Introduction

The title of this chapter may have sparked a reaction in you, perhaps even evoking feelings of frustration or rage. And we understand your sentiments completely. The topic we’re about to explore is indeed controversial and potentially unsettling. But please, bear with us. We know that living with type 1 diabetes (T1D) is far from advantageous. We wrote this chapter to explore uncharted territory and stimulate discussions. To our knowledge, there are no detailed discussions on this topic anywhere else.

The discovery of insulin by Frederick Banting and Charles Best in 1921 is widely regarded as one of the most significant breakthroughs in the history of medicine, providing a dramatic example of how basic science can be translated into remarkable patient benefits [1, 2]. If we were to travel back in time to just over a century ago, a diagnosis of T1D was akin to a death sentence. Fast forward to today, and the narrative has shifted dramatically. Thanks to insulin and other advancements in diabetes technology, people with T1D can now envision a near-normal life expectancy and a high quality of life. We are now witnessing athletes with T1D pushing the boundaries of sport and even competing at the professional level [3-5] – a feat considered almost impossible until relatively recently.

Despite the advances in insulins and other diabetes therapies, managing blood glucose levels when living with T1D remains a constant challenge. It requires a lifetime of relentless decision-making to ensure that glucose levels stay in the target range and to avoid the potentially devastating effects of hypoglycaemia. Each and every day, people with T1D have to administer insulin, which can, in reality, be a potentially lethal substance if miscalculated, and their survival depends on it.

However, insulin is prohibited for individuals without diabetes in athletic competitions [6, 7]. This is because insulin has certain effects on skeletal muscle, which has led to suggestions that it can help build muscle mass and strength due to its anabolic and anti-catabolic effects. There are also suggestions that insulin may increase the recovery rate after exhaustive exercise, thus improving endurance exercise performance. The proposed mechanism for this is that abnormally high levels of insulin (i.e., supraphysiological insulin concentrations) increase the rate of muscle glycogen resynthesis (the carbohydrate stored in your muscles). Because of these proposed advantages, insulin is on the banned substances list for competitive sports, and there are accounts of insulin being misused by competitive and recreational athletes without diabetes with the aim of improving their exercise performance.

In this chapter, we will explore a provocative question: Could endurance athletes with T1D ever have a performance advantage compared to their competitors without diabetes? We will delve into topics related to athletic performance and T1D, including the impact of T1D on maximal exercise capacity, the effect of blood glucose concentration on athletic performance, and whether there are differences in muscle glycogen resynthesis rates. We aim to provide a balanced discussion of any potential benefits of exogenous insulin use and to shed light on the additional challenges that athletes with T1D must overcome to compete in sports.

To structure this exploration, this chapter is divided into four key questions:

To reiterate, we are acutely aware that aspects of this chapter touch upon sensitive and contentious topics. We do not condone doping or intend to jeopardise the careers of any athletes living with T1D. It is our firm belief that athletes with T1D have no metabolic advantage compared to their peers without diabetes, and there is no evidence to support any performance benefits for athletes with T1D. Insulin is essential for the survival of everyone living with T1D, and the risks of hypoglycaemia can be devastating both for athletic performance and overall health. Furthermore, the logistical and psychological challenges associated with T1D can make competing at a professional level extremely difficult, clearly placing these individuals at a disadvantage.

 

Question 1: Can Taking Insulin Boost Muscle Size and Endurance?

First, let's delve into the complex relationships between insulin, muscle mass, and endurance capacity and consider what this means for athletes living with T1D. We’re starting here because insulin is occasionally discussed for its role in building muscle (also referred to as anabolic and anti-catabolic processes). This has resulted in its illegal misuse as a performance-enhancing substance among some fitness enthusiasts and professional bodybuilders without T1D [8-10].

Theoretically, Why Might Someone Take Insulin to Increase Muscle Mass?

