Circadian Misalignment and Insulin Sensitivity

Impact of Circadian Misalignment on Insulin Sensitivity

This study will evaluate the effect of circadian misalignment on insulin sensitivity in healthy lean subjects in a randomized cross-over design. Subjects will be admitted to the research facility for two study periods of 3 and 3.5 days. In one of the study periods, the behavioral cycle will be shifted by 12 hours. Insulin sensitivity will be measured with a hyperinsulinemic euglycemic clamp.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Insulin Resistance
• Intervention / Treatment: Behavioral: Circadian Misalignment

Detailed Description

Recent evidence shows that misalignment of the circadian rhythm (e.g. by rotating shift work) impairs glucose metabolism markedly, possibly by decreasing insulin sensitivity in peripheral tissues and liver. Nowadays our society is indispensably connected to a lifestyle that allows wakefulness at every time of the 24 hours cycle. Social jetlag is a phenomenon that affects a large part of the general population, thus circadian misalignment extends far beyond those who are on a shift work schedule. Therefore, decreased insulin sensitivity in individuals affected by circadian misalignment may help to explain the increased prevalence of T2DM in night shift workers that has been found in epidemiological studies.

The study is an interventional randomized crossover trial in which each subject serves as it owns control. For the study, the investigators ask the subjects to participate in two study periods, one of 3 days length (control condition) and the other of 3.5 days length (misalignment condition). During the 3.5 day misalignment condition, subjects will shift their day-night rhythm by 12 hours, which will lead to maximal circadian misalignment. Insulin sensitivity will be measured by a hyperinsulinemic euglycemic clamp. Secondary parameters will include ex-vivo skeletal muscle mitochondrial function and whole-body energy metabolism.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Caucasian
• Healthy (as determined by dependent physician based on medical questionnaire)
• Male
• Age: 18-35 years
• Normal BMI (18-25 kg/m2)
• Regular sleeping time (normally 7 - 9h daily)
• Habitual bedtime at 11 PM ± 2 hours

Exclusion Criteria:

• Extreme early bird or extreme night person
• Heavily varying sleep-wake rhythm
• Shiftwork during last 3 months
• Travel across >1 time zone in the last 3 months
• Engagement in exercise > 3 hours total per week
• Using > 400mg caffeine daily
• Smoking
• Unstable body weight (weight gain or loss > 3kg in the last 3 months)
• Significant food allergies/intolerance (seriously hampering study meals)
• Participation in another biomedical study within 1 month before the first study visit
• Claustrophobia
• Medication use hampering the study (as determined by responsible physician)
• Recent blood donation.
• Any contra-indication to the telemetric pill:
• Any acute condition, exacerbation of chronic condition, or medical history that would in the investigator's opinion interfere with the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; 3 days with normal circadian alignment.
Experimental: Circadian Misalignment; 3.5 days in which the subjects will undergo a maximal circadian misalignment of 12 hours by means of a midday nap during the second day, and a subsequent start of a new normal wake period, shifted 12 hours.	Behavioral: Circadian Misalignment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	Measured with hyperinsulinemic euglycemic clamp	2 days after circadian misalignment and matched time in control arm.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative glucose disposal		2 days after circadian misalignment and matched time in control arm.
Non-oxidative glucose disposal		2 days after circadian misalignment and matched time in control arm.
Skeletal muscle mitochondrial function	Measured with high-resolution respirometry on permeabilized muscle fibers after muscle biopsy	1 and 2 days after circadian misalignment and matched times in control arm
Whole body energy metabolism while awake	Measured by indirect calorimetry	1 and 2 days after circadian misalignment and matched times in control arm
Sleeping metabolic rate	Measured by indirect calorimetry	1.5 days after circadian misalignment and matched time in control arm
Skeletal muscle mtDNA	Measured by qPCR	1 and 2 days after circadian misalignment and matched times in control arm
Skeletal muscle mRNA	Measured by qPCR and Western Blotting	1 and 2 days after circadian misalignment and matched times in control arm
Skeletal muscle proteins	Measured by Western Blotting	1 and 2 days after circadian misalignment and matched times in control arm
Metabolic compounds in the blood (e.g. glucose, insulin, FFA's, Triglycerides, cholesterol)		1 and 2 days after circadian misalignment and matched times in control arm
Core-body-temperature	Measured by a telemetric pill	1 day after circadian misalignment and matched time in control arm
Peripheral skin temperature	Measured by skin temperature sensors	1 day after circadian misalignment and matched time in control arm
Central skin temperature	Measured by skin temperature sensors	1 day after circadian misalignment and matched time in control arm
Heart rate	Measured by heart rate monitor	1 day after circadian misalignment and matched time in control arm

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: October 14, 2015
• First Submitted That Met QC Criteria: October 16, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): June 9, 2017
• Last Update Submitted That Met QC Criteria: June 8, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Circadian Rhythm; Insulin Sensitivity; Circadian Misalignment
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Hypersensitivity; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: NL54897.068.15