Disentangling the Effect of Brain Insulin Resistance on Brain Health (BIR 1)

Disentangling the Effect of Brain Insulin Resistance on Brain Health (BIR-BrainHealth)

People with diabetes are at increased risk of developing dementia, including Alzheimer's disease and vascular dementia. In addition, persons with diabetes have more pronounced age-related brain atrophy and cognitive difficulties compared to people without diabetes. The mechanisms behind the effects on the brain of diabetes are still unclear. New research suggests that the brains of some people with diabetes do not respond normally to insulin signals, a condition known as brain insulin resistance (BIR). To date, there have been no large clinical studies investigating BIR and its impact on brain health, but several smaller studies suggest that BIR may be a cause of cognitive decline and impaired brain health in people with diabetes. Another mechanism that may contribute to impaired 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. In this project, we will investigate the relationship between BIR and brain blood vessel dysfunction and its relationship to cognition and brain function. This is done by examining patients with type 1 diabetes (T1D), type 2 diabetes (T2D) and healthy controls. The participants will undergo MRI brain scans to assess the impact of BIR on the brain physiology and to evaluate brain blood vessel health. Participants will undergo comprehensive assessments of their cognitive abilities and thorough health examination.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Type 1; Diabetes Type 2

Detailed Description

The BIR-BrainHealth project investigates the role of brain insulin resistance (BIR) as a key mechanism linking diabetes to cognitive decline and dementia risk. By combining cognitive testing with advanced neuroimaging (MRI and PET), metabolic profiling, and multi-omics analyses, the study aims to uncover how BIR affects brain physiology, energy metabolism, and neurovascular function. The present trial registration specifically covers the MRI components of the project and does not include PET imaging.

Diabetes significantly increases the risk of mild cognitive impairment and dementia. The exact link between diabetes and cognitive decline is yet to be fully understood. Early cognitive decline in diabetes suggests a unique pathogenetic trajectory. One hypothesized mechanism involves impaired insulin signaling/transport in the brain, referred to as brain insulin resistance (BIR). Evidence indicates that in some individuals with diabetes, neuronal insulin signaling is abnormal, resulting in dysregulated cerebral metabolism and function. Another possible pathway is cerebrovascular pathology, which may compromise cerebral perfusion and energy metabolism. The present project will investigate the relationship between BIR and cerebrovascular dysfunction, and their impact on cognition and brain function.

We will set up a multicenter study in Denmark and Germany. Initially the study will include 50 participants with type 1 diabetes, 50 participants with type 2 diabetes, and 50 control participants without diabetes. 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 following standardized tests:

• Rey Auditory Verbal Learning Test (RAVLT)
• Trail Making Test (TMT) part A and B
• Symbol Digit Modalities Test (SDMT)
• RBANS Digit Span forward (Version A)
• Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS)
• Verbal Fluency test (phonetic and semantic)
• Grooved Pegboard
• Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses
• The Montreal Cognitive Assessment (MoCA)

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.

Magnetic resonance imaging (MRI) will be performed to assess BIR and structural brain changes, including atrophy. All MRI-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.

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. Lipidomic analysis will quantify approximately 650 lipid species, including phospholipids, lysophos-pholipids, ceramides, sphingolipids, diacylglycerols, and triacylglycerols, using liquid chromatography-mass spectrometry. Metabolomic profiling will measure approximately 300 metabolites, including citric acid cycle intermediates, short-chain fatty acids, ketones, and amino acids, using gas chromatography-mass spectrometry. Proteomic analysis will be conducted using a validated, clinically applicable mass spectrometry method, and transcriptomic profiling will be performed using RNA-based methods. The participants will be genotyped using the Illumina Infinium Global Screening Array (GSA v2.4), with exclusion of rare variants and clinically relevant mutations listed by the American College of Medical Genetics, in accordance with the guidelines of the National Science Ethics Committee on genomic research.

A subset of participants will undergo additional advanced MRI-scanning for assessments of cerebro-vascular 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 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.

