Clinical trial NCT05314855: Brain Clock and Insulin Resistance
Official title: Role of the Central Brain Clock in the Pathophysiology of Insulin Resistance
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Insulin Resistance
Type 2 Diabetes
Keywords: Type 2 Diabetes Mellitus
Insulin resistance
Suprachiasmatic nucleus
functional MRI
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2022-04-06
Enrollment: 30
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Primary care clinics, community sample

Brief summary: In this observational cohort study the investigators will determine the activity rhythm of the suprachiasmatic nucleus in humans with progressive stages of insulin resistance, using advanced functional brain imaging (7 Tesla functional MRI).

Detailed description: Type 2 diabetes mellitus (T2DM) has an increasing worldwide incidence. Insulin resistance is a key pathophysiological process in the development of hyperglycemia in patients with T2DM. Disruption of circadian synchrony leads to insulin resistance. Animal studies and post-mortem human brain studies suggest that the master brain clock in the hypothalamic suprachiasmatic nucleus (SCN) plays a role in the development of insulin resistance. Up to now, no-one has investigated whether the in vivo activity rhythm of the SCN is affected in patients with insulin resistance. The investigators hypothesize that the master brain clock has an important role in the development of human insulin resistance.

Eligibility criteria: Inclusion Criteria:

Group 1: obese people with normal insulin sensitivity

* age 25-65 years
* BMI\>30
* fasting plasma insulin ≤62 pmol/L
* fasting plasma glucose \<5.6 mmol/L
* Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≤ 4.5

Group 2: obese people with insulin resistance

* age 25-65 years
* BMI\>30
* fasting plasma insulin \>62 pmol/L
* not fulfilling the American Diabetes Association (ADA) criteria for type 2 DM

Group 3: obese subjects with overt type 2 DM

* age 25-65 years
* BMI\>30
* diagnosis type 2 DM according to ADA criteria

Exclusion Criteria:

* An extreme chronotype (midpoint of sleep on free days (MSFsc) before 2:00 or after 6:00).
* Active psychiatric disorder (including circadian rhythm sleep disorder) as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM) 5
* Disorders of the central nervous system (Early-onset dementia, stroke, epilepsy, Parkinson's disease, brain tumor)
* Severe visual impairment (WHO classification)
* Shift workers
* Crossing \> 2 time zones in the 3 months before the study
* Patients with type 2 DM receiving insulin treatment or glucagon-like peptide (GLP) 1 agonists
* MRI contraindications

Primary outcomes:
measure: SCN blood oxygen level dependent (BOLD) response to light: mean SCN activity
timeFrame: mean activity over 24 hours
measure: SCN BOLD response to light: time point of peak SCN activity
timeFrame: 24 hours
measure: SCN BOLD) response to light: time point of trough SCN activity
timeFrame: 24 hours
measure: Amplitude of SCN activity rhythm (peak-trough change in SCN activity)
timeFrame: 24 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centers, location AMC
state: Noord-Holland
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Dr. D.J. Stenvers
role: PRINCIPAL_INVESTIGATOR
References:
citation: World Health Organization, Global report on diabetes., in WHO Library. 2016
citation: Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR. Insulin resistance in type 1 diabetes: what is 'double diabetes' and what are the risks? Diabetologia. 2013 Jul;56(7):1462-70. doi: 10.1007/s00125-013-2904-2. Epub 2013 Apr 24.
citation: Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2019 Feb;15(2):75-89. doi: 10.1038/s41574-018-0122-1.
citation: Hogenboom R, Kalsbeek MJ, Korpel NL, de Goede P, Koenen M, Buijs RM, Romijn JA, Swaab DF, Kalsbeek A, Yi CX. Loss of arginine vasopressin- and vasoactive intestinal polypeptide-containing neurons and glial cells in the suprachiasmatic nucleus of individuals with type 2 diabetes. Diabetologia. 2019 Nov;62(11):2088-2093. doi: 10.1007/s00125-019-4953-7. Epub 2019 Jul 20.
citation: ter Horst KW, Gilijamse PW, Koopman KE, de Weijer BA, Brands M, Kootte RS, Romijn JA, Ackermans MT, Nieuwdorp M, Soeters MR, Serlie MJ. Insulin resistance in obesity can be reliably identified from fasting plasma insulin. Int J Obes (Lond). 2015 Dec;39(12):1703-9. doi: 10.1038/ijo.2015.125. Epub 2015 Jul 9.
citation: American Diabetes Association. (2) Classification and diagnosis of diabetes. Diabetes Care. 2015 Jan;38 Suppl:S8-S16. doi: 10.2337/dc15-S005. No abstract available.
citation: Roenneberg T, Kuehnle T, Pramstaller PP, Ricken J, Havel M, Guth A, Merrow M. A marker for the end of adolescence. Curr Biol. 2004 Dec 29;14(24):R1038-9. doi: 10.1016/j.cub.2004.11.039. No abstract available.
citation: World report on vision. Geneva: World Health Organization. 2019