Disentangling the effect of brain insulin resistance on brain health

ISRCTN	ISRCTN15687967
DOI	https://doi.org/10.1186/ISRCTN15687967
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	H-25045491
Sponsor	Rigshospitalet
Funder	Novo Nordisk Fonden

Submission date: 21/10/2025
Registration date: 28/10/2025
Last edited: 23/10/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
People with diabetes have a higher risk of dementia, including Alzheimer’s disease and vascular dementia. They also show greater age-related brain atrophy and more cognitive difficulties compared to people without diabetes
The mechanisms behind the effects on the brain of diabetes are still unclear. New research indicates that, in some individuals with diabetes, the brain responds poorly to insulin signals. This is called brain insulin resistance (BIR). Large clinical studies on BIR are not yet available, but several small studies link BIR with declines in cognitive function
Another mechanism that may contribute to reduced brain health in people with diabetes is damage to the blood vessels in the brain. Damage to blood vessels is a well-known complication of diabetes, but how it affects the brain is not fully described
This project will examine the relationships among BIR, brain vascular dysfunction, and cognition. We will measure markers of insulin signaling and vascular health in the brain and relate them to cognitive performance and brain structure/function. The goal is to clarify how these mechanisms contribute to cognitive impairment in diabetes

Who can participate?
Patients with type 1 diabetes or type 2 diabetes and healthy controls. All participants will be aged between 50 and 80 years old

What does the study involve?
The participants will undergo four visits
Visit A: Participants will complete comprehensive cognitive testing and undergo a health examination
Visit B: Brain MRI scanning will be performed to evaluate brain volume changes and the integrity of white matter in the brain. Brain insulin resistance will be assessed using specialized MRI techniques that measure blood flow changes after participants receive insulin administered using a nasal spray
Visit C: MRI scanning will evaluate blood vessel function in the brain. This includes testing how the brain blood flow changes when participants breathe air with added CO2, and evaluating the blood-brain barrier functioning using a contrast agent injected during MRI scanning
Visit D: Functional MRI will be used to examine how the brain detects and responds to changes in blood sugar levels from drinking water with added sugar

What are the possible benefits and risks of participating?
The study aims to investigate why people with diabetes are more likely to experience cognitive difficulties and overall declines in brain health. By characterizing potential links, such as reduced insulin signaling in the brain or impaired blood flow regulation, the study could lead to new treatments and preventative measures. The findings may also improve our understanding of how neurodegenerative diseases and dementia develop
The study is not associated with any serious risks when safety precautions are taken

Where is the study run from?
Rigshospitalet, Denmark; Steno Diabetes Center Copenhagen, Denmark; and Ulm University Hospital, Germany

When is the study starting and how long is it expected to run for?
The enrolment of participants will start beginning of November 2025 and the project will be completed January 2032

Who is funding the study?
The Novo Nordisk Foundation (Denmark)

Who is the main contact?
Henrik Wiberg Bo Larsson, Rigshospitalet (henrik.wiberg.bo.larsson@regionh.dk)
Jørgen Rungby, Steno Diabetes Center Copenhagen (joergen.rungby@regionh.dk)
Flemming Pociot, Steno Diabetes Center Copenhagen (flemming.pociot@regionh.dk)
Martin Heni, Ulm University Hospital (martin.heni@uniklinik-ulm.de)

Contact information

Prof Henrik Bo Wiberg Larsson
Principal investigator

Valdemar Hansens Vej 1-27
Glostrup
2600
Denmark

ORCID ID	0000-0002-1348-7749
Phone	+45 24824294
Email	henrik.bo.wiberg.larsson@regionh.dk

Mr Mark Bitsch Vestergaard
Scientific

Valdemar Hansens Vej 1-27
Glostrup
2600
Denmark

ORCID ID	0000-0002-9737-9672
Phone	+45 41430112
Email	mark.bitsch.vestergaard@regionh.dk

Mrs Nicole Jacqueline Jensen
Public

Borgmester Ib Juuls Vej 83
Herlev
2730
Denmark

ORCID ID	0000-0002-1202-4056
Phone	+45 52191619
Email	nicole.jensen.01@regionh.dk

