Brain Glucose Transport Study for Type 2 Diabetes

Overseen by Elizabeth Sanchez Rangel, MD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Yale University

Must not be taking: Steroids, Illicit drugs

Disqualifiers: Uncontrolled hypertension, Neurological disorders, Malignancy, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn about the effects of high blood glucose levels in the brain and assess if the changes seen in individuals with poorly control T2DM can be reversed with good glucose control. The main question\[s\] it aims to answer are: * To determine, whether abnormalities in brain glucose transport seen in individuals with uncontrolled diabetes, can be improved with better glucose control. * Assess which factors, (duration of diabetes mellitus (DM) and glycemic control) contribute to changes in glucose transport Participants will have: * A screening visit * placement of a continuous glucose monitor (CGM) 2 weeks before the first magnetic resonance spectroscopy (MRS) at week 0 * Additional visits/phone calls for intensification of diabetes management and nutrition visits * Second magnetic resonance spectroscopy (MRS) at week 12

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must be willing to follow an intensified diabetes management plan, which might involve changes to your current diabetes treatment.

What data supports the effectiveness of the treatment MRSI, Magnetic Resonance Spectroscopy Imaging, for Type 2 Diabetes?

Research shows that Magnetic Resonance Spectroscopy (MRS) can reliably measure changes in brain glucose and other important chemicals in people with diabetes, which helps understand how diabetes affects the brain. This suggests that MRSI could be useful in studying and potentially improving brain glucose transport in Type 2 Diabetes. ^{1 2 3 4 5}

Is Magnetic Resonance Spectroscopic Imaging (MRSI) safe for humans?

MRSI is a non-invasive and safe method used to study brain glucose metabolism and other metabolic processes in humans, as shown in studies involving healthy volunteers and various conditions. ^{1 6 7 8 9}

How is the MRSI treatment unique for type 2 diabetes?

MRSI (Magnetic Resonance Spectroscopy Imaging) is unique because it allows researchers to measure changes in brain glucose levels and neurotransmitter responses, providing insights into how the brain processes glucose in people with type 2 diabetes, which is different from traditional treatments that focus on blood sugar control. ^{1 2 3 10 11}

Research Team

Elizabeth Sanchez Rangel, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults aged 18-60 with Type 2 diabetes who have high blood sugar levels (HbA1c > 7.5%) and a BMI of at least 18 kg/m2. Participants must consent to the study's procedures, be available throughout its duration, and agree to intensify their diabetes management.

Inclusion Criteria

I have a history of Type 2 diabetes.

I have a history of Type 2 diabetes.

I am willing and able to follow all study rules and attend all appointments.

Exclusion Criteria

I am not pregnant, trying to get pregnant, or breastfeeding.

Illicit drug use

I have a diagnosed neurological disorder.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Pre-Treatment

Placement of a continuous glucose monitor (CGM) 2 weeks before the first magnetic resonance spectroscopy (MRS) at week 0

2 weeks

1 visit (in-person)

Treatment

Intensification of diabetes management and nutrition visits, with a second MRS at week 12

12 weeks

Multiple visits/phone calls

Follow-up

Participants are monitored for changes in brain glucose transport and glycemic control

4 weeks

Treatment Details

Interventions

• MRSI (Imaging)

Trial Overview The study uses Magnetic Resonance Spectroscopy Imaging (MRSI) to see if brain glucose transport changes in people with uncontrolled Type 2 diabetes can be reversed by improving blood sugar control over a period of three months.

Participant Groups

Group I: Aim 1 Experimental Treatment 3 Interventions

Intervention before and after study with subjects with uncontrolled T2DM to measured brain glucose transport specifically in the occipital lobe during acute hyperglycemia

MRSI is already approved in Canada for the following indications:

Approved in Canada as Magnetic Resonance Spectroscopy Imaging for:

• Diagnostic imaging for various conditions including brain disorders

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Executive Officer since 2007

MD, M.A.C.P.

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Medical Officer since 2007

MD, M.A.C.P.

