Exercise, Chronotype, and Prediabetes

Official title

Timed Exercise in Prediabetes With Extreme Chronotype

Overview

The goal of this clinical trial is to find out whether exercising at the right time of day, based on a person's natural body clock, leads to greater health benefits in people living with prediabetes. The main question it aims to answer is whether doing a single session of exercise in the morning or in the evening affects how the body handles sugar differently in adults with prediabetes who have an extreme natural body clock. This will be done by comparing three conditions (no-exercise, morning exercise, and evening exercise) within the same participant. Each condition will be tested on a different day, with at least 14 days between the test days. During the no-exercise test days, participants will come to the study centre and will only be allowed to do sedentary activities (e.g. office work, reading, or screen time). During the morning exercise test days, participants will perform an exercise session at 9:00 am that involves short periods of very hard effort followed by short rest periods. Whereas for the evening exercise test days, the same type of exercise will be performed at 5:00 pm.

Detailed description

Chronotype refers to an individual's circadian preferences for being active and fully functional at certain times of the day. Using validated questionnaires, individual's chronotype can be categorized to either a morning (lark), evening (owl), or intermediate (neutral) chronotypes. Individuals with morning chronotype wake up and go to bed early. Therefore, their calorie distribution as well as peak mental and physical performances predominantly occur earlier in the day. This is in contrast with individuals with evening chronotype that wake up and go to bed late, resulting in most of their calorie consumption happens later in the day. They are also more active and alert in the evening. Growing evidence has shown that late afternoon or evening exercise is better than morning exercise for blood glucose control in individuals with type 2 diabetes (T2D) or those at risk of T2D. In men with T2D, two weeks of high-intensity interval training (HIIT) reduced continuous glucose monitor (CGM)-based glucose concentration when performed in the afternoon than in the morning. This finding was further supported by a retrospective study involving men at risk for or T2D that found afternoon exercise led to superior peripheral insulin sensitivity, insulin-mediated suppression of adipose tissue lipolysis, and fasting plasma glucose. Interestingly, in a recently published crossover trial involving men and women, with and without T2D, no difference was observed in 24-hour glucose profile assessed using CGM across all cohorts (including gender and diabetes status) between morning and evening exercise. However, morning exercise increased post-exercise blood glucose levels during the two hours recovery period in both men and women with T2D, which was not observed following the evening exercise. It is important to note that all the above-mentioned studies are either excluding individuals with extreme chronotype or the chronotype of the participants was not clearly reported. This limitation raises an important research question: Do people living with extreme chronotype respond differently to timed exercise? Therefore, in this study, it is hypothesize that people living with prediabetes and extreme chronotype will gain superior metabolic benefits when the timing of exercise is aligned with their chronotype. To test this, a randomized controlled cross-over study is conducted in which participants are subjected to three conditions that are no-exercise, morning exercise, and evening exercise. The main outcome is insulin sensitivity determined by a 2-step hyperinsulinemic-euglycemic clamp.

Interventions

• Behavioral Timing of exercise
  An acute exercise bout of cycling performed in the morning at 9 AM
• Behavioral Timing of exercise
  An acute exercise bout of cycling performed in the morning at at 5 PM
• Behavioral Control
  No exercise

Primary outcome measures

• Insulin sensitivity [Time frame: 12 to 24 hours post-exercise intervention]

Secondary outcome measures (12)

• Skeletal muscle metabolites [Time frame: 12 to 24 hours post-exercise intervention]
• Skeletal muscle clock genes [Time frame: 12 to 24 hours post-exercise intervention]
• Adipose tissue metabolites [Time frame: 12 to 24 hours post-exercise intervention]
• Adipose tissue clock genes [Time frame: 12 to 24 hours post-exercise intervention]
• Hepatic glycogen content assessed using 13C Magnetic Resonance Spectroscopy [Time frame: Post-dinner on exercise day]
• Serum glucose [Time frame: 12 to 24 hours post-exercise intervention]
• Serum free fatty acids [Time frame: 12 to 24 hours post-exercise intervention]
• Serum triglycerides [Time frame: 12 to 24 hours post-exercise intervention]
• Serum cholesterol [Time frame: 12 to 24 hours post-exercise intervention]
• Serum insulin [Time frame: 12 to 24 hours post-exercise intervention]
• Resting energy expenditure assessed using indirect calorimetry [Time frame: 12 to 24 hours post-exercise intervention]
• Objective sleep quantity and quality assessed using an actighrapy device [Time frame: The nighttime of exercise intervention day]

Eligibility criteria

Inclusion criteria

• Able to provide signed and dated written informed consent prior to any study specific procedures
• Adult men and women aged between more than 18 and ≤ 75 years
• Body mass index (BMI) of 25 - 35 kg/m2
• Stable weight (no weight loss or gain > 3 kg in the past 3 months)
• Pre-diabetes defined as an isolated impaired glucose tolerance or a combination of impaired glucose tolerance and impaired fasting glucose (values are based on the American Diabetes Association (ADA):

• impaired glucose tolerance (plasma glucose 140 mg/dL to 199 mg/dL, 120 minutes after consumption of 75g of glucose)
• impaired fasting glucose (fasting plasma glucose 100 mg/dL to 125 mg/dL)
• Morning (Morningness-Eveningness Questionnaire \[MEQ\] score ≥ 59) or evening (MEQ score ≤ 41) chronotype

Exclusion criteria

• Previously diagnosed with type 2 diabetes
• Moderate to severe anemia (hemoglobin < 10 g/L)
• Uncontrolled hypertension
• Abnormal electrocardiogram (ECG) at rest judged by the study physician
• Pregnancy or breastfeeding
• HIV, hepatitis B, or C infection
• Disorders of blood clotting or wound healing
• Positive history of venous thrombosis (contraindication for clamp)
• Hypersensitivity to local anesthetics (contraindication for fat/muscle biopsies)
• Night shift work in the last 3 months
• Travel across > 1 time zone in the last 3 months
• Participation in another clinical trials that may possibly hamper the study results
• Engagement in structured exercise activities > 2 hours a week
• Any acute condition, exacerbation of chronic condition, or medical history that in the investigator's opinion would interfere with the study
• Any contraindication for MRI scanning
• Medication use known to hamper safety during the study procedures
• Non-German speaking

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Treatment

Study locations

Germany · 1 center

• German Diabetes Center (DDZ) — Düsseldorf

Publications

• Keller MJ, Brady AJ, Smith JAB, Savikj M, MacGregor K, Jollet M, Oberg SB, Nylen C, Bjornholm M, Rickenlund A, Carlsson M, Caidahl K, Krook A, Pillon NJ, Zierath JR, Wallberg-Henriksson H. 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. PMID 40580209
• Mancilla R, Brouwers B, Schrauwen-Hinderling VB, Hesselink MKC, Hoeks J, Schrauwen P. Exercise training elicits superior metabolic effects when performed in the afternoon compared to morning in metabolically compromised humans. Physiol Rep. 2021 Jan;8(24):e14669. doi: 10.14814/phy2.14669. PMID 33356015
• Savikj M, Gabriel BM, Alm PS, Smith J, Caidahl K, Bjornholm M, Fritz T, Krook A, Zierath JR, Wallberg-Henriksson H. Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial. Diabetologia. 2019 Feb;62(2):233-237. doi: 10.1007/s00125-018-4767-z. Epub 2018 Nov 13. PMID 30426166

Identifiers

NCT: NCT07389005 · REALIGN

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