Study information

Primary study design	Observational
Study design	Multicenter case-control study
Secondary study design	Case-control study
Study type	Participant information sheet
Scientific title	Disentangling the effect of Brain Insulin Resistance on brain health (BIR-BrainHealth)
Study acronym	BIR 1
Study objectives	People with diabetes exhibit an accelerated age-related cognitive decline and have a significantly heightened risk of dementia, including both Alzheimer’s disease and vascular dementia. They also experience more pronounced age-related brain atrophy compared to individuals without diabetes. While it is evident that diabetes adversely affects the brain, the precise mechanisms and specific areas of pathology remain unclear. One recent proposed mechanism is brain insulin resistance (BIR), which is an emerging concept defined as the failure of brain cells to respond to insulin signalling. Another more established mechanism involves impaired cerebrovascular function caused by damages to the brain vessels. In this project, we will examine how both mechanisms contribute to cognitive decline and neurodegeneration. The aims of the BIR-BrainHealth project are to: 1. Examine the degree and severity of brain insulin resistance (BIR) in different types and subgroups of diabetes 2. Assess the clinical impact of BIR in relation to cognitive performance, structural changes in the brain (brain atrophy, white matter lesions, and white matter integrity), cerebrovascular function, and systemic metabolism including decline/worsening of these measures 3. Disentangle which part of the declining brain health is due to cerebrovascular damage and which part occurs because of BIR 4. Find biomarkers related to BIR, cognitive dysfunction, and poor brain health status using a multiomics approach
Ethics approval(s)	Approved 09/10/2025, Health Ethics Committee of Copenhagen (Borgervænget 3, st., Copenhagen, 2100, Denmark; +45 38666395; vek@regionh.dk), ref: H-25045491
Health condition(s) or problem(s) studied	Diabetes type 1 and diabetes type 2
Intervention	All participants will undergo a comprehensive clinical evaluation to characterize diabetes duration, severity, and systemic comorbidities. The cognitive performance of the participants will be assessed using a neuropsychological test battery of standardized tests. Tests will be grouped by cognitive domains, and each domain score is calculated as the mean of the individual component z-scores. A cognitive composite (global score) will be derived from the mean of the domains: learning and memory, executive function and working memory, processing speed, and attention. Blood, urine and stool will be collected for biomarker development and characterization of patients with BIR. A multi-omics approach will be applied to identify reliable biomarkers of BIR, incorporating lipidomics, metabolomics, proteomics, and transcriptomics. Magnetic resonance imaging (MRI) will be performed to assess BIR and structural brain changes, including atrophy. All MRS-scans will be performed on a research-optimized 3 Tesla MRI scanner. BIR will be evaluated by measuring changes in cerebral perfusion from administration of intranasal insulin delivered via nasal spray. A subset of participants will undergo additional advanced MRI-scanning for assessments of cerebrovascular function. Brain perfusion, blood–brain barrier integrity, and capillary perfusion distribution will be measured using dynamic contrast-enhanced MRI. Cerebrovascular reactivity will be measured by perfusion-weighted MRI during inhalation of air enriched with 5% CO2, a potent cerebral vasodilator. Cerebral blood flow responses to neuronal activation induced by visual stimulation will be assessed using perfusion-weighted MRI. Lastly, in a subset of participants the brain glucose sensing will be assessed using functional MRI (fMRI). fMRI will be measured prior to, during and following oral ingestion of water containing 75 grams of glucose. The glucose drink is given through a long straw while the participants are lying in the scanner and will be consumed over a period of 5 minutes. Blood samples will be collected throughout the scan for measurements of blood glucose.
Intervention type	Mixed
Primary outcome measure(s)	1. Brain insulin response is measured using changes in cerebral blood flow assessed by arterial spin labelling (ASL) MRI following intranasal insulin administration at baseline 2. Cerebrovascular reactivity is measured using changes in cerebral blood flow responses to inhalation of hypercapnic air assessed by blood-oxygen-level-dependent (BOLD) MRI, arterial spin labelling (ASL) MRI, and phase contrast mapping (PCM) MRI at baseline 3. Verbal learning is measured using the Rey Auditory Verbal Learning Test (RAVLT) at baseline 4. Processing speed and executive function are measured using the Trail Making Test (TMT) part A and B at baseline 5. Attention and processing speed are measured using the Symbol Digit Modalities Test (SDMT) at baseline 6. Working memory is measured using the RBANS Digit Span forward (Version A) at baseline 7. Working memory and sequencing ability are measured using the Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS) at baseline 8. Verbal fluency is measured using the Verbal Fluency test (phonetic and semantic) at baseline 9. Sustained attention is measured using the Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB), using A' (RVP-A) and mean latency for correct responses at baseline 10. Motor function is measured using the Grooved Pegboard test at baseline 11. Global cognitive function is measured using the Montreal Cognitive Assessment (MoCA) at baseline
Key secondary outcome measure(s)	1. Blood-brain-barrier permeability is measured using dynamic contrast enhanced MRI at baseline 2. Neurovascular coupling is measured using cerebral blood flow responses to visual stimulation assessed by ASL MRI at baseline 3. Hypothalamic glucose sensing is measured using cerebral blood flow response in the hypothalamus to glucose ingestion assessed by combined BOLD and ASL MRI at baseline 4. Brain insulin response is measured using changes in cerebral blood flow following intranasal insulin administration assessed by ASL MRI at baseline 5. Cerebrovascular reactivity is measured using changes in cerebral blood flow in response to inhalation of hypercapnic air assessed by BOLD MRI, ASL MRI, and phase contrast mapping (PCM) MRI at baseline 6. Brain atrophy is measured using T1-weighted structural MRI at baseline 7. White matter lesion load is measured using Fluid-Attenuated Inversion Recovery (FLAIR) MRI at baseline 8. Cerebral microbleeds are measured using susceptibility-weighted MRI at baseline 9. Structural connectivity is measured using diffusion tensor imaging (DTI) MRI at baseline 10. White matter diffusion integrity is measured using DTI MRI at baseline 11. White matter diffusion is measured using DTI MRI at baseline 12. Resting cerebral blood flow is measured using ASL MRI and PCM MRI at baseline 13. Cerebral metabolic rate of oxygen is measured using PCM MRI and susceptibility-based oximetry (SBO) MRI at baseline 14. Regional brain glucose sensing is measured using cerebral blood flow response to glucose ingestion assessed by combined BOLD and ASL MRI at baseline 15. Cerebral blood flow response in the hypothalamus to glucose ingestion is measured using combined BOLD and ASL MRI at baseline 16. Brain insulin sensing biomarkers are measured using a multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping at baseline 17. Brain insulin response is measured using changes in cerebral blood flow following intranasal insulin administration assessed by ASL MRI at baseline 18. Neuronal damage, neuroinflammation, and brain insulin resistance biomarkers are measured using a multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping at baseline 19. Blood-brain-barrier permeability is measured using dynamic contrast enhanced MRI at baseline 20. Vascular function and blood-brain barrier integrity biomarkers are measured using a multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping at baseline 21. Cognitive biomarkers are measured using a multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping at baseline
Completion date	31/01/2032

