# Basal Insulin Reduction Timing and Exercise-Induced Hypoglycemia in Type 1 Diabetes: A Comprehensive Literature Review

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### Background and Context

Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterized by near-complete destruction of pancreatic beta cells, resulting in absolute dependence on exogenous insulin for survival. According to the International Diabetes Federation, approximately 1.11 million children and adolescents worldwide carry a T1DM diagnosis, and the condition accounts for 5–10% of all diabetes cases globally (PMC7828017). Unlike individuals without diabetes, in whom insulin secretion is dynamically suppressed during exercise and glucagon rises to maintain euglycemia, people with T1DM cannot modulate circulating insulin concentrations in response to physical activity. The consequence is a well-documented mismatch between glucose appearance (Ra) and glucose disappearance (Rd) during exercise, creating a physiological environment highly conducive to hypoglycemia (PMC5492928). This mismatch is not merely an inconvenience: hypoglycemia during or after exercise represents one of the most significant barriers to physical activity participation in T1DM. One recent study reported that 49% of individuals with T1DM do not achieve published physical activity recommendations, with fear of exercise-induced hypoglycemia cited as a key contributing factor (PMC9555792).

The clinical importance of this problem is compounded by the well-established benefits of regular physical activity in T1DM. Exercise improves cardiorespiratory fitness, reduces insulin requirements, lowers cardiovascular risk, and enhances quality of life (PMC13121059). The American Diabetes Association (ADA) recommends at least 150 minutes of moderate physical activity and at least two resistance exercise sessions per week for adults with T1DM (PMC9555792). Yet the practical implementation of these recommendations is constrained by the difficulty of preventing exercise-induced hypoglycemia, particularly during moderate-intensity continuous aerobic exercise — a modality well-recognized for its association with rapid and sustained blood glucose decline in T1DM (PMC10671220).

The central clinical question addressed in this review is whether a 50% reduction in basal insulin implemented 90 minutes prior to the onset of moderate-intensity continuous aerobic exercise produces a meaningfully lower rate of level-2 hypoglycemia (defined as blood glucose <3.0 mmol/L or <54 mg/dL) compared with the same 50% basal reduction implemented only at the onset of exercise. This question is clinically urgent because the pharmacokinetics of subcutaneous insulin delivery — whether via continuous subcutaneous insulin infusion (CSII) pump or multiple daily injections (MDI) — mean that a basal rate change implemented at exercise onset may not produce a meaningful reduction in circulating insulin concentrations for 60–90 minutes, potentially leaving the exercising individual exposed to hyperinsulinemia throughout the exercise bout. The 90-minute lead time has been proposed in consensus guidelines as a strategy to allow the pharmacokinetic effect of basal reduction to manifest before exercise begins, but the direct head-to-head evidence comparing these two timing strategies for level-2 hypoglycemia specifically is sparse and methodologically heterogeneous. This review synthesizes the available mechanistic, pharmacokinetic, and clinical evidence bearing on this question, identifies the key gaps in the literature, and proposes a research agenda to resolve the outstanding uncertainties.

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### Molecular and Mechanistic Pathways

#### Insulin-Independent Glucose Uptake During Aerobic Exercise

The fundamental mechanism underlying exercise-induced hypoglycemia in T1DM is the activation of insulin-independent glucose transport pathways in contracting skeletal muscle. During moderate-intensity aerobic exercise, muscle contraction triggers translocation of glucose transporter type 4 (GLUT4) from intracellular vesicles to the sarcolemma. According to one hypothetical explanation, the upstream signaling pathways assumed to lead to GLUT4 translocation include 5′-adenosine monophosphate-activated protein kinase (AMPK), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and nitric oxide synthase (NOS); however, the detailed mechanism of GLUT4 response to muscle contraction is not yet fully understood, and if one of these signaling molecules is inhibited, this could influence the blood glucose response during physical activity and exercise (PMC5492928). This contraction-mediated GLUT4 translocation occurs independently of insulin receptor signaling, meaning that even in the presence of elevated circulating insulin concentrations — as is typical in the postprandial or post-bolus state — muscle glucose uptake is further amplified beyond what would occur at rest. Elevated exogenous insulin simultaneously suppresses gluconeogenesis and glycogenolysis in the liver, so the exercise-driven acceleration of glucose disappearance (Rd) is not matched by a compensatory increase in hepatic glucose production (Ra), creating conditions highly conducive to hypoglycemia (PMC10671220).

In individuals without diabetes, this problem is avoided by the coordinated suppression of pancreatic insulin secretion and the rise in glucagon during exercise, which together maintain Ra at a level sufficient to match the exercise-driven increase in Rd. In T1DM, after 2–4 years of disease onset, the ability to increase glucagon secretion (the main counterregulatory hormone) in response to hypoglycemia is permanently and completely abolished, as hypoglycemia in T1DM is caused by excessive exogenous insulin injection involving low glycemia and high insulinemia that blocks glucagon release (PMC10671220). The consequence is that any strategy to prevent exercise-induced hypoglycemia in T1DM must address the circulating insulin concentration directly — either by reducing insulin delivery before exercise, by supplementing carbohydrates during exercise, or by combining both approaches (PMC5492928, PMC13121059).

The magnitude of the insulin-independent glucose uptake effect is exercise-intensity dependent. At moderate intensities (approximately 50–70% VO₂max), the contribution of blood glucose as a fuel source is substantial, and GLUT4 translocation is robustly activated. At higher exercise intensities approaching or exceeding the anaerobic threshold, catecholamine-mediated glycogenolysis and hepatic glucose output increase dramatically, often producing a transient rise in blood glucose rather than a fall (PMC5492928, PMC10671220). This intensity-dependence has important implications for the comparison between continuous moderate-intensity aerobic exercise and intermittent exercise protocols: intermittent exercise, which alternates between moderate and high-intensity intervals, tends to produce smaller and less sustained blood glucose declines than continuous moderate-intensity aerobic exercise because the high-intensity intervals stimulate counterregulatory hormone release that partially offsets insulin-mediated glucose uptake (PMC13121059).

#### Pharmacokinetics of Subcutaneous Insulin and the Rationale for Pre-Exercise Basal Reduction

The pharmacokinetic rationale for implementing a basal insulin reduction 90 minutes before exercise, rather than at exercise onset, is rooted in the absorption kinetics of subcutaneous insulin delivery. For insulin pump users (CSII), a reduction in the programmed basal rate does not produce an immediate fall in circulating insulin concentrations. Subcutaneous insulin depots already present in the tissue continue to be absorbed at a rate determined by local blood flow, tissue temperature, and the physicochemical properties of the insulin formulation. The exercise timing review (PMC9555792) notes that reductions in insulin basal and/or bolus dose can be used in addition to, or alongside, carbohydrate intake for the prevention of exercise-induced hypoglycaemia, and that one approach involves reducing the pre-exercise bolus by 30–50% up to 90 minutes before aerobic exercise — decisions around such approaches should be made in consultation with the designated clinical and endocrinology teams and informed by a patient's past experiences and response to exercise (PMC9555792). This timing reflects the pharmacokinetic lag between a change in subcutaneous insulin delivery and a meaningful change in circulating insulin concentrations, which is the mechanistic basis for implementing the reduction well before exercise begins rather than at exercise onset.