In simple terms, two factors influence muscle function and size: muscle protein synthesis (MPS) [11] and muscle protein breakdown (MPB). As their names suggest, MPS relates to processes that build muscle tissue, while MPB breaks it down. In normal physiology, these two processes fluctuate throughout the day. The balance between MPS and MPB determines whether you gain or lose muscle [12, 13]. Importantly, MPS, and to some extent MPB, can be modified by various physiological and environmental stimuli such as nutrition, exercise, and disease.

Insulin, which is present in high concentrations in the blood after a meal containing carbohydrates and/or protein, stimulates MPS and reduces MPB [13-15]. In this context, insulin's role is to use the building blocks provided by food (carbohydrates and proteins) to build and maintain tissues. Exercise training further amplifies this anabolic stimulus [12], leading to adaptations in the skeletal muscle (an increase in exercise-specific proteins; for example, exercise stimulates the synthesis of cytosolic and mitochondrial enzymes involved in carbohydrate and fat oxidation pathways), which means the individual is better adapted to match the energy production required for a given workload in subsequent exercise sessions [16-18]. This anabolic stimulus is strongest after meals containing carbohydrates and protein [19].

In addition to aiding muscles in absorbing glucose from the bloodstream, insulin also performs the following functions to enhance muscle growth:

Therefore, insulin may promote muscle growth not only by helping muscles to take in glucose but also by increasing the supply of essential nutrients and creating an ideal environment for building muscle.

But Wait… Does Using Insulin Illegally for Muscle Growth Actually Work?

Despite some reports of illegal misuse, research shows that taking insulin does not boost MPS in healthy young or older adults [31]. While studies conducted on cells [32-34] and animals [35-37] suggest that insulin could increase MPS, human studies tell a different story [38]. It appears that an increase in MPS would only occur in humans under extreme conditions involving very high insulin doses coupled with elevated levels of amino acids in the bloodstream. Achieving these conditions is risky, as it can lead to dangerous side effects like hypoglycaemia. Therefore, it appears that in practice, using insulin illegally for muscle growth is not effective and can be extremely dangerous unless very closely monitored.

Could There Be Downsides to Taking Insulin for Building Muscle Mass?

Yes, it appears that there could be several potential downsides:

While insulin plays an important role in muscle growth, misusing it for this purpose can lead to serious side effects and health risks.

 

Question 2: Is Exercising at a Higher Blood Glucose and/or Insulin Concentration Beneficial for Performance?

The idea behind this question is intriguing: Could exercising with higher blood glucose levels (hyperglycaemia) enhance performance due to the increased fuel availability from circulating glucose? The theory suggests that higher glucose levels might lead to greater glucose concentration-dependent GLUT-4 translocation and contraction-mediated glucose uptake into skeletal muscle, potentially aiding performance. Several studies have explored how varying plasma glucose and insulin concentrations affect exercise-related fuel metabolism in individuals with T1D [44-48].

 

The Impact of Blood Glucose Levels on Fuel Metabolism

A study by Jenni et al. investigated the impact of different blood glucose concentrations, with similar insulin levels, on fuel metabolism during moderate-intensity aerobic exercise in people with T1D [44]. They found that under conditions of normal glucose concentration (euglycaemia), the relative contributions of carbohydrate and lipid oxidation to overall energy production were virtually the same as in healthy individuals without T1D [49, 50]. However, in the condition with high blood glucose levels (hyperglycaemia), there was a higher rate of carbohydrate oxidation and reduced fat oxidation rates [44].

These results suggest that when glucose is within the normal range, people with T1D process fuels similarly to individuals without diabetes. However, hyperglycaemia leads to increased carbohydrate oxidation [50]. While the increase in carbohydrate oxidation with higher blood glucose might be seen as potentially beneficial for energy efficiency during exercise (generation of energy equivalents in relation to oxygen consumption, i.e., carbohydrates give relatively more energy for a given amount of oxygen), there is no proof that this actually improves performance [45]. Therefore, it’s still unclear whether this change in fuel usage has any real advantages.

