Proposed Practical Guidelines to Improve Glycaemic Management by Reducing Glycaemic Variability in People with Type 1 Diabetes Mellitus

Abstract

Introduction

For decades, glycaemic variability (GV) was ignored in clinical practice because its precise assessment was challenging and there were no specific recommendations to reduce it. However, the current widespread use of continuous glucose monitoring (CGM) systems has changed this situation. Associations between high GV and risk of hypoglycaemia, onset of macro- and microvascular complications and mortality have been described in type 1 diabetes (T1D). It is therefore important to identify the causes of excessive glycaemic excursions and make recommendations for people with T1D to achieve better glycaemic management by minimising GV in both the short term and the long term.

Methods

To achieve these aims, a panel comprising four endocrinologists, one diabetes nurse educator and one nutritionist worked together to reach a consensus on the detection of triggers of GV and propose clinical guidelines to reduce GV and improve glycaemic management by reducing the risk of hypoglycaemias.

Results and Conclusions

In total, four different areas of interest were identified, in which the insufficient education and/or training of people with T1D could lead to higher GV: physical activity; dietary habits; insulin therapy, especially when pump-based systems are not used; and other causes of GV increase. Practical, easy-to-follow recommendations to reduce GV in daily activities were then issued, with the aim of enabling people with T1D to reduce either hypoglycaemia or hyperglycaemia episodes. By doing this, their quality of life may be improved, and progression of chronic complications may be prevented or delayed.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13300-025-01703-0.

Key Summary Points

High glycaemic variability (GV) is reliably associated with macro- and microvascular complications, as well as mortality, in people with type 1 diabetes (T1D).

High GV remains a main limitation of T1D treatment, since specific guidelines to decrease it, and thus increase time in range (TIR), are not available.

An interdisciplinary panel met to propose practical, easy-to-follow guidelines for people with T1D, especially for those who are not using pump-based systems to manage insulin therapy, to reduce glycaemic excursions and increase TIR.

The recommendations for people with T1D are focused on four areas, namely physical activity, dietary habits, insulin therapy and other causes of GV increase, and were consensually agreed upon by all authors.

Introduction

Definition and Assessment Procedures

Glycaemic variability (GV) is defined as the magnitude of glycaemia oscillations during a predefined period of time [1]. Until the last decade, GV was not considered to be a useful tool to evaluate the efficacy and safety of therapies for people with type 1 diabetes mellitus (T1D). Regular home capillary glucose monitoring was cumbersome and there was no clinical evidence of diabetes complications linked to high GV. However, the current widespread use of continuous glucose monitoring (CGM) systems allows for easy assessment of several parameters related to GV and its evolution over time (reviewed in [2]) (Supplementary Material: Table S1). Among these, the coefficient of variation, which is the ratio between the standard deviation and the average of the glycaemic values, is frequently used. Most software programs calculate it automatically, providing information about glycaemic oscillations [3–5]. The ambulatory glucose profile (AGP) is also useful to determine GV by analysing the information provided by the interquartile range (IQR 25th–75th) and 5th to 95th percentile band. In cases of high GV, this estimator may guide practitioners towards a problem with treatment, lifestyle or both [6].

Consequences of Not Achieving Glycaemic Targets

Indeed, it has long been known that repeated hypoglycaemia episodes negatively impact the quality of life of people with T1D [7, 8]. Importantly, regular reporting of GV has made it possible to establish solid associations between high GV and macro- and microvascular complications and mortality (reviewed in [9, 10]). Reducing GV improves insulin resistance and diminishes intima-media thickness, thus lowering cardiovascular risk. SYNTAX scores, whose values are associated with severity of coronary artery lesions by combining anatomic and clinical prognostic variables, are associated with high GV beyond glycosylated haemoglobin (HbA1c) levels, suggesting a potential causal relationship and positioning GV as a therapeutic target for cardiovascular prevention [11]. Accordingly, prospective studies have found that long-term GV is a strong predictive factor for midterm cardiovascular disease (CVD) and all-cause mortality [12, 13].

GV is also involved in promoting the onset of microvascular complications. A significant association has been found between GV and kidney disease, and GV reduction has been shown to slow down renal function impairment [14, 15]. The role of GV in peripheral neuropathy (PN) is more controversial [16], although several studies have found an association between high GV and higher PN risk in both T1D and type 2 diabetes mellitus [17–19]. Finally, GV has also been found to be a risk factor for retinopathy in people with T1D [20].

Although the pathophysiological mechanisms underlying GV as a cause of vascular complications are potentially related to endothelial dysfunction, they may differ according to the type of glycaemic excursion. When hyperglycaemia prevails, vascular damage is mediated by oxidative stress and epigenetic changes. Further, it seems that hypoglycaemia induces platelet activation. In both cases, the release of inflammatory cytokines plays a notable role in causing vascular damage [10].

Daily Activities and Procedures that May Increase GV

The inappropriate actions that may lead to a suboptimal control of glycaemia, and thus to more frequent excursions out of the suitable range, can be arranged into two categories: lifestyle habits, which in turn can be divided into insufficient training in insulin management when planning physical activity and inappropriate dietary habits that hamper glycaemic management by rapid insulins; and inappropriate insulin therapy. Table 1 the most common scenarios.

Table 1.

Situations that may promote glycaemic variability

Category	Inappropriate training/procedure/conduct
Physical activity	Incomplete knowledge about glycaemic response to the different types of physical activity
	Not enough education about managing insulin adequately according to the type of physical activity to be performed
	Lack of coordination with the healthcare team to plan physical activities
	Physical activities irregularly scheduled throughout the day/week
Dietary habits	Excessive differences between meals in carbohydrate amount and/or origin
	Inappropriate choice of other macronutrients to accompany carbohydrates
	Not enough education on glycaemic index of each food type
	Incorrect carbohydrate balance throughout daily meals
	Incomplete knowledge regarding coordination between meals and physical activity
	Not enough education regarding influence of either meal schedule or quantity on dosing and/or adjustment of basal/rapid insulin
	Not enough knowledge about suitable sequential nutrient intake
	Inappropriate food cooking/processing
Insulin therapy	Insufficient understanding of how long- and short-acting insulins control glycaemia
	Suboptimal compliance regarding dosing times
	Inappropriate behaviour in the event of missing doses
	Incomplete knowledge of time relationship between meal times and rapid insulins
	Not enough training regarding dose adjustment, inappropriate use of ISF
	Too low frequency of rotation of injection sites within one area; use of too many different areas
	Not enough education hindering people with T1D from deriving maximum benefit from devices such as integrated pumps, connected pens or connected caps
Others	Distress-promoting situations/behaviours (insufficient education to gain self-confidence; reticence to speak about T1D condition; no/little time devoted to rewarding activities)
	Inappropriate sleep quality

ISF insulin sensitivity factor, T1D type 1 diabetes

The Importance of Analysing GV Data in the Context of Time in Range

In clinical practice, GV can be assessed as intra-day or day-to-day fluctuations. High day-to-day GV may occur even with small intra-daily GV, for instance, if meal schedules or physical activity vary from one day to another [21]. People with T1D with large day-to-day GV are unlikely to achieve good glycaemic management [22]. It is important to note that a low GV does not necessarily suggest that glucose levels are being correctly controlled, since stable values may be also found out of the consensus target range of 70–180 mg/dL. For this reason, GV values have to be analysed in the context of the so-called time in range (TIR), that is, the time during which glucose levels are within the desired target range [23].

Purpose

In spite of the consensus to consider high GV as a main limitation of insulin treatment, specific guidelines to decrease GV, and thus increase TIR, are not available. To fill this gap, a panel comprising four endocrinologists, one diabetes nurse educator (DNE) and one nutritionist met to propose a series of practical, easy-to-follow guidelines aimed to keep GV at a minimum level, mainly focusing on physical activity, dietary habits, insulin therapy and other causes of GV increase.

Methods

The panel convened across virtual meetings with the final aim of proposing consensus guidelines to minimise GV in this population. Once the panel reached the consensus that physical activity, dietary habits and insulin therapy were the major areas to work on to find useful suggestions to improve glycaemic management, a comprehensive, updated review of the literature was planned. For this purpose, appropriate keyword combinations to identify articles of relevance to the different topics were agreed. These combinations are specified in the Supplementary Material (Table S2). Other minor causes of GV were also considered. Likewise, an additional search for reviews addressing the topic of GV in the last 5 years was also performed to ensure that other potential causes of GV had not been overlooked. For searches regarding insulin therapy, those articles addressing GV in people with T1D who are not users of pump-based systems were prioritised.

By sharing their proposals, the panel was able to reach an agreement on the final set of proposed practical guidelines to follow in each area to achieve low GV, appropriate TIR values and low risk of hypoglycaemia.

This article is based on previously conducted studies as well as on previous authors’ observations and does not contain any new studies with human participants or animals performed by any of the authors.

Proposed Guidelines to Minimise GV

Many people with T1D are not aware of how lifestyle changes that are related to physical activity and meal schedules may help to improve their glycaemic management. In addition, the correct use of insulin is essential to prevent undesired glycemic excursions. Thus, people with T1D have to be educated to know as many aspects as possible regarding T1D (underlying mechanisms, suitable behaviour, mid-/long-term complications derived from out-of-target glycaemia, basic mechanism of action of insulin). The greater the knowledge of the disease and how to manage it, the higher the self-confidence and the lower the trend to distress. The main causes of GV are associated with lifestyle habits concerning physical activity and diet and inappropriate use of insulin. There are other causes that may also increase GV. All of them are outlined below together with some recommendations to mitigate their impact. Table 2 summarises the main recommendations that are discussed in the forthcoming sections.