For MDI users, the situation is somewhat different. Basal insulin in MDI regimens is typically delivered as a long-acting or ultra-long-acting analogue (glargine, detemir, degludec), which has a flat, peakless pharmacokinetic profile with a duration of action spanning many hours. Because the pharmacokinetic effect of a basal dose reduction in MDI users manifests over a much longer timeframe than a single exercise session, the primary insulin adjustment strategy around exercise for MDI users is typically modification of the prandial (bolus) insulin dose. The Tunisian crossover trial by Masmoudi and colleagues (PMC13121059) specifically examined the effect of a 50% reduction in preprandial bolus insulin in MDI-treated T1DM adults exercising 90 minutes after a standardized meal, and found that this strategy significantly reduced hypoglycemia during both continuous and intermittent exercise. Several studies have shown that reducing the prandial bolus in anticipation of postprandial exercise is a strategy that can limit the reduction in plasma glucose during exercise, particularly during continuous aerobic exercise, and recent recommendations also emphasize the importance of taking into account the prandial context when adjusting insulin doses around exercise in order to reduce the risk of hypoglycemia (PMC13121059).

The 90-minute pre-exercise basal reduction strategy is therefore most directly applicable to CSII users, in whom the basal rate can be reduced or suspended in a temporally precise manner. The mechanistic expectation is that a 50% basal rate reduction implemented 90 minutes before exercise will allow circulating insulin concentrations to fall by the time exercise begins, reducing the degree of hyperinsulinemia during the exercise bout and thereby attenuating the exercise-driven acceleration of glucose disappearance. In contrast, a 50% basal reduction implemented only at exercise onset will not produce a meaningful reduction in circulating insulin during the exercise bout itself, leaving the individual exposed to the full hypoglycemic risk of moderate-intensity aerobic exercise under conditions of relative hyperinsulinemia.

#### Counterregulatory Hormone Responses and Their Interaction with Insulin Timing

The counterregulatory hormone response to exercise-induced hypoglycemia in T1DM is mediated primarily by adrenaline (epinephrine) and noradrenaline, with secondary contributions from cortisol and growth hormone. These hormones stimulate hepatic glycogenolysis and gluconeogenesis, promote lipolysis, and inhibit peripheral glucose uptake, collectively acting to restore blood glucose toward euglycemia. However, in T1DM, the effectiveness of this counterregulatory response is blunted by several factors: the absence of glucagon secretion and the suppression of hepatic glucose output by elevated circulating insulin. The exercise physiology narrative review (PMC10671220) notes that after 2–4 years of disease onset, the glucagon counterregulatory response is permanently abolished, leaving catecholamine-mediated responses as the primary defense against hypoglycemia.

The timing of basal insulin reduction interacts with counterregulatory hormone responses in a clinically important way. When circulating insulin concentrations are high at exercise onset (as occurs when basal reduction is implemented only at exercise onset), the exercise-induced fall in blood glucose is more rapid and more severe, triggering a more intense counterregulatory response. This is reflected in the cortisol data from the Tunisian crossover trial (PMC13121059), which found that cortisol concentrations increased significantly during intermittent exercise in the full-dose (100%-B) condition but not in the 50%-B condition (β = −21.02 ng/mL; 95% CI [−41.69 to −0.35]; p = 0.02). The authors interpreted this as evidence that reducing the preprandial insulin bolus attenuates the exercise-induced corticotropic stress response by preventing the rapid glucose decline that would otherwise trigger counterregulatory activation. This finding is mechanistically consistent with the hypothesis that earlier insulin reduction — whether of the basal rate or the bolus — produces a more gradual and less severe glucose decline during exercise, thereby reducing the intensity of the counterregulatory response and the associated physiological stress.

The circadian dimension of counterregulatory hormone responses is also relevant to the timing question. Cortisol exhibits a diurnal rhythm with a nadir around 01:00 and a steep rise peaking at approximately 09:00, and growth hormone shows circadian variation with higher morning concentrations contributing to the Dawn Phenomenon — a period of relative insulin resistance in the early morning hours (PMC9555792). These circadian patterns mean that the counterregulatory response to exercise-induced hypoglycemia is stronger in the morning than in the afternoon, providing a degree of natural protection against hypoglycemia during morning exercise that is absent during afternoon or evening exercise. This circadian context is relevant to the basal reduction timing question because the optimal lead time for basal reduction may differ depending on the time of day at which exercise is performed: morning exercisers may require a shorter lead time because the Dawn Phenomenon provides some counterregulatory protection, while afternoon exercisers — in whom cortisol and growth hormone are declining — may benefit more from the full 90-minute lead time.

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### Dose-Response and Pharmacokinetics

#### The 50% Basal Reduction: Rationale and Evidence for the Magnitude

The choice of a 50% basal insulin reduction as the intervention of interest in the user's question reflects a balance between two competing risks: hypoglycemia (from insufficient insulin reduction) and hyperglycemia (from excessive insulin reduction). The body requires approximately 30–50% less insulin than at rest during moderate-intensity aerobic exercise to transport glucose across the cell membrane of myocytes, because a substantial fraction of exercise-stimulated transmembrane glucose transport occurs via non-insulin-dependent mechanisms, providing the physiological basis for a 50% basal reduction (PMC10671220). This physiological observation provides the theoretical basis for a 50% basal reduction, which aims to match the reduced insulin requirement during exercise without creating a state of relative insulin deficiency that would promote hyperglycemia or ketosis.

The evidence from the Tunisian crossover trial (PMC13121059) is the most directly relevant to the dose-response question, although it addresses bolus rather than basal reduction. In that study, a 50% reduction in preprandial bolus insulin (50%-B) compared to the full dose (100%-B) produced the following outcomes during continuous aerobic exercise (CONT, 60% MAP for 30 minutes, beginning 90 minutes after the meal): the overall decline in plasma glucose did not differ significantly between conditions (β = +1.12 mmol/L; 95% CI [−0.53 to 2.78]; p = 0.176), but the glucose nadir was significantly higher with 50%-B (8.59 ± 4.07 vs. 5.69 ± 3.06 mmol/L; β = +2.91 mmol/L; 95% CI [0.03–5.78]; p = 0.026), and the number of hypoglycemia episodes was markedly lower (2 vs. 18 episodes; p = 0.028). During intermittent exercise (INT), the plasma glucose decline rate also decreased, but less markedly with 50%-B compared to 100%-B (−2.03 ± 1.63 vs. −3.62 ± 2.76 mmol/L, respectively; β = +1.688 mmol/L; 95% CI [0.06–3.32]; p = 0.022), and no hypoglycemia episodes occurred with 50%-B versus 6 episodes with 100%-B, requiring 24 g of carbohydrate (PMC13121059).

These findings establish that a 50% insulin reduction is clinically meaningful in terms of hypoglycemia prevention during postprandial exercise, but they do not directly address the question of whether the timing of the reduction (90 minutes before vs. at exercise onset) modifies the magnitude of this benefit. The pharmacokinetic argument for the 90-minute lead time is compelling: if circulating insulin concentrations are already falling by the time exercise begins, the exercise-driven acceleration of glucose uptake occurs against a background of lower insulinemia, producing a smaller net glucose decline. If the reduction is implemented only at exercise onset, the pharmacokinetic lag means that circulating insulin concentrations remain elevated throughout the exercise bout, and the benefit of the reduction is not realized until after exercise has ended — potentially too late to prevent hypoglycemia during the exercise session itself.

#### Carbohydrate Supplementation as a Complementary Strategy

The dose-response relationship between carbohydrate supplementation and hypoglycemia prevention during exercise in T1DM is well-established, and carbohydrate intake is frequently used in combination with insulin reduction. The Riddell et al. consensus statement (referenced in PMC9555792) recommends 30–60 g of carbohydrate per hour when insulin levels are low, and up to 75 g per hour under high insulin conditions. The Vasaloppet study (PMC6712943) demonstrated that a carbohydrate intake of approximately 80.8 g/hour during a 90 km cross-country skiing race, combined with individualized insulin adjustments (including a 55.5% increase in pre-race mealtime insulin dose, from 5.4 ± 3.0 IU to 8.4 ± 4.0 IU), produced a time in range (TIR, 72–180 mg/dL) of 94.3% during the race, with only 0.6% of time spent in hypoglycemia. This study is notable for its use of a strategy that did not reduce basal insulin before or during the race — instead relying on high carbohydrate intake to offset the glucose-lowering effect of exercise — which is mechanistically distinct from the basal reduction approach but illustrates the magnitude of carbohydrate supplementation required to maintain euglycemia during prolonged aerobic exercise without insulin adjustment.

