Clinical trial NCT06243172: Determining Circadian Metabolic and Behavioural Rhythms in Patients with and Without Type 2 Diabetes
Official title: 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
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Type 2 Diabetes
Circadian Rhythm
Keywords: Type 2 Diabetes
Circadian Rhythm
Cognition
Sleep
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Glostrup University Hospital, Copenhagen
name: University Hospital Bispebjerg and Frederiksberg
First posted: 2024-02-06
Enrollment: 60
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: Primary care clinic, Steno Diabetes Center Copenhagen out-patient clinic, community sample

Brief summary: 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

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.

Eligibility criteria: Inclusion Criteria:

Individuals with T2D:

* Informed and written consent.
* Clinically diagnosed diabetes mellitus type 2 for at least 5 years (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

Primary outcomes:
measure: Melatonin oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: Cortisol oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Secondary outcomes:
measure: Dim light melatonin onset
timeFrame: 24-hour in-hospital day, blood samples taken every hour from 18:00 until 00:00 (7 timepoints in total)
measure: Phase angle (time between dim light melatonin onset and sleep)
timeFrame: 24-hour in-hospital day, blood samples taken every hour from 18:00 until 00:00 (7 timepoints in total)
measure: Cortisol awakening response
timeFrame: 24-hour in-hospital day, blood samples taken at wake up, and 15-, 30-, and 60-minutes post-wake up
measure: Diary on sleeping habits
timeFrame: 30 days
measure: Diary on eating window
timeFrame: 30 days
measure: Glycaemic variability
timeFrame: 10-14 days
measure: Sleep and waking states
timeFrame: 10-14 days
measure: Heart rate variability (fluctuations in time intervals between adjacent heart beats)
timeFrame: 24-hour in-hospital day
measure: Sleep architecture
timeFrame: 24-hour in-hospital day
measure: Cognition (verbal memory)
timeFrame: 24-hour in-hospital day
measure: Cognition (psychomotor speed and executive function)
timeFrame: 24-hour in-hospital day
measure: Cognition (executive function)
timeFrame: 24-hour in-hospital day
measure: Cognition (sustained attention)
timeFrame: 24-hour in-hospital day
measure: Cognition (verbal IQ)
timeFrame: 24-hour in-hospital day
measure: Insulin oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: C-peptide oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: TSH oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: Glucose oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: Glucagon oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
measure: Glucagon-like peptide-1 (GLP-1) oscillations (amplitude, peak, mesor, phase, period length (TAU))
timeFrame: 24-hour in-hospital day, blood samples taken every third hour for 24 hours (9 timepoints in total)
Other outcomes:
measure: Chronotype (diurnal preference)
timeFrame: At screening
measure: Sleep apnea
timeFrame: 24-hour in-hospital day
measure: Blood pressure variations
timeFrame: 24-hour in-hospital day
measure: Cardiovascular autonomic neuropathy
timeFrame: At screening
Locations:
city: Herlev
country: Denmark
facility: Steno Diabetes Center Copenhagen
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Jørgen Rungby, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References: