Determining Circadian Metabolic and Behavioural Rhythms in Patients With and Without Type 2 Diabetes (Cir-D-Brain)

Determining Circadian Metabolic and Behavioural Rhythms in Patients With and Without Type 2 Diabetes and Identifying the Relation to Hormone and Glucose Fluctuations, and Cognition

The goal of the present clinical descriptive study is to characterize and quantify the potential hormonal chronobiological differences between individuals with type 2 diabetes (T2D) and healthy age and weight-matched controls as either circadian aligned or misaligned. The investigators hypothesize that individuals with T2D have a misaligned and different circadian rhythmicity of circadian biomarkers (melatonin and cortisol) than controls, and that this difference in turn is related to 24h hormonal fluctuations, behaviour, and metabolic-, cardiac-, and cognitive parameters.

Participants will be asked to:

• fill-out a diary on eating and sleeping habits for 30 days
• wear an actigraphy and continuous glucose monitor for 10-14 days
• stay overnight at the research facility, including continuous blood sampling and polysomnography

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes; Circadian Rhythm

Detailed Description

T2D is associated with cognitive dysfunction and an increased risk of developing dementia. This negative effect on cognition is worsened by T2D duration, yet the mechanisms are unknown.

Sleep disturbances increase peripheral insulin resistance, and is associated with the development of T2D, temporarily worsened cognitive function, and the development of cognitive impairment. In turn, T2D is associated with circadian misalignment (a condition where the internal physiological clock is unaligned with the external behavior). A major external signal (also known as zeitgeber) for synchronizing the internal and external clock is sleep in accordance with the day-night cycle.

Determining the circadian rhythm of an individual and whether it is aligned or misaligned is complex and can't be done by one measurement. However, melatonin and cortisol are often used as "circadian biomarkers" due to significant and well-defined circadian rhythm profiles. Another measure of the circadian phase is the timing of melatonin production under dim light conditions (dim light melatonin onset) which is an individual phase marker depending on the persons habitual time of sleep. Most studies focusing on circadian alignment in an everyday setting have used questionnaires, and to our knowledge, no studies have described 24-h circadian oscillations between individuals with T2D and healthy age and weight matched controls. Mapping these potential differences could help explain the pathophysiological mechanisms behind T2D and circadian misalignment.

The Cir-D-Brain study is a clinical descriptive study. The study comprises of an information visit, a screening visit, a midway visit (2 weeks after screening), a 24-h in-hospital day (a day between the midway visit and the final visit), and a final visit (2 weeks after the midway visit). Participants will keep a diary on eating and sleeping habits for all 30 days. At the midway visit, participants will be equipped with an actigraphy and a continuous glucose monitor. At the 24-h in-hospital day, participants will have their blood sampled every third hour for 24 hours to measure their circadian rhythm, every hour from 6 pm till 12 am to map dim light melatonin onset, and at wake-up to map cortisol awakening response. At the 24-h in-hospital day, participants will furthermore have their sleep stages measured by polysomnography. The study will include 30 participants with T2D and 30 age and BMI matched controls.

The specific objectives are:

1. To characterize and quantify the hormonal chronobiological differences between individuals with T2D and healthy matched controls measured by circadian biomarkers.
2. To relate the findings to 24-h hormonal fluctuations, different patterns in metabolism, behavioural circadian rhythms differences (sleep-wake and eating habits), sleep stages, glycaemic variability, inflammation, heart rate variability, and cognition.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Helena Z Wodschow, MD; Phone Number: +45 30313426; Email: helena.zander.wodschow.03@regionh.dk
• Study Contact Backup: Name: Jørgen Rungby, MD, DMSc; Phone Number: +45 21686620; Email: joergen.rungby@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Recruiting
    • Steno Diabetes Center Copenhagen
    • Contact: Helena Z Wodschow, MD; Phone Number: +45 30313426; Email: helena.zander.wodschow.03@regionh.dk
    • Contact: Jørgen Rungby, MD, DMSc; Phone Number: +45 21686620; Email: joergen.rungby@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Primary care clinic, Steno Diabetes Center Copenhagen out-patient clinic, community sample

Description

Inclusion Criteria:

Individuals with T2D:

• Informed and written consent.
• Clinically diagnosed diabetes mellitus type 2 for at least 3 months (diagnosed according to criteria of World Health Organization (WHO)).
• HbA1c >53 mmol/mol
• Stable medical treatment for at least 8 weeks.
• Plasma haemoglobin ≥8.00 mmol/L (male) or ≥6.4 mmol/L (female).
• Male or female participants aged 50-75 years.

Healthy matched controls:

• Informed and written consent.
• Normal haemoglobin ≥8.00 mmol/L (male) or ≥6.4 mmol/L (female).
• Male or female participants aged 50-75 years.