Table 2.

Day-to-day recommendations for people with T1D to reduce GV and increase TIR

Physical activity
Education
Learn the differences between endurance training versus HIIT
Communication
Organise physical activity in coordination with the healthcare team
Actions before and during activity according to type of physical activity
Endurance physical activity
Reduce insulin on board; reduction of basal insulin may be considered for long duration activities
Monitor glucose regularly, consider carbohydrate intake when necessary
HIIT
Start with a previous short session of aerobic activity
Consider a rapid insulin dose immediately before starting anaerobic activity

Dietary habits
Consistency among meals
Avoid excessive differences in carbohydrate amount and/or origin among meals
Be familiar with the ratio between carbohydrate amount and insulin dose
Carbohydrate intake
Try to have a carbohydrate intake of 75–130 g per meal, combined with vegetables, wholegrain cereals, fibre, lean protein and healthy fat
Choose complex carbohydrate sources and fibre, and limit/avoid refined sugars, sweets, candy, cakes, soft drinks and sugar-rich or ultra-processed foods
Glycaemic index
Choose preferably foods with low index values
High-fat and high-protein meals
Learn that high-fat and high-protein meals increase insulin requirement
Be aware that dual wave mealtime insulin dosing may be required in the event of high-fat meal intake
Bear in mind that high-protein meals may contribute to improve glycaemic management
Meal schedule and frequency
Carbohydrate distribution throughout the day
Balance carbohydrate intake throughout all daily meals
Meals and physical activity
Watch out for coordination between meals and physical activity (plan the larger meals for the first part of the day if physical activity as such is not planned)
Meals and insulin dosing
Follow closely the proposed guidelines regarding insulin use around meals
Sequential nutrient intake  As a general (not mandatory) rule, ingest vegetables, fibre, proteins and fat earlier than carbohydrates
Food cooking/processing  Use short cooking times, preferably with solid foods rather than liquid ones

Insulin therapy
Treatment regimen
Achieve empowerment to understand treatment (why, when, how)
Missing insulin doses
If using them, take advantage of CGM devices to avoid missing or wrong doses
Missing long-acting insulin doses
Within time frame
Administer usual dose
Out of time frame
Follow specific guidelines proposed by your HCP
Regardless time frame
Monitor glucose level and administer short-acting insulin in the event of acute hyperglycaemia
Missing short-acting insulin doses
Within 2 h
Administer usual dose
Regardless time frame
Monitor glucose level regularly, administer short-acting insulin in the event of acute hyperglycaemia
Use of short-acting insulin when high/moderate glycaemic index foods are consumed
Administer rapid insulin 15–20 min before meal, and ultra-rapid insulin 5–10 min before meal (precise times should be estimated according to CGM profile)
Insulin dose adjusting
Empower yourself to understand and apply the ISF as well as to manage the information regarding glucose trends
Dose adjustment among main meals
Monitor glucose if time between major meals is long and administer a corrective dose in the event of acute hyperglycaemia, except if rapid insulin was injected < 2 h before
Rotation of insulin injection sites
Rotate insulin injection site regularly
Devices useful for therapeutic management  Take advantage of the information provided by connected pens/caps to avoid dose omission and wrong doses

Others
Control of emotional distress
Ensure fluent communication with HCPs to receive a complete education regarding all aspects of your disease to improve self-confidence
Control glucose levels by yourself
Seek support in relatives, friends, support groups
Devote daily time to rewarding activities, consider learning relaxation techniques
Sleep quality
Practice healthy sleeping habits

CGM continuous glucose monitoring, GV glycaemic variability, HCP healthcare provider, HIIT high-intensity interval training, ISF insulin sensitivity factor, T1D type 1 diabetes, TIR time in range

Before addressing GV causes separately, it must be remarked that irregular times for daily activities may hinder management of diabetes, and may equally affect physical activity, mealtimes and insulin administration. Indeed, maintaining regular schedules as much as possible may help when these behaviours are associated with excessive GV. Particular care has to be taken in situations such as shift work, holidays or weekends [24, 25].

Lifestyle Habits

Physical Activity

Not Regularly Performing Physical Activity

Generally speaking, physical activity promotes a reduction in glucose levels [26]. Nevertheless, predicting the effect size, or even whether this will be positive or negative, may be challenging. Changes in glucose values are not the same when exercise is aerobic or anaerobic (strength training) or when duration and/or intensity are low, moderate or high. The effect of physical activity may vary greatly according to time of day and timing relationship with meal times and/or insulin dosing. It is recommended that each individual follows a unique, personalised plan according to their particular conditions to avoid hypoglycaemia or hyperglycaemia episodes. Time of the day, day(s) of the week and type/duration/intensity of physical activity should be organised on a regular basis [27, 28].

Lack of Awareness of the Consequences of Doing Different Types of Physical Activity

As mentioned above, people with T1D have to be educated to distinguish between the different types of physical activity, namely endurance, explosive, high-intensity interval training (HIIT) and resistance exercise [28]. Endurance exercise, typically of moderate/long duration and moderate/high intensity (swimming, cycling, running, rowing), prompts muscles to consume more glucose than the liver is able to produce. The other types of exercise (cross fit, squash, and gym work) are usually performed for shorter periods of time at higher intensities. In these cases, hepatic glucose production exceeds the needs of muscles. Therefore, people with T1D may be at risk of hypoglycaemia in the first case and hyperglycaemia in the second [28, 29]. Decisions regarding kind and intensity of physical activity, and guidelines to minimise risks, have to be shared with the healthcare team. When planned adequately, the time and intensity of physical activity are directly associated with lower glucose circulating levels, higher TIR and less time in hyperglycaemia, while hypoglycaemia still warrants caution, especially in people with T1D with intensive glycaemic management [30–33]. The type of physical activity also influences GV. HIIT has been described to induce fewer hypoglycaemic events than aerobic training [34, 35]. Finally, sex might influence response to physical activity. A recent report described a small cohort of people with T1D where men always experienced blood glucose reductions after aerobic exercise, regardless of whether it was continuous or intervalic. In contrast, blood glucose level remained unaltered in women after a session of interval aerobic training [36].

• Recommendations for Doing Endurance Physical Activity

The concept of endurance physical activity covers those activities that are predominantly aerobic, such as running, swimming or cycling, and are performed at moderate/high intensity during long periods of time. In these cases, starting activity in hyperglycaemia is not required. It is important to remark that insulin on board should be reduced. For this purpose, the amount of basal insulin should be lower if physical activity was planned for early morning. In those cases where physical activity was arranged to start after a meal, the amount of rapid insulin to be administered as bolus should also be lower. In those cases where the risk of hypoglycaemia is high according to previous experiences, starting once the activity of rapid insulin has entered the downward phase, that is, roughly 3 h after bolus administration, is recommended.

When glucose levels are roughly 150 mg/dL or lower, carbohydrate intake before initiating physical activity should be considered. During physical activity, carbohydrate intake should be decided according to regularly monitored values. If long duration is planned, for instance long-distance cycling or running, reduction of basal insulin dose may be considered (Fig. 1) [29, 37, 38].

• Recommendations for Practising HIIT Physical Activity

Fig. 1.

Recommendations for people with T1D to engage in physical activity safely. IOB insulin on board, T1D type 1 diabetes

The concept of HIIT, also called resistance training, refers to an explosive, interval exercise which is performed at high intensity during short periods of time. A short previous session of aerobic work is recommended to balance the hyperglycaemic effect of the planned activity (never the other way around). Starting anaerobic physical activity with rapid insulin to avoid glucose release by the liver may also be advisable (Fig. 1) [29, 37]. Indeed, it must be remarked that carbohydrate supplements should not be used.

Dietary Habits

Although most people with T1D are aware of the meaningful influence of diet on GV, a concerning lack of knowledge regarding specific dietary habits to follow or to avoid to prevent glycaemic excursions can be observed in day-to-day practice.

Appropriate Balance of Nutrients in Each Meal

In the classical diet scenario in DM, a meal is supposed to consist of two constituents: carbohydrates and ‘everything else’, namely proteins, fibre and fat. However, the first concept to teach is that carbohydrates, although indeed playing a key role in daily glycaemic levels, are not the only elements influencing these. A correct nutrient balance is achieved when vegetables, wholegrain cereals, extra amount of fibre, lean protein and healthy fat are added to the daily carbohydrate portion. This practice will produce benefits, among which stabilisation of glucose levels after meals will be the main one: the classically observed increase in glucose levels will be delayed and peaks will be lower in intensity. Thus, GV will be lower, and interestingly, the feeling of satiety will increase [39].

Once people with T1D have been educated to acknowledge the importance of all dietary constituents, a series of specific guidelines can be proposed to optimise each meal balance.

• Some Consistency amongst Meals Must Be Observed

Consuming not very different amounts of carbohydrates of similar origin in each meal may help in insulin dose calculation. However, this practice is not mandatory. In fact, it has been shown that appropriate training in insulin dose adjustment facilitates some dietary freedom. Thus, people with T1D should be educated to match insulin doses to their food choices. For this purpose, they should be familiar with the ratio between a given amount of carbohydrates and insulin dose [40].

• Carbohydrate Intake Should Be Quantified

Reference guides agree in considering the counting of carbohydrates to be a necessary strategy to achieve a good control of GV [41, 42]. To improve glucose response, people with T1D should be encouraged to follow nutritional advice to achieve a controlled intake of carbohydrates. An excessive amount of carbohydrates may be prejudicial to control [43], but too few carbohydrates are not recommended either. Eating a consistent amount of carbohydrates makes insulin dosing easier, although this practice may result in monotonous diet patterns and is difficult to accomplish in everyday life situations such as parties or travel [44]. Requirements may change according to individual hallmarks and the individual glycaemic management target. Importantly, a recent study found a direct association between the amount of carbohydrates per meal and GV in the following 3 h [43]. Indeed, carbohydrate intake influences the level of post-prandial plasma glucose, which in turn contributes to GV and influences glucose excursions [44]. This does not necessarily mean that carbohydrates have to be strictly avoided, since there is no agreement regarding suitability of diets based on very low carbohydrate intake [41].

• Carbohydrate Suitability Is Largely Influenced by the Source

Carbohydrates have to come from complex sources and fibre. Suitable foods to reduce excessive post-prandial glucose excursions are starch-free vegetables (broccoli, spinach, kale), carbohydrate-low fruit (strawberry, cranberry, avocado) and wholemeal products (oatmeal, quinoa, brown rice). The intake of refined sugars, sweets, candy, cakes, soft drinks and sugar-rich or ultra-processed foods has to be avoided or strictly limited.

• Some Knowledge about Food Glycaemic Index Is Advisable

People with T1D have to be educated to learn the glycaemic index of each food type, or at least the range within which each value is located. The glycaemic index ranks foods according to their effect on blood glucose level. As a general rule, foods with low glycaemic index should be preferred, since the increase in circulating glucose level that is achieved subsequent to their intake is more gradual and controlled. Table 3 stratifies foods according to glycaemic index. In any case, it is important to consider that this variable provides rather relative information, since the value is contingent upon food combination and the way food is cooked. Furthermore, glycaemic index calculations have been generally performed in people with no T1D. In any case, the glycaemic index is useful to decide the right moment to administer pre-prandial insulin. As a general rule, high glycaemic index foods will require longer delays between insulin injection and food intake. More information regarding this topic may be found elsewhere [45–47].

• Effect of High-Fat and High-Protein Meals

Table 3.

Foods stratified according to glycaemic index

Glycaemic index
High (≥ 70)
White bread
Potato chips
White rice
Pop corn
Sugary cereals
Sweet beverages
Honey
Medium (56–69)
Ripe bananas
Whole-wheat pasta
Canned pineapple in its juice
Oatmeal
Low (≤ 55)
Legumes (lentils, chickpeas, beans)
Apples
Raw carrots
Sugar-free natural yogurt
Milk
Nuts (almonds, walnuts)
Quinoa
Starch-free vegetables (broccoli, spinach, kale)

High-fat and high-protein meals also increase insulin requirement. Several studies demonstrated that, despite identical carbohydrate contents, high-fat and high-protein meals may enhance insulin demand [48–50]. Furthermore, their effect is additive [51]. A dose–response relationship between the amount of fat, regardless of the type, and post-prandial glycaemia, has been reported. Mealtime insulin doses may need to be increased by up to 20% for 60 g fat meals. Moreover, dual wave dosing may be required for optimisation of glycaemic responses. In these cases, the amount of insulin in the first and second injections, and the time between these, are highly dependent on the total amount of fat [52]. Further, a high-protein diet has been described to exert a positive effect on glycaemic management in people with T1D, who exhibit lower glycaemic variability and spend a shorter time in hypoglycaemia [53]. It must be remarked that high-protein diet (daily intake ≥ 1.2 g/kg/day) has been associated with improved glycaemic management after physical activity in adolescents with T1D [54].

Meal Schedule and Frequency

Although meal schedule may vary for people with T1D according to individual requirement and/or preferences, there are a few useful general guidelines that may be proposed.

• Carbohydrate Distribution throughout the Day

Carbohydrate intake has to be balanced throughout all daily meals instead of being concentrated in only one main meal.

• Coordination between Meals and Physical Activity

There must be a proper coordination between meals and physical activity. As a general rule, it is better to plan the larger meals for the first part of the day. Carbohydrate intake in the evening/night should be lower, as physical activity usually decreases at that time. Before starting any kind of physical activity, the glucose level has to be monitored. Intake of carbohydrate, which is recommended before endurance physical activity starts, will be dependent upon baseline glucose value. If this is suitable, the carbohydrate intake has to be lower than that to be consumed in the event that glucose circulating levels are under the desired range (Fig. 1).