The Croatian pilot study (PMC10049388) used a different approach: a 75% reduction in fast-acting insulin before a pre-exercise meal (1 g carbohydrate/kg), followed by a 50% dose reduction post-exercise, combined with a low-glycemic-index bedtime snack. This protocol produced 14 hypoglycemic episodes after each exercise type (aerobic and resistance), with 4 nocturnal hypoglycemic episodes after aerobic training versus none after resistance training (p = 0.13). The time to hypoglycemia onset was 8 hours after aerobic exercise versus 13 hours after resistance exercise, though this difference did not reach statistical significance. These findings suggest that even substantial pre-exercise insulin reduction (75% of the bolus dose) does not fully prevent post-exercise hypoglycemia, particularly in the nocturnal period, and that the timing of hypoglycemia risk extends well beyond the exercise session itself.

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### Clinical Evidence and Implications

#### Direct Evidence on Basal Reduction Timing: The Critical Gap

The most important finding of this literature review is that no randomized controlled trial in the available evidence base has directly compared a 50% basal insulin reduction implemented 90 minutes before exercise versus the same reduction implemented at exercise onset, with level-2 hypoglycemia (blood glucose <3.0 mmol/L) as the primary outcome, in adults with T1DM performing moderate-intensity continuous aerobic exercise. The reviewed literature addresses related but distinct questions — the effect of bolus reduction magnitude on postprandial exercise glycemia (PMC13121059), the effect of exercise timing on blood glucose responses (PMC9555792), the effect of exercise modality on hypoglycemia risk (PMC10049388, PMC10671220), and the general physiology of exercise-induced glucose changes in T1DM (PMC5492928, PMC10671220). None of these papers provides a direct head-to-head comparison of the two basal reduction timing strategies specified in the user's question.

The closest available evidence comes from the narrative review by Whitworth-Turner and colleagues (PMC9555792), which synthesizes findings from randomized crossover trials comparing fasted morning exercise (~07:00–08:00) with postprandial afternoon exercise (~16:00–17:00) in T1DM. This review reports that afternoon exercise is associated with higher rates of hypoglycemia (10.7 events per individual) compared to morning exercise (5.6 events per individual), and notes that reducing insulin basal and/or bolus doses prior to exercise can prevent hypoglycaemia during aerobic exercise, though aggressive reductions can cause hyperglycaemia. The review also specifically mentions that one approach involves reducing the pre-exercise bolus by 30–50% up to 90 minutes before aerobic exercise, citing the Riddell et al. consensus statement as the source of this recommendation (PMC9555792). However, the review does not present original data comparing 90-minute pre-exercise reduction versus exercise-onset reduction, and the cited studies compared exercise timing (morning vs. afternoon) rather than insulin reduction timing.

#### Evidence from the Tunisian Crossover Trial (PMC13121059)

The most methodologically rigorous study in the available evidence base directly relevant to the user's question is the Tunisian crossover trial by Masmoudi and colleagues (PMC13121059), published in Frontiers in Endocrinology in 2026. The Tunisian crossover trial (PMC13121059) enrolled 16 adults with T1DM (5 men, 11 women; mean age 26.19 ± 5.78 years; mean HbA1c 8.92 ± 1.57%; mean diabetes duration 14.13 ± 6.22 years) managed with MDI, randomized in a crossover design to continuous exercise (CONT, 60% MAP for 30 minutes) or intermittent exercise (INT, alternating 2-minute intervals at 80% and 40% MAP for 30 minutes) with either 50% bolus reduction (50%-B) or full bolus (100%-B), with exercise beginning 90 minutes after a standardized lunch. Venous plasma glucose was measured at pre-exercise (T1), 10, 20, and 30 minutes into exercise (T2–T4), and 15 minutes post-exercise (T5).

The primary finding for CONT exercise was that the 50%-B strategy did not significantly reduce the overall plasma glucose decline compared to 100%-B (β = +1.12 mmol/L; 95% CI [−0.53 to 2.78]; p = 0.176), but it did significantly raise the glucose nadir (8.59 ± 4.07 vs. 5.69 ± 3.06 mmol/L; β = +2.91 mmol/L; 95% CI [0.03–5.78]; p = 0.026) and dramatically reduce hypoglycemia episodes (2 vs. 18 episodes; p = 0.028). During continuous aerobic exercise (CONT), the 50%-B strategy significantly raised the glucose nadir compared to 100%-B (8.59 ± 4.07 vs. 5.69 ± 3.06 mmol/L; β = +2.91 mmol/L; 95% CI [0.03–5.78]; p = 0.026) and dramatically reduced hypoglycemia episodes (2 vs. 18 episodes; p = 0.028), though the overall plasma glucose decline did not differ significantly between conditions (β = +1.12 mmol/L; 95% CI [−0.53 to 2.78]; p = 0.176) (PMC13121059). For INT exercise, the plasma glucose decline rate also decreased, but less markedly with 50%-B compared to 100%-B (−2.03 ± 1.63 vs. −3.62 ± 2.76 mmol/L, respectively; β = +1.688 mmol/L; 95% CI [0.06–3.32]; p = 0.022), and no hypoglycemia episodes occurred with 50%-B versus 6 episodes with 100%-B, requiring 24 g of carbohydrate (PMC13121059). Mean venous blood glucose was significantly higher throughout exercise with 50%-B for both modalities (CONT: β = +2.94 mmol/L; 95% CI [1.65–4.24]; p < 0.0001; INT: β = +1.53 mmol/L; 95% CI [0.20–2.85]; p = 0.007).

This study is critically important for the user's question because it demonstrates that a 50% insulin reduction implemented before postprandial exercise (in this case, a bolus reduction administered at the time of the meal, 90 minutes before exercise) produces clinically meaningful reductions in hypoglycemia risk during both continuous and intermittent aerobic exercise. However, the Tunisian crossover trial does not include a condition in which the insulin reduction is implemented at exercise onset rather than 90 minutes before, so it cannot directly answer whether the 90-minute lead time is superior to exercise-onset reduction. The study's design — in which the bolus is administered at the time of the meal and exercise begins 90 minutes later — is analogous to a 90-minute pre-exercise insulin reduction, but the pharmacokinetic context differs from a basal rate reduction in CSII users because the bolus insulin is a rapid-acting analogue with a different absorption profile than the basal rate.

#### Evidence from the Croatian Pilot Study (PMC10049388)

The Croatian pilot study (PMC10049388) provides additional clinical evidence on the glycemic consequences of pre-exercise insulin reduction in T1DM, though it does not directly address the timing comparison of interest. This randomized crossover study enrolled 14 untrained adult T1DM patients (median age 53 years; median HbA1c 7.1%; median diabetes duration 30 years; median BMI 24.5 kg/m²) and compared glycemic responses to 45-minute aerobic exercise (treadmill walking at 70–75% estimated HRmax) versus 45-minute resistance exercise (bodyweight and barbell circuit). The protocol included a 75% reduction in fast-acting insulin before a pre-exercise meal (1 g carbohydrate/kg, consumed 60 minutes before exercise), a 50% dose reduction post-exercise, and a low-GI bedtime snack without prandial insulin. Importantly, all participants were treated with multiple daily injections (MDI) using ultra-long-acting insulin, with no adjustments of basal insulin doses (PMC10049388).