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Henrik BW Larsson, Professor; Phone Number: +45 24824294; Email: henrik.bo.wiberg.larsson@regionh.dk

Study Locations

• Denmark
  • Glostrup Municipality, Denmark, 2600
    • Recruiting
    • Rigshospitalet
  • Herlev, Denmark, 2730
    • Recruiting
    • Steno Diabetes Center Copenhagen
• Germany
  • Ulm, Germany, 89081
    • Recruiting
    • University of Ulm

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

It is planned to recruit participants in the Greater Copenhagen area in Denmark and the Ulm area in Germany. The participants will be recruited from the outpatient clinic at Steno Diabetes Center Copenhagen and Ulm University Hospital and primary care settings in Denmark and Germany.

In addition to this, participants will be sought by physical advertisements in the local area, through recruitment platforms (join.trialtree.com) and social media.

Description

Inclusion Criteria (all):

• age 50-80 years

Inclusion Criteria (diabetes only):

• Diagnosis of either type 1 diabetes or type 2 diabetes
• Diabetes duration of ≥10 years for individuals with type 1 diabetes and ≥5 years for individuals with type 2 diabetes

Exclusion Criteria:

• HbA1c >100 mmol/mol
• Other type of diabetes
• Weight >140 Kg
• Treatment with drugs that cannot be paused for 12 hours
• Diagnosis of dementia
• Active and recent (1year) malignant disease
• History of major stroke
• Major depression and/or treatment with antipsychotics
• History of traumatic brain injury
• 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.
• 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.)
• Severe claustrophobia
• 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)
• Participants who do not wish to be informed about accidental findings by MRI
• eGFR measurement <45 within 3 months of study visit