• Coordination between Meals and Insulin Dosing

People with T1D must be aware of the importance of closely following the proposed guidelines regarding close coordination between meal schedule and insulin dosing [55].

Sequential Nutrient Intake

Sequential nutrient intake is a strategy aimed to reduce meal-induced glycaemic variation. The rule is simple: to prevent glucose peaks subsequent to meals, vegetables, proteins and fat should be ingested earlier than starchy foods or fruits [56]. By doing this, gastric emptying is delayed, which allows for a more gradual passage of carbohydrates to blood [57].

Food Cooking/Processing

Cooking times should be short, since lightly cooked foods will pass more slowly to the bloodstream. Solid foods should be chosen before liquid ones. It is important to note that keeping starchy foods for a long time (≥ 24 h) at low temperatures impairs starch absorption and thus results in reduced glycaemic responses, which may increase the risk of hypoglycaemia [58]. Vinegar and fermented or organic acid-rich foods have also been suggested to reduce glycaemic response, although their mechanism of action is not totally understood [59, 60].

Insulin Therapy

Insulin pumps, particularly in combination with glucose sensors in advanced hybrid closed loop (AHCL) systems, have undoubtedly demonstrated better glycaemic management as compared with multiple daily injections (MDI) by reducing glycaemic excursions and promoting sustained improvement of TIR, Glycaemia Risk Index (GRI) and other CGM metrics [61–65], reviewed in ⁶⁶. However, this technology is not available to many people with T1D yet. AHCL systems require user training for adequate mealtime bolusing, pump set changes, CGM device insertion and other actions. Limited access, higher costs and lack of trained staff also represent barriers for the widespread use of AHCL systems [67, 68]. Therefore, for the time being, MDI-based regimens will remain the cornerstone for the treatment of many people with T1D in the forthcoming years, and thus guidelines to reduce GV when using MDI therapies are needed. The following recommendations are focused on this population.

A correct use of basal insulin is mandatory to reduce the risk of glycaemic excursions, particularly at night-time and in-between the meals. The type of long-acting insulin might have an influence on GV. Glycaemic variability is lower in magnitude with second-generation basal insulins (glargine U300, degludec) that have a longer duration and a more protracted and sustained insulin profile than with first-generation basal insulins (glargine U100, detemir). However, despite these advantages, second-generation basal insulins have not demonstrated a clear superiority in terms of HbA1c reduction as compared with the first-generation basal insulins [69–71].

Physicians have to personalise insulin regimen according to individual characteristics and needs of people with T1D, adjusting type of insulin regime, insulin doses and number of injections when required. People with T1D need to receive appropriate diabetes education, particularly to avoid missed or mistimed insulin doses that are some of the main causes of high GV [72].

Missing Insulin Injections

Missing insulin doses or mistimed insulin administration are not uncommon in people with T1D. People with T1D using CGM systems may manually take note of time and amount of each insulin administration. For those using connected pens or caps (described below) registration of time and dosing is automated.

• Missing Long-Acting Insulin Analogues Administration

When first-generation basal insulins are being used, it is recommended to administer them at the same time of the day. However, the second generation basal insulin allows for a wider time window for insulin dosing. Glargine U300 and degludec may be administered within a time window of 4 h and up to at least 8 h or more, respectively [73, 74].

People with T1D need to know what they should do if they skip doses or administer insulin later than expected. In any case, action(s) to correct this situation should not be delayed. People with T1D should check glucose level and proceed according to their hypoglycaemia risk. If this is low, correcting doses of short-acting insulin may be used with glucose levels in the range of grade 1 hyperglycaemia or higher (> 180 mg/dL). People with T1D with a high risk of hypoglycaemia should not use rapid-acting insulin unless they present with glucose levels indicating at least grade 2 hyperglycaemia (> 250 mg/dL). It must be noted that individual insulin sensitivity factor (ISF), which indicates the estimated amount of glucose concentration that is reduced by 1 unit of rapid-acting insulin, should be used to assess appropriate correcting doses. Thereafter, the usual basal insulin dosing scheme should be resumed. It is important to educate people with T1D to avoid the injection of a double dose to compensate for the forgotten one.

• Missing Rapid-Acting Insulin Analogues Administration

In this context, rapid-acting and ultra-rapid short-acting insulin analogues present an advantage over their long-acting insulin analogues, since their correcting effect occurs earlier on. When people with T1D realise the omission in the following 2 h after the scheduled dosage time, rapid-acting insulin should be injected at the usual dose as soon as possible. When the omission is noted later than 2 h after the scheduled dosage time, rapid-acting insulin should be injected promptly. However, people with T1D may have to reduce and recalculate the dose if a new meal is close. In both situations, blood glucose levels should be closely monitored in the following hours.