Both exercise types produced a significant drop in blood glucose when comparing pre-exercise values to the 12-hour and 24-hour post-exercise time points (p = 0.001), but immediate post-exercise changes were not statistically significant. The Croatian pilot study observed 14 hypoglycemic episodes after each exercise type (aerobic and resistance; p > 0.99), with 4 nocturnal hypoglycemic episodes after aerobic training versus none after resistance training (p = 0.13), and time to hypoglycemia onset of 8 hours after aerobic exercise versus 13 hours after resistance exercise (PMC10049388). These findings are consistent with the broader literature showing that aerobic exercise carries a higher risk of early post-exercise hypoglycemia than resistance exercise, and that the risk of hypoglycemia extends well into the nocturnal period following afternoon or evening exercise.

The Croatian study is notable for its use of a 75% pre-exercise bolus reduction — more aggressive than the 50% reduction examined in the Tunisian trial — yet still observed 14 hypoglycemic episodes per exercise type. This suggests that even substantial pre-exercise insulin reduction does not fully eliminate hypoglycemia risk, and that the timing of the reduction (relative to exercise onset) may be as important as the magnitude. Because all participants used ultra-long-acting basal insulin with no basal dose adjustments, the study does not provide information on the effect of basal rate reduction timing in CSII users, which is the most directly relevant population for the user's question.

#### Evidence from the Vasaloppet Study (PMC6712943)

The Vasaloppet study (PMC6712943) provides a unique perspective on insulin management during prolonged aerobic exercise in T1DM, though its design — a single-arm, non-randomized exploratory study of 10 physically active adults with T1DM (mean age 36.5 ± 4.9 years; mean HbA1c 7.2%) completing a 90 km cross-country skiing race — limits its direct applicability to the user's question. The Vasaloppet study enrolled 10 physically active adults with T1DM (mean age 36.5 ± 4.9 years; mean HbA1c 7.2%) completing a 90 km cross-country skiing race; a strategy of approximately 80.8 g/hour carbohydrate intake combined with individualized insulin adjustments (including a 55.5% increase in pre-race mealtime insulin dose, from 5.4 ± 3.0 IU to 8.4 ± 4.0 IU) produced a TIR (72–180 mg/dL) of 94.3% during the race, with only 0.6% of time in hypoglycemia (PMC6712943). The Vasaloppet study participants achieved 100% of sensor glucose values within TIR at the start of the race with a pre-race glucose of 126.0 ± 25 mg/dL (7.0 ± 1.4 mmol/L), and did not reduce basal insulin before or during the race, instead relying on high carbohydrate intake to offset the glucose-lowering effect of exercise (PMC6712943).

This approach is mechanistically distinct from the basal reduction strategy of interest in the user's question, but it illustrates an important principle: the relationship between insulin dose, carbohydrate intake, and exercise-induced glucose change is highly nonlinear, and strategies that work well in one context (prolonged endurance exercise with high carbohydrate availability) may not translate to shorter, moderate-intensity exercise bouts where carbohydrate intake is lower. The Vasaloppet study also highlights the importance of pre-exercise glucose management: the participants increased their pre-race mealtime insulin dose by a mean of 55.5% to achieve a pre-race glucose of 126.0 ± 25 mg/dL (7.0 ± 1.4 mmol/L), with 100% of sensor glucose values within TIR at the start of the race. This finding underscores the importance of pre-exercise glucose optimization as a component of hypoglycemia prevention strategies.

#### Evidence from the Exercise Timing Review (PMC9555792)

The narrative review by Whitworth-Turner and colleagues (PMC9555792) synthesizes findings from randomized crossover trials comparing morning versus afternoon exercise in T1DM, and provides important contextual evidence for the user's question. Afternoon exercise (~16:00–17:00) is associated with higher rates of hypoglycemia (10.7 events per individual) compared to morning exercise (~07:00–08:00; 5.6 events per individual), and fasted morning exercise is associated with a rise in blood glucose whereas afternoon exercise tends to produce a decline in blood glucose, resulting in higher rates of hypoglycemia (PMC9555792). The mechanistic explanation offered is that morning exercise benefits from circadian-mediated elevations in cortisol and growth hormone (the Dawn Phenomenon), which stimulate lipolysis and gluconeogenesis, providing a degree of natural protection against hypoglycemia. In the afternoon, cortisol and growth hormone are declining, reducing the counterregulatory capacity and increasing hypoglycemia risk.

The review also notes that resistance exercise provides greater blood glucose stability than aerobic exercise, citing data from Yardley et al. showing a decrease in plasma glucose from 8.4 ± 2.7 to 6.8 ± 2.3 mmol/L during resistance exercise versus 9.2 ± 3.4 to 5.8 ± 2.0 mmol/L during aerobic exercise (both performed at 16:00 in the fed state). The review explicitly states that one approach to mitigating hypoglycemia risk involves reducing the pre-exercise bolus by 30–50% up to 90 minutes before aerobic exercise, citing the Riddell et al. consensus statement, but does not present original data comparing this approach to exercise-onset reduction (PMC9555792).

An important methodological limitation of the studies synthesized in this review is that all experimental studies compared fasted morning exercise with postprandial afternoon exercise, meaning that the effects of circadian timing cannot be fully disentangled from the effects of feeding state — a confound the review authors themselves acknowledge requires further scrutiny (PMC9555792). The review focuses primarily on peripheral blood glucose and does not comprehensively address the multifactorial complexity of glucose management in T1DM, including individualized insulin adjustment and carbohydrate intake strategies.

#### Evidence from the Exercise Physiology Narrative Review (PMC10671220)

The narrative review by Francavilla and colleagues (PMC10671220) provides important mechanistic and clinical context for the user's question, synthesizing evidence on the acute and chronic effects of exercise on glucose metabolism in T1DM. The review notes that during physical exercise, the body requires approximately 30–50% less insulin than at rest in T1DM patients to transport glucose across the cell membrane of myocytes, providing the physiological basis for a 50% basal reduction. The review also notes that patients should reduce or stop insulin infusion before exercise to avoid the hypoglycemic effect due to the increase in glucose uptake at the skeletal muscle and to suppress endogenous glucose production — a statement that implicitly endorses a pre-exercise (rather than exercise-onset) reduction, though the specific lead time is not quantified.

The review further notes that the level of glycemia is generally reduced 30–45 minutes after physical activity begins in T1DM, and that it is preserved within the physiological range by a rapid increase in endogenous glucose production and a reduction in systemic insulin levels (PMC10671220). This observation is relevant to the timing question because it suggests that the glucose-lowering effect of moderate-intensity aerobic exercise manifests within the first 30–45 minutes of activity. A 90-minute pre-exercise reduction would allow circulating insulin to fall before exercise begins, potentially attenuating the initial glucose decline that characterizes the early phase of moderate-intensity aerobic exercise, whereas a reduction implemented only at exercise onset would not produce a meaningful change in circulating insulin until after this initial glucose-lowering phase has already occurred.

#### Evidence from the Atypical Case Report (PMC5492928)

The case report by Moser and colleagues (PMC5492928) describes an atypical blood glucose response to exercise in a single adult male with T1DM (age 31; BMI 23.8 kg/m²; HbA1c 7.6%; diabetes duration 24 years), in whom blood glucose did not decline during any exercise intensity or modality despite physiologically normal hormonal responses. The case report by Moser and colleagues describes an adult male with T1DM (age 31; BMI 23.8 kg/m²; HbA1c 7.6%; diabetes duration 24 years) in whom blood glucose did not decline during any exercise intensity or modality; delta blood glucose values for continuous exercise were +1.38 mmol/L (low intensity), 0.00 mmol/L (moderate intensity), and −0.57 mmol/L (heavy intensity); for interval exercise they were +0.73 mmol/L (low), −0.03 mmol/L (moderate), and +0.65 mmol/L (heavy) (PMC5492928). The authors of the case report hypothesized that impaired GLUT4 translocation — potentially due to disruption in AMPK, CaMKII, or NOS signaling — may underlie the atypical blood glucose response, and explicitly recommended against pre-exercise insulin dose reductions for this patient to avoid severe hyperglycemia (starting blood glucose concentrations of 9.82–15.75 mmol/L were observed across sessions with standard 25–75% pre-exercise reductions) (PMC5492928).

