not seem to work in the context of a specific CwD, it is probable that more of the same will not work either and the diabetes team, in cooperation with the family, needs to reevaluate the situation of the individual child.

In a small study on QOL in preschoolers, investigators did not observe any positive or negative correlation between QOL and HbA_1c (50). Data on this are scarce in preschoolers.

The main purpose of delaying complications is to enhance QOL. In a young population of individuals with T1D with a mean diabetes duration of 23 years, QOL was equal to that of control participants as long as no significant retinopathy was present; however, in the subgroup with retinopathy, QOL was significantly lower (51).

Kimbell et al. (23) reviewed qualitative studies published after 2002 regarding parental experiences of caring for children <8 years old with T1D. They report two categories of results. The first is that diabetes is so overwhelming it monopolizes life. In this category, fear of hypoglycemia, but also fear of hyperglycemia-related complications, is a major contributor. The second category is parental experiences of professional and informal support. Regarding professional support, they stress the importance of avoiding mixed messages, having individual education plans, and discussing treatment plans together with the family (23).

It is important to be aware that there are no randomized controlled trials with comparison of TITR and TIR as clinical tools. Hence, we have to discuss clinical observational data where TITR is integrated in care.

The first concern is often the assumption that lowering the target range will increase time spent in a state of hypoglycemia. Hypoglycemia is potentially harmful for a developing brain. Recent data, however, suggest that hyperglycemia and ketoacidosis are more associated with brain injury than is hypoglycemia (4). This supports the use of TITR to avoid hyperglycemia without increasing hypoglycemia. It has been shown that a reduction in hypoglycemic events is possible in using CGM (38). Although the percentage of children in Sweden with HbA_1c <6.5% (48 mmol/mol) increased from 14.0% to 45.4% between 2008 and 2018, the TBT was 7.8% and severe hypoglycemia, defined as unconsciousness with or without seizures, was 3.3% in 2018 (25). With access to AID systems the TBT can be lowered overnight to less than the recommended <4% without increasing hyperglycemia (32).

The fear that lower HbA_1c is associated with higher risk of severe hypoglycemia has impacted insulin treatment heavily since the Diabetes Control and Complications Trial (DCCT)(1). International register data show that there is no longer any association between lower HbA_1c and a higher frequency of severe hypoglycemia with loss of consciousness and seizures. On the contrary, there is a correlation between higher HbA_1c and more severe hypoglycemia (52–55). Preschoolers with T1D need help with all aspects of insulin treatment, including treatment of hypoglycemia. This makes the consensus definition of level three (severe) hypoglycemia (56) hard to use in this age-group, and statistics regarding hypoglycemia need to be interpreted cautiously.

Fear of hypoglycemia is a common concern among parents with younger CwD. This fear is somewhat lessened by the use of modern diabetes technology (57,58). CwD have a higher mortality risk than the general population, mainly attributable to acute diabetes complications, where ketoacidosis is the most common cause (59–62). Even after a thorough literature search, no cases with documented hypoglycemia as cause of death in preschoolers with T1D have been found in the preceding two decades. The health care team should take care to avoid installing fear of hypoglycemia in caregivers.

Another concern that sometimes is raised is that parents will be burdened by fear of hyperglycemia as part of their understanding of the concept of normoglycemia. This fear already exists (57) as parents are well aware of the complication risks associated with hyperglycemia. Explaining, “We aim for your child’s most common glucose value to be normal. There will be high and low values, but as long as the most common value is within the normal range the risk of complications is low,” may be helpful.

Among Swedish CwD <7 years old, 30% have overweight or obesity. However, no increase has been shown in overweight or obesity, although there has been an increase in TITR over the years (24) (Fig. 5).

Another concern that is expressed is that a more physiological glucose target would increase the risk of parental burnout. The clinical experience in Sweden was that parental stress was reduced after the introduction of TITR. Additionally, the use of AID in young CwD has been shown to reduce parental distress and increase TITR (58,63).

In parents of CwD, no association has been found between the child’s HbA_1c and parental burnout (64). Other factors such as ability to ask for practical support and access to leisure time were associated with lower risk of parental burnout (64).

For families already living with diabetes, either in a parent or child, it can be a challenge to rethink glycemic targets. Clinical experience from the time of changing glycemic targets in Sweden was that, with patience and a nonjudgemental approach from the diabetes team, most families accepted the new treatment targets. A teaching strategy was to tell the families the story of what we currently tell those who are new to diabetes and why we perceive targets to be important, with framing as an offer to the families to give their child with diabetes a brighter future.

The biggest challenge is probably the mindset of health care professionals. If the health care professionals believe that achievement of normoglycemia is impossible, this will probably be a self-fulfilling prophecy.

In 2022 the first drug aimed at slowing diabetes development (teplizumab) was approved by the U.S. Food and Drug Administration. This means that in the near future hopefully the population of children with relative, rather than absolute, insulin deficiency will be increasing. For these children and their diabetes teams, monitoring of normoglycemia will be a natural part of follow-up. Less than 90% TITR has been suggested as a marker of overt dysglycemia in this patient group (65).

As insulin treatment improves, a reasonable goal is to strive for as much time with normoglycemia as possible, and this can easily be explained to families of CwD. In everyday diabetes care this can be monitored as TITR. For children with access to good diabetes treatment a currently realistic target can be at least half of the time in normoglycemic range, i.e., TITR >50%.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. F.S. drafted the first manuscript, researched the literature, retrieved data from the national registry NDR, discussed clinical experiences among the author group, and edited the text and figures. C.E.S. researched the literature, discussed clinical experiences among the author group, and edited the text and figures. J.S. researched the literature, discussed clinical experiences among the author group, and edited the text and figures. K.Å. retrieved data from NDR, researched the literature, discussed clinical experiences among the author group, and edited the text and figures. L.K. researched the literature, discussed clinical experiences among the author group, and edited the text and figures.

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Kristen J. Nadeau.