If omissions have been repeated for several times in a short period of time, reporting to the health team is recommended.

Mistimed Dosing of Rapid-Acting Insulin in Relation to Meals

From CGM registries, we know now that rapid and ultra-rapid insulin should be administered 15–20 or 5–10 min before mealtime, respectively. If it is injected later, either during or shortly after the meal, post-prandial hyperglycaemia is the consequence, or there is also an increased risk of late hypoglycaemia. This recommendation is particularly relevant when eating high or moderate glycaemic index foods [55], while it may be unnecessary when eating low glycaemic foods.

Light Meals without Prior Insulin Dosing

People with T1D have to be aware of the major impact on glycaemic management exerted by even light meals with few carbohydrate content taken as snacks at mid-morning, mid-evening and so on, if insulin is not administered. The contribution of snacks to total dietary intake has been recently acknowledged, and the association of their intake with hyperglycaemia risk is stronger with MDI using connected pens or caps as compared with AHCL systems [75].

Improper Adjusting of Insulin Dose

It is important to empower people with T1D to know and use the ISF. This is estimated by dividing 1800 by the total (basal and mealtime insulins) daily dose of insulin (TDD). ISF, which is expressed in mg/dL, is useful for people with T1D to adjust the dose of rapid insulin required before each meal according to pre-meal measured and post-meal target glucose values. The adjusted dose calculated according to ISF value is added to, or subtracted from, the planned dose to cover the amount of carbohydrates of each meal [76]. Table 4 presents adjustment recommendations according to glucose level, trend and ISF in adults and children [77]. When using CGM, trend arrows such as those included in this table provide valuable information for making insulin dosing decisions, especially around mealtimes, and for preventing hypoglycaemia. While trend arrows enhance diabetes management by offering real-time feedback on glucose dynamics, their interpretation requires careful consideration and may vary among individuals, and collaborative efforts between people with T1D and healthcare providers are thus essential for optimising insulin dosing strategies on the basis of these tools.

Table 4.

Recommendations to adjust prandial insulin dose in adults and children using FreeStyle Libre-based systems

Adapted from Chico et al., J Diabetes Sci Technol 2020;14(1):155–164 [77]

Recommendations have been issued according to the glucose level and arrow trend in subjects using ISF for calculations (usually supported by tools for bolus calculation)

^aConsider starting intake with 10–20 g of fast-absorbing CHs and not administering the insulin bolus until 15–30 min after the start of intake. It is recommended to repeat the glucose reading every 30 min, until glucose level normalises and up to 2 h after bolus administration

^bThe calculated ranges are based on the median ISF used in our setting

^cA total of five ISF ranges are given. Younger people with T1D usually have higher insulin sensitivity (higher ISF), while older people with T1D have lower insulin sensitivity (lower ISF)

^dAdjustments may also be made at bedtime, but with caution when insulin administration is required. A bedtime blood glucose level of 130 mg/dL is suggested when glucose is stable (→) or changing slowly, increasing by 1–2 mg/dL per min

If glucose level < 70 mg/dL or > 180 mg/dL, add or subtract from the proposed units by standard calculation, usually provided by a bolus calculator (therefore incorporating ISF), the IUs indicated in the table

In people with T1D using insulin pens that do not allow half units to be administered, round up or down on an individual basis. Children aged 2–6 years: often use ISF ≥ 125; children aged 7–12 years: highly variable ISFs; adolescents/young adults aged 13–22 years: often use ISF 25–50 or < 50

adjust adjustment, CH carbohydrate, glu glucose, ISF insulin sensitivity factor, IU international units, min minutes, T1D type 1 diabetes

Correcting Insulin Dosing between Main Meals

In the event that the time between main meals is rather long, glucose monitoring is recommended. Corrective doses should be generally avoided unless a major error in previous carbohydrates estimation is noticed or where high glucose levels, roughly > 250 mg/dL, are detected. In these cases, insulin bolus calculators, either as mobile phone apps or integrated in connected devices or insulin pumps, may be useful for a more precise correction of hyperglycaemia, since they consider the amount of circulating active insulin. Indeed, calculations should also consider ISF [78].

Insufficient Rotation of Insulin Injection Sites

For insulin injection, a rotation around the same injection area is recommended to avoid lipodystrophies that would result in uneven insulin absorption and therefore unforeseen effects [79, 80]. By contrast, frequent change of injection areas may introduce undesired variability regarding insulin effect [81].