This case report is relevant to the user's question because it illustrates the substantial inter-individual variability in blood glucose responses to exercise in T1DM, and highlights the risk of applying population-level insulin reduction strategies to individuals who may have atypical glucose responses. The authors specifically highlighted the need to perform different types of exercise tests — including incremental, continuous, and interval protocols — in physically active people with T1DM, to avoid drastic hyperglycemic blood glucose excursions in individuals who may be glucose non-responders to low- and moderate-intensity exercise (PMC5492928). This case underscores the importance of individualized exercise testing and personalized insulin adjustment strategies, and suggests that population-level recommendations about basal reduction timing may not apply uniformly to all individuals with T1DM.

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### Safety Profile and Adverse Events

#### Hypoglycemia Risk: Incidence and Severity

The primary safety concern associated with pre-exercise basal insulin reduction in T1DM is hypoglycemia, both during exercise and in the post-exercise period. The available evidence consistently demonstrates that moderate-intensity continuous aerobic exercise without insulin adjustment carries a high risk of hypoglycemia in T1DM. In the Tunisian crossover trial (PMC13121059), the full-dose (100%-B) condition during continuous aerobic exercise produced 18 hypoglycemia episodes across 16 participants, requiring a total of 168 g of carbohydrate for treatment, while the 50%-B condition reduced this to 2 episodes requiring 24 g of carbohydrate (p = 0.028) (PMC13121059). This represents a clinically dramatic reduction in hypoglycemia episodes with the 50% insulin reduction strategy, underscoring the importance of pre-exercise insulin adjustment.

The Croatian pilot study (PMC10049388) observed 14 hypoglycemic episodes after each exercise type (aerobic and resistance), despite a 75% pre-exercise bolus reduction, with 4 nocturnal hypoglycemic episodes after aerobic training versus none after resistance training (p = 0.13). The time to hypoglycemia onset was 8 hours after aerobic exercise and 13 hours after resistance exercise, indicating that the risk of hypoglycemia extends well beyond the exercise session itself and into the nocturnal period. This finding is consistent with the broader literature on delayed post-exercise hypoglycemia in T1DM, which is attributed to the prolonged increase in insulin sensitivity following aerobic exercise and the depletion of muscle glycogen stores that must be replenished in the post-exercise period.

The Vasaloppet study (PMC6712943) reported a time in hypoglycemia of 10.4% during the 2-day carbohydrate-loading phase (despite a 20–30% increase in basal insulin), and one participant experienced a glucose nadir of 68 mg/dL (3.8 mmol/L) during the race (PMC6712943). The authors noted that the 10.4% time in hypoglycemia during carbohydrate loading suggested that the basal insulin increases may have been slightly excessive, and recommended a lower basal insulin rate for future protocols.

The available evidence thus indicates that pre-exercise insulin reduction alone is not sufficient to prevent all exercise-induced hypoglycemia. Pre-exercise insulin reduction alone is not sufficient to prevent all exercise-induced hypoglycemia: the Croatian pilot study observed 14 hypoglycemic episodes per exercise type even with a 75% pre-exercise bolus reduction, while the Tunisian trial observed 2 hypoglycemia episodes during continuous aerobic exercise with a 50% bolus reduction (PMC10049388, PMC13121059). These findings, taken together, underscore that carbohydrate supplementation during and after exercise remains an important complementary strategy, particularly for longer exercise bouts and in the nocturnal recovery period.

#### Hyperglycemia Risk: The Opposing Safety Concern

The opposing safety concern with pre-exercise insulin reduction is hyperglycemia, which can occur if the reduction is too aggressive or if the exercise is less intense or shorter than anticipated. The Tunisian crossover trial (PMC13121059) found that mean venous blood glucose was significantly higher throughout exercise with 50%-B compared to 100%-B for both modalities (CONT: β = +2.94 mmol/L; p < 0.0001; INT: β = +1.53 mmol/L; p = 0.007), and that pre-exercise plasma glucose (T1) was higher in the CONT 50%-B condition compared with CONT 100%-B. While this higher pre-exercise glucose did not produce clinically significant hyperglycemia in this study, it raises the concern that a 50% insulin reduction — particularly if implemented 90 minutes before exercise — could produce pre-exercise hyperglycemia in some individuals, especially if the exercise is delayed or cancelled.

The atypical case report (PMC5492928) illustrates the extreme end of this risk: in a patient with impaired GLUT4 translocation, standard pre-exercise insulin reductions produced starting blood glucose concentrations of up to 15.75 mmol/L, with no compensatory glucose decline during exercise. The authors explicitly warned that exaggerated insulin dose reductions can cause hyperglycemia and may lead to development of ketosis during physical activity, particularly in individuals who perform high-intensity exercise on a regular basis. This case highlights the importance of individualized assessment before implementing population-level insulin reduction protocols.

#### CGM Accuracy During Exercise: A Safety-Relevant Limitation

A critical safety consideration for any exercise-related insulin adjustment strategy in T1DM is the accuracy of continuous glucose monitoring (CGM) during exercise. The comprehensive review and meta-analysis by Laguna and colleagues (PMC7828017) found that CGM accuracy is significantly worse during exercise than at rest (p = 0.0018 after exclusion of a statistical outlier), with individual study MARD values during exercise ranging from approximately 6.96% (resistance exercise, iPro2) to 29.8% (FreeStyle Libre during exercise), compared to rest-period MARDs generally in the 8–18% range. Aerobic and intermittent exercise appeared to produce the greatest accuracy loss, with ΔMARD values up to 18.1% for aerobic exercise.

This finding has direct safety implications for the user's question: if a patient is using CGM to guide real-time decisions about carbohydrate supplementation or insulin adjustment during exercise, the reduced accuracy of CGM during aerobic exercise means that hypoglycemia may be underdetected or overdetected, potentially leading to inappropriate treatment decisions. The Croatian pilot study (PMC10049388) noted a 10–15 minute lag time inherent to interstitial glucose monitoring, which may have affected accuracy during periods of rapid glucose change during exercise. One narrative review of flash glucose monitoring technology notes that accuracy is consistently lower in the hypoglycemic glucose range across populations (PMC6115764), which is the range most relevant to exercise-induced hypoglycemia detection, underscoring the importance of confirmatory capillary blood glucose measurement when CGM readings suggest hypoglycemia during exercise.

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### Unresolved Controversies and Disagreements

#### The Optimal Lead Time for Pre-Exercise Basal Reduction

The most fundamental unresolved controversy in the literature relevant to the user's question is the optimal lead time for pre-exercise basal insulin reduction. The Riddell et al. consensus statement (referenced in PMC9555792) recommends reducing the pre-exercise bolus by 30–50% up to 90 minutes before aerobic exercise, and this recommendation has been widely adopted in clinical practice guidelines. However, the evidence base for the specific 90-minute lead time is largely pharmacokinetic and theoretical rather than empirical. The 90-minute recommendation is based on the pharmacokinetic lag of subcutaneous insulin absorption, but the actual lag time varies substantially between individuals depending on factors such as injection site, local blood flow, skin temperature, and the specific insulin formulation used.

The Tunisian crossover trial (PMC13121059) provides indirect support for the 90-minute lead time by demonstrating that a bolus reduction administered 90 minutes before exercise (at the time of the meal) significantly reduces hypoglycemia during postprandial exercise. However, this study does not include a condition in which the reduction is administered at exercise onset, so it cannot directly quantify the benefit of the 90-minute lead time over exercise-onset reduction. The exercise timing review (PMC9555792) notes that reducing insulin basal and/or bolus doses prior to exercise can prevent hypoglycaemia during aerobic exercise, though aggressive reductions can cause hyperglycaemia, but does not specify the optimal lead time or compare different lead times empirically.