Eligibility

Participant type(s)	Healthy volunteer, Patient
Age group	Adult
Lower age limit	50 Years
Upper age limit	80 Years
Sex	All
Target sample size at registration	150
Key inclusion criteria	1. Type 1 diabetes with a duration of ≥10 years 2. Type 2 diabetes with a duration of ≥5 years 3. Healthy controls
Key exclusion criteria	1. HbA1c >100 mmol/mol 2. Other type of diabetes 3. Weight >140 Kg 4. Treatment with drugs that cannot be paused for 12 hours 5. Diagnosis of dementia 6. Active and recent (1year) malignant disease 7. History of major stroke 8. Major depression and/or treatment with antipsychotics 9. History of traumatic brain injury 10. Other medical condition or disorder (e.g., epilepsy, recent concussion) 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. 11. Inability to perform neuropsychological tests (e.g., severe vision and hearing impairment that cannot be improved with aids such as glasses and hearing aids, or language barrier.) 12. Severe claustrophobia 13. Foreign bodies of metal in the body which prohibits brain MRI scans (e.g. pacemaker or screws/plates from surgery in the head or neck region) 14. Participants who do not wish to be informed about accidental findings by MRI 15. eGFR measurement <45 within 3 months of study visit
Date of first enrolment	01/11/2025
Date of final enrolment	31/10/2031

Locations

Countries of recruitment

Denmark
Germany

Study participating centres

Rigshospitalet

Blegdamsvej 9
København Ø
2100
Denmark

Steno Diabetes Center Copenhagen

Borgmester Ib Juuls Vej 83
Herlev
2730
Denmark

Ulm University Hospital

Albert-Einstein-Allee 23
Ulm
89081
Germany

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data-sharing plans for the current study are unknown and will be made available at a later date

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

21/10/2025: Trial's existence confirmed by Region Hovedstaden.