Study background and disease burden
Type 2 diabetes mellitus (T2DM) represents a leading global health challenge, characterized by chronic hyperglycaemia and associated metabolic dysregulation that increase risk for cardiovascular disease, renal failure, and neuropathy. Effective glycaemic control remains paramount to reducing such complications. Exercise is a cornerstone non-pharmacologic intervention for optimizing glucose metabolism, with high-intensity interval training (HIIT) gaining traction for its potent metabolic effects and time efficiency. However, interindividual variability in exercise responses and emerging insights into circadian rhythms complicate exercise recommendations.
The circadian system governs daily physiological fluctuations including hormone secretion, glucose tolerance, and inflammatory status. Cortisol, a glucocorticoid with pronounced morning peaks, influences gluconeogenesis and immune function. Inflammation markers such as C-reactive protein (CRP) also show diurnal variation and are closely tied to insulin resistance. Understanding how the timing of exercise interacts with these circadian changes could improve personalized exercise prescriptions in T2DM. Furthermore, regular meal timing may modulate glycaemic variability, an important dimension of glucose control linked to adverse outcomes.
This context frames the recent crossover trial by Keller et al. investigating effects of exercise timing on glucose and inflammatory markers in individuals with and without T2DM using continuous glucose monitoring and controlled diet interventions.
Study design
This randomized crossover study included 48 participants: 24 with clinically diagnosed T2DM (12 men, 12 women) and 24 matched controls without diabetes (12 men, 12 women). Participants underwent two sessions of supervised high-intensity interval exercise (HIIT), scheduled in the morning at 09:00 hours and in the afternoon at 16:00 hours, spaced at least 7 days apart to minimize carryover effects.
Standardized meals were administered the day before, the day of, and the day following each exercise session to control for dietary influence on glucose measurements. Continuous glucose monitoring (CGM) captured 24-hour glucose profiles to assess the primary outcome of glycaemic control. Glycaemic variability was quantified using mean amplitude of glycaemic excursions (MAGE). Inflammatory and stress biomarkers—C-reactive protein (CRP), NT-proBNP (a marker associated with cardiac stress), and cortisol—were measured to understand systemic responses related to exercise timing and metabolic status.
Key findings
The study revealed nuanced findings emphasizing the circadian modulation of glucose metabolism and inflammation in T2DM:
– Overall 24-hour glucose levels: No significant differences emerged between morning and afternoon HIIT across the entire cohort, indicating that exercise timing does not alter daily integrated glucose exposure markedly.
– Post-exercise glucose excursions: In T2DM participants, blood glucose increased during the immediate two hours following morning exercise (significant in both men and women), while afternoon exercise did not significantly affect glucose levels post-exercise. This suggests impaired acute glucose regulation after morning HIIT in T2DM.
– Glycaemic variability: The controlled 3-day meal intervention yielded significant reductions in MAGE in men and women with T2DM, underscoring the beneficial impact of regular, standardized eating patterns on glucose fluctuations. No such improvement was observed in non-diabetic individuals.
– Cortisol patterns: Both diabetic and non-diabetic participants exhibited higher cortisol levels in the morning than in the afternoon, consistent with known circadian rhythms. Elevated morning cortisol likely contributes to greater glucose production and insulin resistance during morning hours.
– Inflammatory markers: In T2DM, CRP and NT-proBNP levels were significantly higher in the morning compared to the afternoon, indicating a pro-inflammatory and cardiovascular stress state in early day. This contrasts with relatively lower inflammation in the afternoon.
Collectively, these data imply that morning HIIT may acutely increase glycaemia and inflammatory stress in T2DM, whereas afternoon exercise avoids these spikes and may better support glucose regulation.
Expert commentary
Keller et al. provide compelling evidence that circadian biology critically influences exercise efficacy in T2DM. Elevated morning cortisol and inflammation likely impair insulin-mediated glucose disposal post-exercise in the morning. This aligns with broader literature identifying cortisol’s catabolic effects and CRP as mediators of insulin resistance.
Though 24-hour glucose profiles were unaffected by exercise timing, the post-exercise hyperglycaemia observed with morning activity might promote adverse metabolic stress if sustained chronically. The study’s crossover design and controlled diet strengthen causal inference, though limited sample size and short intervention period may constrain generalizability.
The findings complement emerging guidelines suggesting personalization of exercise prescriptions, potentially favoring afternoon or early evening sessions in T2DM for optimal metabolic benefit. Furthermore, the demonstrated benefit of consistent meal timing on reducing glycaemic variability advocates for combined lifestyle strategies.
Future research should investigate mechanistic pathways linking circadian hormones, immune activation, and skeletal muscle glucose uptake during varied exercise timing. Additionally, exploring whether pharmacologic modulation of morning cortisol could enhance morning exercise efficacy represents a promising avenue.
Conclusion
This study underscores the importance of considering time of day for high-intensity exercise in individuals with type 2 diabetes. Afternoon HIIT appears superior to morning sessions in preventing post-exercise hyperglycaemia and heightened inflammation, phenomena driven by circadian fluctuations in cortisol and inflammatory markers. Complementary dietary strategies involving consistent meal timing further reduce glycaemic variability, enhancing glucose management.
Clinicians should incorporate circadian biology principles when advising exercise timing in T2DM care. These findings highlight the need for integrative approaches aligning exercise prescriptions with hormonal rhythms and dietary control to maximize therapeutic benefit. Ongoing studies will further clarify the chronobiology of exercise metabolism and inform precision medicine strategies in diabetes management.
References
1. Keller MJ, Brady AJ, Smith JAB, et al. Inflammatory markers and blood glucose are higher after morning vs afternoon exercise in type 2 diabetes. Diabetologia. 2025 Sep;68(9):2023-2035. doi: 10.1007/s00125-025-06477-5. Epub 2025 Jun 28.
2. Van Cauter E, Polonsky KS, Scheen AJ. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev. 1997 Jun;18(5):716-38.
3. Kirschbaum C, Kudielka BM, Gaab J, et al. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med. 1999 Jul-Aug;61(2):154-62.
4. Benedict C, Brooks SJ, Fatoni A, et al. A positive relationship between cortisol awakening response and physical activity in healthy individuals. Stress. 2019;22(2):145-151.
5. Solomon TPJ, Haus JM, Marchetti CM, et al. Detraining-induced insulin resistance occurs with reductions in skeletal muscle GLUT4 and glycemic control: role of exercise timing and intensity. J Clin Endocrinol Metab. 2014;99(11):E2445–E2452.