Exercise Timing and the Circadian Clock in Individuals With Type 2 Diabetes and Those at Risk

Many investigations have been done to determine the exercise that can elicit the greatest benefits on glycemic control and metabolic health, with findings suggesting that incorporation of higher intensity and longer duration of exercise prescribed may eliminate much of the "non-response" observed following exercise training. Even with the incorporation of higher intensity exercise into interventions aimed at improving glycemic control in individuals with type 2 diabetes mellitus (T2DM), the investigators and others continue to have mixed results, with not all individuals with T2DM obtaining benefits in insulin sensitivity and glycemic control to a given exercise training program.

Many of the metabolic processes involved in glucose homeostasis, such as insulin production and sensitivity, undergo daily circadian rhythms, controlled by cellular clock machinery located both centrally and peripherally (i.e. skeletal muscle). However, in adults with T2DM, these diurnal rhythms are impaired, with reduced insulin sensitivity in the morning, which is thought to contribute to the fasting hyperglycemia (i.e., "dawn phenomenon") observed in these individuals. Exercise may be a non-photic cue that can amplify or alter these metabolic rhythms. It has been suggested that skeletal muscle metabolic inflexibility in metabolic disorders such as overweight/obesity and T2DM is associated with reduced mitochondrial fatty acid oxidative capacity. It has been demonstrated that exercise can increase mitochondrial oxidative capacity by remodeling mitochondrial morphology and dynamics. It is unknown if potential differences in metabolic flexibility can be found in response to exercise at different times of the day.

Most of the experimental evidence originates from animal models with only 3 studies performed in humans with T2DM, which displayed conflicting results.

To overcome the shortcomings in the literature, the main objective of this research project is to assess the effects of performing exercise at different times of the day on glycemic control and related outcomes on the inter-individual response variability in glycemic control and related metabolic health parameters in two distinct populations: 1) individuals with T2DM on the most common mono-hyperglycemic drug therapy (i.e., metformin); and 2) age-matched sedentary overweight/obese individuals, where glycemic control is known to deteriorate, hence increasing the risk of developing insulin resistance and T2DM.

To detect a predicted mean difference in 24-hour area under the curve (AUC) continuous glucose measure (CGM)-based glucose of 1.0 mmol/L with a within patient standard deviation (SD) of 0.85 mmol/L (24) considering a type I error of 5%, a power of 80%, and a 30% dropout rate, the investigators calculated a required sample size of 17 individuals for each group, making a total sample of 34 individuals (Group 1: T2DM; Group 2: age-matched overweight/obese).

Participants will be recruited through: flyers and posters in pharmacies, health centers and supermarkets; ads via national radios and television programs; and the database of the Portuguese Association for the Protection of Diabetics (APDP).

To improve exercise adherence, the following strategies will be implemented:

* Inform that participation in the study is completely voluntary and that all data will be confidential
* Inform people that they will be able to do physical exercise (guided by professionals) for free
* Inform that they will have individual follow-up by a personal trainer
* Inform that they will carry out several analyzes and exams free of charge that will contribute to the control of their health status
* Inform that they will be able to control their blood glucose levels and prevent or delay the complications of diabetes
* Inform that they will learn appropriate physical exercises to better control diabetes (Group 1), prevent diabetes (Group 2), and improve overall health (both Group 1 and 2) All study measurements will be collected at the Faculty of Human Kinetics, University of Lisbon. Body composition, cardiopulmonary exercise test (CPET), blood collection, metabolic flexibility, dietary records, and 24-hr CGM recording will be done at baseline as well as at the end of each 2-week intervention block. Physical activity assessment will be performed at baseline and during each 2-week washout period. The evaluations inherent to the project at baseline and at the end of each 2-week intervention block will take place on two different days.

Eligibility Criteria:
Inclusion Criteria (Group 1):

* previous diagnosis of T2DM
* currently taking metformin (Group 1 only);
* Adults aged 55 to 75 years
* Physically inactive people (i.e. with less than 20 minutes per day of exercise, maximum 3 days per week)

Exclusion Criteria (Group 1):

* Use of exogenous insulin and taking any other antihyperglycemic medication beyond metformin
* having major micro- or macro-vascular complications from T2DM
* History of cardiovascular incidents
* People with motor limitations (musculoskeletal or neurological) that limit the practice of physical exercise
* inability to provide informed consent

Inclusion Criteria (Group 2):

* BMI ≥25 without diagnosis of T2DM
* Adults aged 55 to 75 years
* Physically inactive people (i.e. with less than 20 minutes per day of exercise, maximum 3 days per week)

Exclusion Criteria (Group 2):

* History of cardiovascular incidents
* People with motor limitations (musculoskeletal or neurological) that limit the practice of physical exercise
* inability to provide informed consent