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Type 1 Diabetes; Individuals who have a type 1 diabetes diagnose and meet the inclusion and exclusion criteria.
Type 2 Diabetes; Individuals who have a type 2 diabetes diagnose and meet the inclusion and exclusion criteria.
Controls; Individuals who do not have a diabetes diagnose and meet the inclusion and exclusion criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between brain insulin response and cognitive measures	Brain insulin response is assessed by measuring changes in cerebral blood flow following intranasal insulin administration, using arterial spin labelling (ASL) MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
Correlation between cerebrovascular reactivity and cognitive measures	Cerebrovascular reactivity is assessed by measuring changes in cerebral blood flow responses to inhalation of hypercapnic air (air enriched with 5% CO2). Cerebral blood flow is measured using combined blood-oxygen-level-dependent (BOLD) MRI, ASL MRI, and phase contrast mapping (PCM) MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood-brain-barrier permability	Differences in blood-brain-barrier permeability between groups, measured by dynamic contrast enhanced MRI.	Baseline (only measured once)
Neurovascular coupling	Differences in cerebral blood flow responses to visual stimulation between groups, assessed with ASL MRI.	Baseline (only measured once)
Hypothalamic glucose sensing	Differences in cerebral blood flow response in the hypothalamus to glucose ingestion between groups, assessed by combined BOLD and ASL MRI.	Baseline (only measured once)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain insulin response	Differences in brain insulin response between groups, assessed by measuring changes in cerebral blood flow following intranasal insulin administration using ASL MRI.	Baseline (only measured once)
Cerebrovascular reactivity	Differences in cerebrovascular reactivity between groups, assessed by measuring changes in cerebral blood flow in response to inhalation of hypercapnic air (air enriched with 5% CO2). Cerebral blood flow is measured using combined blood-oxygen-level-dependent (BOLD) MRI, ASL MRI, and phase contrast mapping (PCM) MRI.	Baseline (only measured once)
Brain atrophy and white matter lesion	Differences in brain atrophy and white matter lesion load between groups, assessed by T1- weighted structural MRI and Fluid-Attenuated Inversion Recovery (FLAIR) MRI.	Baseline (only measured once)
Correlation between brain atrophy and white matter lesions load and cognitive measures	Brain atrophy and white matter lesion load is assessed by T1- weighted structural MRI and FLAIR MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
Cerebral microbleeds	Differences in the amount of cerebral microbleeds between groups, assessed by susceptibility-weighted MRI.	Baseline (only measured once)
Correlation between cerebral microbleeds and cognitive measures	Cerebral microbleeds is assessed by susceptibility-weighted MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
Structural connectivity	Differences in structural connectivity between groups, assessed by diffusion tensor imaging (DTI) MRI.	Baseline (only measured once)
Correlation between structural connectivity and cognitive measures	Structural connectivity is assessed by DTI MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
White matter diffusion integrity	Differences in white matter diffusion parameters between groups, assessed by DTI MRI.	Baseline (only measured once)
Correlation between white matter diffusion integrity and cognitive measures	White matter diffusion is assessed by DTI MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once
Cerebral blood flow	Differences in resting cerebral blood flow between groups, assessed by ASL and PCM MRI.	Baseline (only measured once)
Correlation between resting cerebral blood flow and cognitive measures	Resting cerebral blood flow is assessed by ASL and PCM MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
Cerebral metabolic rate of oxygen	Differences in resting cerebral metabolic rate of oxygen between groups, assessed by combined PCM MRI and susceptibility-based oximetry (SBO) MRI.	Baseline (only measured once)
Correlation between cerebral metabolic rate of oxygen and cognitive measures	Cerebral metabolic rate of oxygen is assessed by combined PCM MRI and SBO MRI. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)
Regional brain glucose sensing	Differences in regional cerebral blood flow in response to glucose ingestion between groups, assessed by combined BOLD and ASL MRI.	Baseline (only measured once)
Correlation between hypothalamic glucose sensing and biomarkers	Cerebral blood flow response in the hypothalamus to glucose ingestion is assessed by combined BOLD and ASL MRI. A multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping will be used to identify reliable biomarkers of brain insulin sensing.	Baseline (only measured once)
Correlation between brain insulin response and hypothalamic glucose sensing	Brain insulin response is assessed by measuring changes in cerebral blood flow following administration of intranasal insulin using arterial spin labelling ASL MRI. Cerebral blood flow response in the hypothalamus to glucose ingestion is measured by combined BOLD and ASL MRI.	Baseline (only measured once)
Biomarkers of neuronal damage, neuroinflammation, and brain insulin response	Brain insulin response is assessed by measuring changes in cerebral blood flow following administration of intranasal insulin using ASL MRI. A multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping will be used to identify biomarkers of neuronal damage, neuroinflammation and brain insulin resistance.	Baseline (only measured once)
Biomarkers of blood-brain-barrier integrity and cerebrovascular function	Blood-brain-barrier permeability is assessed by dynamic contrast enhanced MRI A multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping will be used to identify biomarkers of vascular function and blood brain barrier integrity.	Baseline (only measured once)
Correlation between biomarkers and cognitive measures	A multiomics approach integrating lipidomics, metabolomics, proteomics, transcriptomics, and genotyping will be used to identify biomarkers of cognition. The neuropsychological test battery includes the following: Rey Auditory Verbal Learning Test (RAVLT); Trail Making Test (TMT) part A and B; Symbol Digit Modalities Test (SDMT); RBANS Digit Span forward (Version A); Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS); Verbal Fluency test (phonetic and semantic); Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)	Baseline (only measured once)

Collaborators and Investigators

• Sponsor: Henrik Bo Wiberg Larsson
• Collaborators: University of Ulm; Steno Diabetes Center Copenhagen
• Investigators: Principal Investigator: Henrik BW Larsson, Professor, Rigshospitalet, Denmark; Principal Investigator: Jørgen Rungby, Professor, Steno Diabetes Center Copenhagen; Principal Investigator: Flemming Pociot, Professor, Steno Diabetes Center Copenhagen; Principal Investigator: Martin Heni, Professor, University of Ulm

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Estimated): October 1, 2031
• Study Completion (Estimated): January 1, 2032

Study Registration Dates

• First Submitted: January 20, 2026
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 29, 2026

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Diabetes; biomarkers; cognitive performance; cognitive dysfunction; diabetes type 1; brain health; diabetes type 2; cerebrovascular function; blood-brain-barrier; Brain Insulin Resistance; structural changes in the brain
• Additional Relevant MeSH Terms: Endocrine System Diseases; Mental Disorders; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Neurocognitive Disorders; Glucose Metabolism Disorders; Cognition Disorders; Nutritional and Metabolic Diseases; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: NNF24OC0087481; H-25045491 (Other Identifier: Health Ethics Committee of Copenhagen)

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