 

The Role of Insulin Levels in Muscle Metabolism

Chokkalingam et al. [46] studied how different insulin levels affect whole-body and muscle metabolism during moderate-intensity exercise in people with T1D. Exercising with high insulin levels (hyperinsulinaemia) resulted in a 15% increase in total carbohydrate oxidation, with no glycogen sparing in the muscles. In this study, hyperinsulinaemia also significantly reduced fat oxidation during exercise.

A similar pattern in fuel oxidation was seen in people without T1D when glucose was ingested to induce hyperinsulinaemia [51]. Coyle and colleagues [51] found that ingesting a high glucose load before a 50-minute moderate-intensity exercise session (50% VO2max) led to high glycolytic flux (increased carbohydrate breakdown). They also found reduced intramuscular triglyceride and fatty acid oxidation rates.

Another study by Chokkalingam et al. [52] compared liver glycogen consumption during exercise in people with T1D and individuals without diabetes. Despite the significantly higher insulin and glucose levels in those with T1D, there were no differences between the groups in substrate oxidation (use of different fuels like carbs and fats), liver glycogen breakdown, or total liver glucose production. These findings suggest that high insulin levels can alter fuel usage during exercise. Still, the overall effect on substrate oxidation and liver glycogen breakdown might not differ between people with T1D and those without.

 

Limited Data: Drawing Conclusions is Challenging

Limited published data exists on the potential benefits of a higher plasma glucose concentration during endurance exercise [53]. One study in a group of individuals with T1D demonstrated that plasma glucose concentration had no impact on exercise capacity, peak power output, heart rate, respiratory exchange ratio or rate of perceived exertion [45].

The impact of exercising with an elevated glucose concentration during other exercise tests, such as time trials, which are more ecologically valid for endurance competitions, is currently unknown. However, data from studies performed in individuals without T1D suggest no performance benefit. For example, Carter et al. [54] investigated the effects of glucose infusion on glucose kinetics and performance in a group of endurance cyclists without T1D. During the carbohydrate infusion condition, plasma glucose concentration was increased to 12.4 ± 1.1 mmol/L during exercise, compared to 5.9 ± 0.3 mmol/L in the placebo arm. Despite the increased glucose availability and uptake into the tissues, there was no effect on 1-hour cycling time trial performance [54].

Based on the existing evidence, exercising with elevated blood glucose levels does not confer any performance benefits. Even if there were a benefit, maintaining such target blood glucose values during competition would be challenging, if not impossible. Moreover, exercising with an elevated blood glucose concentration may increase the need to urinate, lead to early dehydration, and increase the risk of acidosis if the hyperglycaemia is due to insufficient insulin 55. These factors may promote early fatigue, consequently decreasing endurance performance.

In summary, there is currently no evidence to support the idea that maintaining higher blood glucose and/or insulin concentrations improves endurance exercise performance. This is because no research has specifically examined these issues in people with T1D, and no study has properly investigated the effect of acute hyperglycaemia and/or hyperinsulinaemia on endurance performance in athletes with T1D. At best, we can only speculate about the potential impacts!

 

Question 3: Does Taking Insulin Affect How Quickly Muscles Replenish and Store Glycogen During Recovery?

Insulin plays a key role in glycogen metabolism and enhances glycogen synthesis through increased glucose uptake and de-phosphorylation, thus activating glycogen synthase [56-58]. Therefore, it seems logical to assume that elevated insulin concentrations above physiologically normal levels, as is often the case in people with T1D due to exogenous insulin use, would stimulate and augment muscle glycogen synthesis. This could potentially offer a performance advantage for endurance athletes where muscle glycogen stores are crucial [59, 60] or where glycogen stores need to be rapidly recovered between intense workouts.

 

The Science Behind Glycogen Synthesis in T1D

The scientific literature on glycogen synthesis rates in individuals with T1D is somewhat sparse [61-64]. One older study by Maehlum et al. [63] compared muscle glycogen production rates between individuals with and without T1D during a 12-hour recovery period after exhaustive cycling. During the recovery period, both groups consumed a high-carbohydrate diet, and the group with T1D took their regular insulin doses. Interestingly, muscle biopsy analyses revealed similar glycogen synthesis rates in both groups, even though the T1D group had much higher plasma glucose levels (20 mmol/L in the group with T1D compared to around 5 mmol/L in the group without T1D). However, insight into the participants' insulin levels would have helped to elaborate on the possible glycogen synthesis differences, but this information was unfortunately not available.