Connected Pens and Caps May Help to Improve Therapeutic Management

Connected pens and caps were developed to register time and dose of insulin administration. In addition, their connection with CGM systems make it possible to track dosing information with glucose profiles [82]. Use of these devices has resulted in reduced dose omissions and improved glycaemic management, higher adherence to appropriate insulin administration and more treatment satisfaction [83]. These devices are particularly useful in those situations where dose omissions may more easily occur such as with adolescents and some young adults. A minimum training by the DNE or other members of the healthcare team is usually necessary. Nevertheless, challenges for widespread implementation of connected pens remain, and barriers have been identified, namely economic burden, need for advanced educational support, minimum digital knowledge, availability of compatible mobile phones or need for updated maintenance of applications [82].

Other Causes of GV Increase

The requirement for non-stop control of glycaemic blood level, the continuous need for insulin therapy or the permanent requirement to control physical activity and dietary habits can lead people with T1D to emotional distress, which has been associated with GV [84]. There are some behaviours that may help to preserve a stable, positive mood and thus minimise the risk of distress. Firstly, people with T1D should maintain a close relationship with physicians, DNEs and nutritionists. The former should provide people with T1D with information and support to control the disease appropriately. Secondly, these should be encouraged to regularly monitor glucose values, learn to recognise those factors influencing control and know/apply those measures required to keep circulating glucose levels within the desired range. By doing this, their empowerment regarding their disease grows, with the subsequent decrease in distress. Furthermore, people with T1D should seek emotional support from relatives, friends and support groups, and learn skills such as deep breathing, meditation or yoga to feel a sense of calm and wellbeing. People with T1D should also devote daily time to their favourite activities, enabling enjoyment and relaxation. Finally, developing healthy sleeping habits is highly advisable: a direct association between inappropriate sleep quality, categorised as good or poor according to a composite variable consisting of sleep efficiency, wake after sleep onset and number of awakenings, has been associated with overnight GV [85].

Conclusions

GV remains a challenge for glucose management in T1D. Excessive GV has been associated with higher risk of CV and chronic diabetes complications, as well as high risk of hypoglycaemia. Glycaemic management can be improved by implementing simple recommendations related to physical activity, dietary habits, insulin therapy and other causes of GV increase.

Supplementary Information

The link to the electronic supplementary material is below.

Author Contributions

The idea for the article was proposed by Alejandra de Torres-Sánchez (A.T.S.) and Pedro Mezquita-Raya (P.M.R.). A.T.S., Francisco Javier Ampudia-Blasco (F.J.A.B.), Serafín Murillo (S.M.), Virginia Bellido (V.B.), Antonio J. Amor (A.J.A.) and P.M.R. contributed practical recommendations, discussed them and finally achieved consensus. A.T.S. and P.M.R. wrote the manuscript. F.J.A.B., S.M., V.B. and A.J.A. reviewed it critically.

Funding

This work was financed with funds obtained from the Foundation for Biosanitary Research of Eastern Andalusia – Alejandro Otero (FIBAO) (Biomedical Research Unit, Area 6, Endocrinology and Nutrition Department). The journal’s Rapid Service Fee was funded by FIBAO.

Declarations

Conflict of Interest

Alejandra de Torres has the following financial relationships: lectures for Novo Nordisk, received grant support from Abbott and research activities from Novo Nordisk and Eli Lilly and Company. Francisco Javier Ampudia-Blasco has served as a consultant/advisor for Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, LifeScan, MannKind Co., Medtronic, Menarini, Merck, Novartis, Novo Nordisk and Sanofi; as a speaker for Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, LifeScan, Eli Lilly, Madaus, Medtronic, Menarini, Merck, Novartis, Novo Nordisk and Sanofi; and has received grant support from Novo Nordisk and Sanofi. Virginia Bellido received consulting fees from Abbott, Eli Lilly, Novo Nordisk and Sanofi; received honoraria from Abbott, Astra Zeneca, Boehringer Ingelheim, Esteve, Eli Lilly, MSD, Mundipharma, Novo Nordisk and Sanofi; and received support to attend meetings from Abbott, Astra Zeneca, Boehringer Ingelheim, Esteve, Eli Lilly, MSD, Novo Nordisk and Sanofi. Antonio J. Amor has the following financial relationships: speaker for Novo Nordisk, Lilly, Sanofi and MSD. Pedro Mezquita-Raya has the following financial relationships: advisor on scientific boards for Abbott, Astra-Zeneca, FAES and Novo Nordisk; lectures for Astra-Zeneca, Eli Lilly and Company, FAES, Fresenius and Novo Nordisk; and research activities for Eli Lilly and Company and Novo Nordisk. Serafín Murillo declares that he has no competing interests. Antonio J. Amor is an Editorial Board member of Diabetes Therapy. Antonio J. Amor was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies as well as on previous authors’ observations and does not contain any new studies with human participants or animals performed by any of the authors.

Springer Healthcare’s Disclosure

Springer Healthcare is not responsible for the validity of the guidelines it publishes.