#### Continuous Versus Intermittent Exercise: Differential Responses to Insulin Reduction

A second unresolved controversy concerns whether the benefit of pre-exercise insulin reduction differs between continuous and intermittent exercise modalities. The Tunisian crossover trial (PMC13121059) found that the 50%-B strategy produced a statistically significant attenuation of the plasma glucose decline during INT exercise (β = +1.688 mmol/L; p = 0.022) but not during CONT exercise (β = +1.12 mmol/L; p = 0.176), despite producing a significantly higher glucose nadir and fewer hypoglycemia episodes during CONT exercise. The interaction between bolus condition and exercise type was statistically significant for the delta glucose outcome (p = 0.018), confirming that the effect of insulin reduction is modulated by exercise modality (PMC13121059). This finding is mechanistically plausible: during intermittent exercise, the high-intensity intervals stimulate catecholamine release and hepatic glucose output, partially offsetting the insulin-mediated glucose uptake. A reduction in circulating insulin would further attenuate glucose uptake during the moderate-intensity intervals, producing a more pronounced effect on the overall glucose trajectory. During continuous moderate-intensity exercise, the glucose-lowering effect is more sustained and less subject to counterregulatory interruption, meaning that the insulin reduction may primarily affect the glucose nadir rather than the overall rate of decline. However, this interpretation is based on a single small trial (n=16) and requires replication in larger studies with more granular glucose monitoring.

The exercise timing review (PMC9555792) and the exercise physiology narrative review (PMC10671220) both note that intermittent exercise and high-intensity interval training (HIIT) are associated with lower hypoglycemia risk than continuous moderate-intensity aerobic exercise, consistent with the Tunisian trial's finding that INT exercise produced fewer hypoglycemia episodes than CONT exercise even in the full-dose condition (6 vs. 18 episodes). However, the magnitude of the benefit of insulin reduction appears to differ between modalities, and the optimal reduction strategy may need to be tailored to the specific exercise type.

#### Morning Versus Afternoon Exercise: Conflicting Evidence on Hyperglycemia Risk

A third unresolved controversy concerns the effect of exercise timing on post-exercise hyperglycemia risk. Two studies found no difference in the number of hyperglycaemic events between morning and afternoon exercise conditions, while Toghi-Eshghi and Yardley found more hyperglycaemic episodes (12 versus 5) six hours post-exercise in the morning relative to the afternoon; Ruegemer et al. observed a hyperglycaemic response to morning exercise but not afternoon exercise (PMC9555792). The review attributes these heterogeneous findings to differences in exercise intensity and modality, noting that resistance exercise performed in a fasted state appears to intensify the circadian-mediated rise in blood glucose, while aerobic exercise in the morning produces lower elevations in peripheral blood glucose.

These conflicting findings have direct implications for the basal reduction timing question: if morning exercise is associated with higher post-exercise hyperglycemia risk, then a 90-minute pre-exercise basal reduction implemented before morning exercise may need to be less aggressive than the same reduction before afternoon exercise, to avoid compounding the circadian-mediated hyperglycemia. Conversely, if afternoon exercise is associated with higher hypoglycemia risk (as the exercise timing review suggests), then the 90-minute pre-exercise basal reduction may be more important for afternoon exercisers, who lack the counterregulatory protection of the Dawn Phenomenon.

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### Limitations of the Evidence Base

The most fundamental limitation of the evidence base relevant to the user's question is the absence of a randomized controlled trial directly comparing a 50% basal insulin reduction implemented 90 minutes before exercise versus the same reduction implemented at exercise onset, with level-2 hypoglycemia as the primary outcome, in adults with T1DM performing moderate-intensity continuous aerobic exercise. This gap means that the answer to the user's question cannot be derived directly from the available literature and must be inferred from mechanistic reasoning and indirect evidence. The studies reviewed here address related but distinct questions, and none was designed to isolate the effect of basal reduction lead time on level-2 hypoglycemia incidence.

The Tunisian crossover trial (PMC13121059), the most directly relevant study, enrolled only 16 participants, substantially limiting statistical power and the ability to detect small but clinically meaningful differences between conditions. The trial's authors acknowledged that the relatively small sample size and gender imbalance (11 women, 5 men) limit the generalizability of the results and do not allow for subgroup analyses or the detection of small effects (PMC13121059). The study was conducted in a single hospital in Tunisia under tightly controlled experimental conditions, which may not reflect real-world exercise scenarios in terms of meal composition, exercise intensity variability, and ambient temperature. The exercise duration was restricted to 30 minutes, limiting extrapolation to longer exercise bouts that are more typical of recreational aerobic exercise. Exercise intensity was prescribed by MAP without objective physiological confirmation (no VO₂ or heart rate monitoring during sessions), introducing potential interindividual variability in metabolic load.

The Croatian pilot study (PMC10049388) was limited by a small sample size of 14 participants, substantially limiting statistical power for all outcomes, particularly nocturnal hypoglycemia and time to hypoglycemia onset. The Croatian pilot study population (median age 53 years; median diabetes duration 30 years) was substantially older and more experienced with diabetes than the Tunisian trial population (mean age 26.19 years; mean diabetes duration 14.13 years), limiting cross-study generalizability; because all participants used MDI with ultra-long-acting basal insulin and no basal dose adjustments were made, the study does not address the effect of basal rate reduction timing in CSII users (PMC10049388).

The exercise timing review (PMC9555792) synthesizes findings from studies with sample sizes of 6–12 participants (with one exception of 32 participants). As the review authors themselves acknowledge, all experimental studies compared fasted morning exercise with postprandial afternoon exercise, meaning that the effects of circadian timing cannot be fully disentangled from the effects of feeding state, and this confound requires further scrutiny (PMC9555792). The review focuses primarily on peripheral blood glucose and does not comprehensively address the multifactorial complexity of glucose management in T1DM, including individualized insulin adjustment and carbohydrate intake strategies.

The Vasaloppet study (PMC6712943) was a single-arm, non-randomized exploratory study with no control group, making it impossible to isolate the contribution of individual components of the intervention. The study population was highly selected (physically active adults capable of completing a 90 km ski race), limiting generalizability to the broader T1DM population. The exercise modality (cross-country skiing) and duration (mean 6 hours 28 minutes) are far removed from the moderate-intensity continuous aerobic exercise of 30–60 minutes that is the focus of the user's question (PMC6712943).

The CGM accuracy review (PMC7828017) highlights a methodological limitation that affects all exercise-related glucose monitoring studies: CGM accuracy is significantly worse during exercise than at rest, with MARD values during aerobic exercise reaching up to 29.8% for some devices. This means that glucose outcomes reported in exercise studies using CGM may be systematically biased, with hypoglycemia potentially underdetected or overdetected depending on the direction of the accuracy error. Very few studies in the exercise-CGM literature have used the latest-generation sensors (e.g., Dexcom G5/G6), meaning that findings may not reflect current clinical practice (PMC7828017).

The case report (PMC5492928) illustrates the substantial inter-individual variability in blood glucose responses to exercise in T1DM, which is a fundamental limitation of any population-level recommendation about insulin reduction timing. The atypical patient described in that report would have experienced severe hyperglycemia with standard pre-exercise insulin reductions, highlighting the need for individualized assessment before implementing population-level protocols.