The reasons behind these similarities in glycogen synthesis rates, despite the very different glucose levels, remain unclear. It's possible that insulin resistance in the T1D group was a factor. Also, although these studies are of high academic interest, the results from these early studies that were conducted in the 1970s need to be considered in the context of the immense development of insulin formulations (i.e., the pharmacodynamic profiles of the old insulins are very different to what people use nowadays) over the last decades.

Another major limitation of Maehlum et al.’s study [63] is that no attempt was made to match food intake between participants with or without T1D. Also, participants with T1D likely didn’t receive enough insulin, as shown by their high blood glucose, which was well above 20 mmol/L (396 mg/dL). This raises the question of whether their glycogen production might have been higher with more adequate insulin doses. For these reasons, the findings of Maehlum et al. should not be taken as evidence that exogenous insulin does not have the potential to enhance muscle glycogen synthesis in people with T1D compared to those without T1D. More research is needed to draw solid conclusions.

A more recent study conducted by a group in Switzerland used advanced technology (13C-magnetic resonance spectroscopy) to compare glycogen stores in the liver and muscles of adults with and without T1D [65]. They found similar liver and intramuscular glycogen stores in both groups under standardised conditions. However, it is important to note that these investigations have only been conducted in moderately trained individuals. We still don’t know the effects of endurance training on glycogen production in athletes with T1D. This is potentially important because studies in people without T1D have demonstrated that endurance training substantially increases the rate of glycogen resynthesis after exercise [66, 67].

In an attempt to study the upper limits of glycogen storage in human muscle, Hansen et al. 68 infused two healthy male participants (without T1D) with glucose and insulin for 8 hours. During this study, their blood glucose levels reached around 21 mmol/L (378 mg/dL) with very high insulin doses (2000 µU/ml). The study suggested a maximal muscle glycogen concentration of close to 4 grams per 100 grams wet weight of muscle – which is however an extreme and unrealistic situation as, in fact, the researchers just infused very high amounts of insulin and carbohydrates to see what would happen.

Moreover, it is important to note that the study by Hansen et al. was prematurely terminated for ethical reasons due to the severe discomfort experienced by the participants. Maintaining such high blood glucose concentrations is unsafe, especially if this is repeated on multiple occasions. Therefore, it will likely impair other aspects of recovery and increase the risk of long-term complications [69].

In summary, while insulin plays a key role in glycogen synthesis, the current evidence does not conclusively show that elevated insulin levels in people with T1D confer a performance advantage through enhanced glycogen storage.

 

Question 4: How Does T1D Affect Exercise Performance or Capacity?

Although it is difficult to answer this question conclusively, some evidence suggests that people with T1D might have a lower maximal aerobic exercise capacity (VO2max) than those without diabetes of the same age and activity level [70-82]. Various cardiovascular, muscular, and metabolic issues associated with T1D have been proposed as the reasons for this [80, 81, 83-85].

A study by Richie Goulding and colleagues [80] shed some light on this topic, revealing that T1D is characterised by marked “metabolic inertia”. This condition slows the rate at which oxygen consumption adjusts to meet the body’s needs during exercise (O2 kinetics). The data indicated that this issue was mainly due to factors within the cells (particularly mitochondrial function) rather than limitations to oxygen delivery.

This idea that oxygen use dynamics (O2 kinetics) in T1D are mainly limited by internal metabolic issues rather than oxygen delivery is further supported by several lines of evidence [81, 86, 87]. For instance, Cynthia Monaco and colleagues [87] found that untrained individuals with T1D had disorganised mitochondrial cristae, increased signs of cellular clean-up (autophagic remnants), and decreased energy production when stimulated by ADP (adenosine triphosphate). These problems within the mitochondria of people with T1D may have been related, in part, to an altered balance between mitochondrial reactive oxygen species production and antioxidant defence.