Exclusion Criteria:

• Body mass index (BMI) <23 kg/m2
• Receipt of any investigational medicinal product within 3 months before screening in this trial.
• Inability to perform neuropsychological tests (e.g., visual impairment or auditory impairment, or language barrier).
• Participants with mental incapacity or language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator or their general practitioner, should not participate in the trial.
• Prior or contemporary use of any kind of hypnotica within 6 months, former p.n. use of melatonin is judged by the investigator.
• Nightshift-worker.
• Known dementia or any other major disorders that in the opinion of the investigator precludes compliance with the protocol, evaluation of the results or represent an unacceptable risk for the participant's safety.
• Diagnosed sleep disorders (e.g., sleep apnoea and narcolepsy).
• Significant history of alcoholism or drug/chemical abuse as per investigator's judgement.
• Severe hypoglycaemic event during the past 6 months requiring medical assistance.
• Diagnosed diabetic retinopathy.
• Severe renal insufficiency defined as estimated glomerular filtration rate (eGFR) ≤ 30 ml/min/1.73m2 or any kind of kidney disease that in the opinion of the investigator involves an unnecessary risk for the participants.

• Cardiac problems including any of the following:

  1. Classified as being in New York Heart Association (NYHA) class III or IV.
  2. Angina pectoris (chest pain) within the last 6 months.
• Inadequately treated blood pressure at screening defined as repeated resting blood pressure outside the rage 90-150 mmHg for systolic and 50-100 mmHg for diastolic blood pressure.
• Known lung disease that in the opinion of the investigator represents an unacceptable risk for the participant's safety.
• Active or recent (≤ 12 months) malignant disease is judged by the investigator.
• For females only: Pregnancy, breast-feeding status, or intention of becoming pregnant during the trial.
• For healthy matched controls: prediabetes defined as HbA1c between 42-47 mmol/mol

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Type 2 Diabetes; Individuals with type 2 diabetes
Controls; Individuals without type 2 diabetes matched on age and body mass index

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Melatonin oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Cortisol oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dim light melatonin onset	Blood samples (pg/ml)	24-hour in-hospital day, blood samples taken every hour from 18:00 until 00:00 (7 timepoints in total)
Phase angle (time between dim light melatonin onset and sleep)	Blood samples	24-hour in-hospital day, blood samples taken every hour from 18:00 until 00:00 (7 timepoints in total)
Cortisol awakening response	Blood samples (pg/ml)	24-hour in-hospital day, blood samples taken at wake up, and 15-, 30-, and 60-minutes post-wake up
Diary on sleeping habits	Expanded Consensus Sleep Diary (time in bed, time to fall asleep, number of awakenings and durations, time of final awakening, time to get out of bed, total sleep time, sleep quality, daytime sleepiness, number of naps and duration, number and last time of alcohol consumption, number and last time of coffein consumption, use of sleep medicine)	30 days
Diary on eating window	The eating window (initiation of first consumption and termination of last consumption of food)	30 days
Glycaemic variability	Continuous glucose monitor (amplitude (mmol/L), frequency, and duration of the fluctuation, mean glucose (mmol/L), time in range, time in hyperglycemic and hypoglycemic range, area under the curve)	10-14 days
Sleep and waking states	Actrigraph worn on the wrist of the non-dominant hand (acceleration at different times)	10-14 days
Heart rate variability (fluctuations in time intervals between adjacent heart beats)	Measured continuously by the polysomnograph (ms)	24-hour in-hospital day
Sleep architecture	Polysomnography (minutes and percentages). Sleep stages (N1, N2, N3, rapid eye movement (REM)), total time asleep, sleep latency, REM sleep latency, arousals, awakenings, total sleep efficiency.	24-hour in-hospital day
Cognition (verbal memory)	Rey Auditory Verbal Learning Test (RAVLT)	24-hour in-hospital day
Cognition (psychomotor speed and executive function)	Trail Making Test (TMT) part A and B ), Symbol Digit Modalities Test (SDMT)	24-hour in-hospital day
Cognition (executive function)	WAIS-III Letter-Number Sequencing test, Verbal fluency test (letters S and D)	24-hour in-hospital day
Cognition (sustained attention)	Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB)	24-hour in-hospital day
Cognition (verbal IQ)	Danish Adult Reading Test (DART) (equivalent to the National Adult Reading Test; NART)	24-hour in-hospital day
Insulin oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
C-peptide oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
TSH oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Glucose oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Glucagon oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Glucagon-like peptide-1 (GLP-1) oscillations (amplitude, peak, mesor, phase, period length (TAU))	Blood samples.	24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronotype (diurnal preference)	Morningness-Eveningness Questionnaire (scoring)	At screening
Sleep apnea	Apnea-hypopnea index (events/hour)	24-hour in-hospital day
Blood pressure variations	Measured continuously by the polysomnograph (mmHg)	24-hour in-hospital day
Cardiovascular autonomic neuropathy	Assessed from three standard cardiovascular autonomic reflex tests: lying-to-standing test, deep breathing test, and Valsalva manoeuvre	At screening

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Glostrup University Hospital, Copenhagen; University Hospital Bispebjerg and Frederiksberg
• Investigators: Principal Investigator: Jørgen Rungby, MD, DMSc, Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: January 28, 2024
• First Submitted That Met QC Criteria: February 5, 2024
• First Posted (Actual): February 6, 2024

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Sleep; Type 2 Diabetes; Cognition; Circadian Rhythm
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: H-22014311

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No