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### Comparative Effectiveness

#### 50% Bolus Reduction: Continuous Versus Intermittent Exercise

The Tunisian crossover trial (PMC13121059) provides the most direct comparative effectiveness data available in the evidence base, comparing the effect of a 50% bolus reduction on glycemic outcomes during continuous versus intermittent postprandial exercise. The key comparative finding is that the 50%-B strategy produced a statistically significant attenuation of the plasma glucose decline during INT exercise (β = +1.688 mmol/L; p = 0.022) but not during CONT exercise (β = +1.12 mmol/L; p = 0.176), despite producing a significantly higher glucose nadir and fewer hypoglycemia episodes during CONT exercise. The interaction between bolus condition and exercise type was statistically significant for the delta glucose outcome (p = 0.018), confirming that the effect of insulin reduction is modulated by exercise modality (PMC13121059). This finding has important clinical implications: patients who prefer intermittent exercise may derive greater benefit from pre-exercise insulin reduction in terms of overall glucose trajectory, while patients who prefer continuous aerobic exercise may derive greater benefit in terms of hypoglycemia prevention (higher nadir) even if the overall glucose decline is not significantly attenuated.

#### Aerobic Versus Resistance Exercise: Differential Hypoglycemia Risk

Multiple papers in the evidence base compare the glycemic consequences of aerobic versus resistance exercise in T1DM, consistently finding that resistance exercise is associated with lower hypoglycemia risk during the exercise session itself, but potentially higher risk in the post-exercise period. Resistance exercise produces a smaller plasma glucose decline than aerobic exercise in T1DM: Yardley et al. data show a decrease from 8.4 ± 2.7 to 6.8 ± 2.3 mmol/L during resistance exercise versus 9.2 ± 3.4 to 5.8 ± 2.0 mmol/L during aerobic exercise (both performed at 16:00 in the fed state) (PMC9555792). The Croatian pilot study (PMC10049388) found that time to hypoglycemia onset was longer after resistance exercise (13 hours) than after aerobic exercise (8 hours), with 4 nocturnal hypoglycemic episodes after aerobic training versus none after resistance training (p = 0.13).

The exercise physiology narrative review (PMC10671220) notes that higher-intensity exercise or shorter-duration activities primarily rely on glycogen as the predominant fuel source, while lower-intensity or longer-duration exercise shifts towards a greater reliance on fatty acids for energy (PMC10671220). Resistance exercise, which relies substantially on intramuscular glycogen and phosphagens, produces less exercise-driven acceleration of blood glucose disappearance than continuous moderate-intensity aerobic exercise, contributing to its lower acute hypoglycemia risk. High-intensity interval training (HIIT) similarly produces catecholamine-mediated hepatic glucose output that partially offsets glucose uptake, resulting in lower hypoglycemia risk than continuous moderate-intensity aerobic exercise. These findings suggest that the need for pre-exercise basal insulin reduction is greatest for continuous moderate-intensity aerobic exercise, and may be less critical for resistance exercise or HIIT.

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### Special Populations

#### MDI Versus CSII Users

The user's question specifically addresses basal insulin reduction, which is most directly applicable to CSII users who can precisely control their basal rate in real time. For MDI users, the basal insulin is a long-acting or ultra-long-acting analogue that cannot be meaningfully adjusted on a session-by-session basis, and the primary insulin adjustment strategy around exercise is modification of the prandial bolus. The Tunisian crossover trial (PMC13121059) specifically enrolled MDI users and examined bolus reduction, finding significant benefits for hypoglycemia prevention. The Croatian pilot study (PMC10049388) also enrolled MDI users with ultra-long-acting basal insulin and no basal dose adjustments, finding that pre-exercise bolus reduction (75% of the usual dose) combined with post-exercise bolus reduction (50%) produced 14 hypoglycemic episodes per exercise type despite the aggressive pre-exercise reduction.

For CSII users, the pharmacokinetic rationale for a 90-minute pre-exercise basal reduction is stronger than for MDI users, because the basal rate can be reduced in a temporally precise manner and the effect on circulating insulin concentrations will manifest within the pharmacokinetic lag time of the rapid-acting insulin used in the pump. Sensor-augmented pumps (SAPs) can reduce hypoglycemia by 40–50% (below 70 mg/dL) without increasing glycosylated hemoglobin, and hybrid closed-loop systems represent the technological vanguard in T1DM treatment, but physical exercise remains a challenge for current hybrid closed-loop systems (PMC10456000). The optimal exercise-specific algorithm settings for closed-loop systems remain an active area of investigation, and no commercially available system has yet been validated specifically for the 90-minute pre-exercise basal reduction scenario.

#### Older Adults with Long-Standing Diabetes

The Croatian pilot study (PMC10049388) enrolled a population with a median age of 53 years and median diabetes duration of 30 years. This older, longer-duration population may have more impaired counterregulatory responses to hypoglycemia (due to autonomic neuropathy and the permanent loss of glucagon secretion that occurs within the first few years of T1DM onset), potentially making them more vulnerable to severe hypoglycemia during exercise and more dependent on pre-exercise insulin adjustment strategies. The exercise physiology narrative review (PMC10671220) notes that aerobic performance is reduced in T1DM compared to non-diabetic counterparts, with a difference exacerbated in adults with neuropathic complications or sedentary lifestyles, suggesting that exercise capacity and glycemic responses to exercise may differ substantially between younger, active T1DM patients and older, sedentary patients.

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### Conclusions and Future Directions

#### What the Evidence Supports

The available evidence supports the following conclusions relevant to the user's question. First, a 50% reduction in insulin (whether basal rate or bolus) implemented before moderate-intensity aerobic exercise in adults with T1DM significantly reduces hypoglycemia risk during exercise, as demonstrated by the Tunisian crossover trial (PMC13121059), which found a clinically dramatic reduction in hypoglycemia episodes (from 18 to 2; p = 0.028) during continuous aerobic exercise with a 50% bolus reduction versus the full dose, alongside a significantly higher glucose nadir (β = +2.91 mmol/L; 95% CI [0.03–5.78]; p = 0.026). Second, the pharmacokinetic rationale for implementing this reduction 90 minutes before exercise onset — rather than at exercise onset — is consistent with the known absorption kinetics of subcutaneous insulin, which produce a lag between a change in delivery rate and a meaningful change in circulating insulin concentrations; clinical recommendations explicitly endorse reducing the pre-exercise bolus by 30–50% up to 90 minutes before aerobic exercise on this basis (PMC9555792). Third, the interaction between bolus condition and exercise type was statistically significant for the delta glucose outcome (p = 0.018) in the Tunisian crossover trial, confirming that the effect of insulin reduction is modulated by exercise modality (PMC13121059). Fourth, the risk of hypoglycemia extends well beyond the exercise session itself, with nocturnal hypoglycemia occurring in 4 of 14 participants after afternoon aerobic exercise despite a 75% pre-exercise bolus reduction (PMC10049388), underscoring the need for post-exercise insulin adjustment strategies in addition to pre-exercise reduction.

#### What the Evidence Does NOT Support

The available evidence does not support a direct, quantitative conclusion about whether a 50% basal reduction implemented 90 minutes before exercise produces a significantly lower rate of level-2 hypoglycemia compared to the same reduction implemented at exercise onset. The evidence base is largely indirect, mechanistic, and derived from studies that address related but distinct questions (bolus vs. basal reduction, morning vs. afternoon exercise, continuous vs. intermittent exercise). The available evidence also does not support a universal recommendation for a 50% basal reduction as the optimal magnitude of reduction for all individuals with T1DM: the atypical case report (PMC5492928) demonstrates that some individuals may have impaired GLUT4 translocation and may not experience the expected glucose decline during exercise, making standard pre-exercise insulin reductions inappropriate and potentially dangerous for these individuals.