But it's not all bad news! Many athletes with T1D excel in endurance sports, presumably all with a high VO2max, showing that any potential deficit can be overcome with a high level of training and adequate glycaemic management [3-5, 88-90]. Unfortunately, to our knowledge, there are no studies that have looked at the mitochondria of athletes living with T1D. Modern therapeutic approaches to glucose management make it possible for individuals with diabetes to achieve an elite-level VO2max. However, attaining high physical endurance requires constant monitoring to maintain safe glucose levels, which places an additional burden on the athlete compared to those who do not have diabetes.

If impairments in VO2max do exist in those living with T1D, they are likely related to the individual's level of metabolic control [70, 71, 84, 91] and insulin treatment. Even with the best modern approaches, insulin therapy still differs from natural physiological conditions, and this can have subtle effects on the muscle [92, 93]. Factors such as muscle oxygenation [84] and altered mitochondrial function and structure might play a role [80, 81, 83].

 

What Do We Know About Blood Glucose Levels and Exercise Performance in T1D

 

Additional Challenges for Athletes with T1D

So far in this chapter, we’ve discussed how people with T1D might conceivably have an advantage during endurance exercise compared to those without diabetes. And it’s pretty clear that there are none. But what about the disadvantages?

First, athletes with T1D must navigate a complex landscape of diabetes management decisions in addition to the demands of their sport [95, 96]. These decisions must be near-perfect to minimise the impact of suboptimal glucose levels on training adaptation and competitive performance. Even with advanced technologies such as hybrid closed-loop insulin pump systems and self-adjusted insulin dosing, decision-making around exercise remains an enormous challenge. Keeping track of all the factors, such as the time and amount of an insulin dose and its relationship to recently ingested food, can be daunting.

Another crucial aspect to consider is the devastating effect of hypoglycaemia on exercise performance and the absolute necessity of avoiding it during competition. Hypoglycaemia poses a significant risk, particularly in sports that involve high speeds or hazardous environments. As hypoglycaemia progresses, it can impair visual information processing, auditory function, and psychomotor function. These deficits can lead to slowed judgement or reaction time, increasing the risk of mistakes and injury.

If an athlete with T1D experiences hypoglycaemia during competition, it's highly unlikely that they'll recover and continue to perform competitively. Any relevant hypoglycaemia will result in an immediate reduction in performance and loss of competitiveness.

Other factors for athletes living with T1D to consider include antecedent hypoglycaemia and the effects of a previous exercise bout on glucose levels [97, 98]. Antecedent hypoglycaemia can blunt the body’s natural counter-regulatory responses to subsequent hypoglycaemia, making it more difficult to detect and manage low glucose levels during future exercise sessions. Additionally, the lingering effects of a previous exercise bout can influence glucose levels, requiring athletes to be even more vigilant in glucose management.

 

Final Reflections on a Potentially Controversial Topic

This discussion aimed to provide a balanced perspective on exercise performance and T1D, recognising that even with the most advanced technological options, T1D continues to present significant challenges.

We firmly believe that endurance athletes with T1D have no metabolic advantage compared to those without diabetes. There is no evidence that insulin helps people with T1D increase muscle mass, recover faster, or boost muscle glycogen resynthesis after exercise. Furthermore, no solid evidence exists that maintaining elevated blood glucose or insulin concentrations would improve efficiency and, therefore, endurance exercise performance.

However, it's crucial to recognise the additional challenges that athletes with T1D face in terms of logistical planning, complex decision-making, and the constant need to avoid hypoglycaemia. These challenges place them at a clear disadvantage compared to people without diabetes.

Despite the remarkable advancements in insulins, diabetes technologies, and other therapeutic agents, the day-to-day management of T1D remains a formidable challenge due to the constant and relentless effort required to manage glycaemia. The fact that there are individuals with T1D not only competing at the professional level but also excelling and reaching the podium in their chosen sports is a testament to their resilience, determination, and adaptability.