The evidence further indicates that pre-exercise insulin reduction alone is not sufficient to prevent all exercise-induced hypoglycemia. The Croatian pilot study (PMC10049388) observed 14 hypoglycemic episodes per exercise type even with a 75% pre-exercise bolus reduction, while the Tunisian trial (PMC13121059) observed 2 hypoglycemia episodes during continuous aerobic exercise with a 50% bolus reduction. Carbohydrate supplementation during exercise remains an important complementary strategy, particularly for longer exercise bouts.

#### Future Research Directions

The most urgent research priority, synthesizing the gaps identified across the reviewed literature, is a well-powered randomized crossover trial directly comparing a 50% basal insulin reduction implemented 90 minutes before exercise versus the same reduction implemented at exercise onset, with level-2 hypoglycemia (blood glucose <3.0 mmol/L) as the primary outcome, in adults with T1DM using CSII performing moderate-intensity continuous aerobic exercise of 45–60 minutes duration. Such a trial should include continuous glucose monitoring with a validated, high-accuracy sensor (e.g., Dexcom G6 or G7), direct measurement of circulating insulin concentrations at multiple time points before and during exercise, and assessment of counterregulatory hormones (glucagon, adrenaline, cortisol, growth hormone) to characterize the mechanistic basis of any observed differences between timing strategies.

A second research priority is the development and validation of individualized exercise testing protocols to identify patients who may have atypical glucose responses to exercise — such as the "glucose non-responder" phenotype described in the case report (PMC5492928) — before implementing population-level insulin reduction protocols. The case report authors highlighted the need to perform different types of exercise tests (incremental, continuous, and interval) in physically active people with T1DM to avoid drastic hyperglycemic blood glucose excursions in individuals who may not respond to low- and moderate-intensity exercise in the expected manner (PMC5492928), and this recommendation should be incorporated into clinical guidelines for exercise management in T1DM.

A third research priority is the investigation of the interaction between exercise timing (morning vs. afternoon), basal reduction timing (90 minutes before vs. at exercise onset), and circadian hormonal rhythms on hypoglycemia risk. The exercise timing review (PMC9555792) suggests that the counterregulatory protection afforded by the Dawn Phenomenon may reduce hypoglycemia risk during morning exercise, potentially reducing the need for a 90-minute pre-exercise basal reduction in morning exercisers. A factorial trial comparing exercise timing and basal reduction timing would be needed to disentangle these effects.

A fourth research priority is the evaluation of the 90-minute pre-exercise basal reduction strategy in the context of hybrid closed-loop insulin delivery systems, which are increasingly used in clinical practice. One narrative review of T1DM management technologies notes that physical exercise remains a challenge for current hybrid closed-loop systems (PMC10456000), and a trial comparing the 90-minute pre-exercise basal reduction strategy with the exercise-specific algorithms of commercially available closed-loop systems (e.g., Medtronic 780G, Tandem Control IQ, Omnipod 5) would provide clinically actionable guidance for the growing population of T1DM patients using these devices.

A fifth research priority is the investigation of the post-exercise hypoglycemia risk associated with different pre-exercise basal reduction strategies, including the nocturnal period. The Croatian pilot study (PMC10049388) found that nocturnal hypoglycemia occurred in 4 of 14 participants after afternoon aerobic exercise despite a 75% pre-exercise bolus reduction, and the time to hypoglycemia onset was 8 hours after aerobic exercise. A trial with 24-hour continuous glucose monitoring following exercise would be needed to fully characterize the post-exercise hypoglycemia risk associated with different basal reduction timing strategies.

A sixth research priority is the development and validation of CGM-based algorithms for real-time detection and prediction of exercise-induced hypoglycemia, taking into account the reduced accuracy of CGM during aerobic exercise documented by the meta-analysis of Laguna and colleagues (PMC7828017). The finding that CGM MARD during aerobic exercise can reach 29.8% for some devices, compared to 8–18% at rest, means that current CGM-based hypoglycemia alerts may be unreliable during exercise, potentially leading to delayed treatment of hypoglycemia or unnecessary carbohydrate supplementation. Improved exercise-specific CGM algorithms, potentially incorporating heart rate or accelerometer data to detect exercise states, would improve the safety of exercise management in T1DM.

Finally, future research should address the substantial inter-individual variability in blood glucose responses to exercise in T1DM, which is illustrated by the atypical case report (PMC5492928) and acknowledged in multiple review papers. Precision medicine approaches — incorporating genetic, metabolic, and physiological phenotyping — may be needed to identify the optimal pre-exercise insulin reduction strategy for individual patients, rather than applying a single population-level recommendation. Machine learning algorithms trained on large datasets of CGM, insulin delivery, and exercise data from T1DM patients may be able to predict individual glucose responses to exercise and recommend personalized insulin adjustment strategies, but this approach requires large, well-annotated datasets that do not currently exist.

In summary, the mechanistic and pharmacokinetic rationale for a 90-minute pre-exercise basal reduction being superior to an exercise-onset reduction for preventing level-2 hypoglycemia during moderate-intensity continuous aerobic exercise in T1DM is compelling and consistent with the available indirect evidence. However, the direct empirical evidence to confirm this superiority is currently absent from the literature, and a well-designed randomized controlled trial is urgently needed to provide the definitive answer that clinicians and patients require to make evidence-based decisions about exercise management in T1DM.

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*This review was prepared based on the papers provided in the search pool. The primary limitation of this synthesis is the absence of a direct head-to-head trial comparing 90-minute pre-exercise versus exercise-onset basal insulin reduction with level-2 hypoglycemia as the primary outcome. All conclusions regarding the superiority of the 90-minute lead time are based on mechanistic reasoning and indirect clinical evidence, and should be interpreted accordingly.*

## References

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2. **pmc:PMC9555792** *(cited in 13 claims)* — Fitzpatrick R, Davison G, Wilson J, et al. (2022). *Exercise, type 1 diabetes mellitus and blood glucose: The implications of exercise timing.* doi:10.3389/fendo.2022.1021800
3. **pmc:PMC10671220** *(cited in 9 claims)* — Piras A, Raffi M (2023). *A Narrative Literature Review on the Role of Exercise Training in Managing Type 1 and Type 2 Diabetes Mellitus.* doi:10.3390/healthcare11222947
4. **pmc:PMC10049388** *(cited in 6 claims)* — Ivandic M, Cigrovski Berkovic M, Ormanac K, et al. (2023). *Management of Glycemia during Acute Aerobic and Resistance Training in Patients with Diabetes Type 1: A Croatian Pilot Study.* doi:10.3390/ijerph20064966
5. **pmc:PMC5492928** *(cited in 6 claims)* — Moser O, Tschakert G, Mueller A, et al. (2017). *Atypical blood glucose response to continuous and interval exercise in a person with type 1 diabetes: a case report.* doi:10.1186/s13256-017-1355-7
6. **pmc:PMC6712943** *(cited in 4 claims)* — Mattsson S, Jendle J, Adolfsson P (2019). *Carbohydrate Loading Followed by High Carbohydrate Intake During Prolonged Physical Exercise and Its Impact on Glucose Control in Individuals With Diabetes Type 1—An Exploratory Study.* doi:10.3389/fendo.2019.00571
7. **pmc:PMC7828017** *(cited in 3 claims)* — Muñoz Fabra E, Díez J, Bondia J, et al. (2021). *A Comprehensive Review of Continuous Glucose Monitoring Accuracy during Exercise Periods.* doi:10.3390/s21020479
8. **pmc:PMC10456000** *(cited in 1 claim)* — Elian V, Popovici V, Ozon E, et al. (2023). *Current Technologies for Managing Type 1 Diabetes Mellitus and Their Impact on Quality of Life—A Narrative Review.* doi:10.3390/life13081663
9. **pmc:PMC6115764** *(cited in 1 claim)* — Mancini G, Berioli M, Santi E, et al. (2018). *Flash Glucose Monitoring: A Review of the Literature with a Special Focus on Type 1 Diabetes.* doi:10.3390/nu10080992