Findings from Research

This study demonstrates that it is feasible to measure glucose concentration changes in the human hypothalamus using a standard 3T MRI system and MR spectroscopy, with reliable results obtained during hyperglycemic conditions.

Increased glucose and taurine concentrations were observed in the hypothalamus during hyperglycemia, particularly in subjects with plasma glucose levels above 300 mg/dl, indicating a significant relationship between hypothalamic glucose levels and blood glucose concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T. Joers, JM., Deelchand, DK., Kumar, A., et al.[2018]

An advanced magnetic resonance spectroscopy (MRS) protocol was developed that significantly improved the measurement of brain metabolites, achieving a 60% increase in signal-to-noise ratio using BaTiO3 dielectric padding, which enhances data quality during scans.

This protocol successfully monitored changes in neurotransmitter levels, showing reliable detection of decreased glucose and a trend of lower glutamate levels during hypoglycemia in patients with type 1 diabetes, facilitating better understanding of brain responses to glycemic changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring the Neurotransmitter Response to Glycemic Changes Using an Advanced Magnetic Resonance Spectroscopy Protocol at 7T. Park, YW., Deelchand, DK., Joers, JM., et al.[2022]

In a study involving 14 patients with poorly controlled diabetes and 14 healthy volunteers, brain glucose concentrations were found to be lower in diabetic patients, but the difference was not statistically significant, suggesting that chronic hyperglycemia may not affect brain glucose levels in humans.

The study utilized proton magnetic resonance spectroscopy to measure glucose levels in the occipital cortex at a plasma glucose level of 300 mg/dL, indicating that even with high blood sugar, brain glucose concentrations remained similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy. Seaquist, ER., Tkac, I., Damberg, G., et al.[2022]

A meta-analysis of 10 studies involving 244 patients with type 2 diabetes mellitus (T2DM) revealed significant changes in brain metabolites, including decreased N-Acetyl Aspartate (NAA) levels and increased choline (Cho) and myo-inositol (MI) levels in various brain regions, indicating potential metabolic disturbances associated with T2DM.

These metabolite alterations, observed through proton magnetic resonance spectroscopy (MRS), suggest a link between brain chemistry changes and clinical symptoms in T2DM, highlighting the importance of understanding these changes for better management of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cerebral metabolites in type 2 diabetes mellitus: A meta-analysis of proton magnetic resonance spectroscopy. Wu, GY., Zhang, Q., Wu, JL., et al.[2018]

In a study of eight children with type 1 diabetes, MRI scans revealed abnormal signals in the frontal brain region, indicating potential cerebral edema, particularly in those presenting with diabetic ketoacidosis (DKA).

The study found increased levels of taurine, myoinositol, and glucose in the brain, suggesting that these metabolic changes may contribute to the vulnerability of diabetic children to cerebral complications during DKA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insights into the acute cerebral metabolic changes associated with childhood diabetes. Cameron, FJ., Kean, MJ., Wellard, RM., et al.[2016]

In a study involving 11 mice with GL261 gliomas, acute hyperglycemia significantly increased glucose levels in brain tumors during hypothermia, with levels rising to an average of 1.6-fold, indicating a metabolic response to temperature changes.

Ex vivo analysis showed even greater glucose increases (up to 6.6-fold) in specific tumor regions during acute hyperglycemia, highlighting the heterogeneity of brain tumors and their varying responses to metabolic challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

1H-MRSI pattern perturbation in a mouse glioma: the effects of acute hyperglycemia and moderate hypothermia. Simões, RV., Delgado-Goñi, T., Lope-Piedrafita, S., et al.[2010]

In a study involving 7 subjects, insulin did not significantly affect brain glucose concentrations during hyperglycemic clamp studies, suggesting that brain glucose metabolism is largely independent of insulin.

The research utilized advanced (1)H-magnetic resonance spectroscopy to measure glucose levels in different brain regions, confirming a linear relationship between plasma and brain glucose, and indicating that most cerebral glucose uptake occurs without insulin involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Seaquist, ER., Damberg, GS., Tkac, I., et al.[2019]

This study used proton magnetic resonance spectroscopy (1H-MRS) to show that brain lactate levels significantly increase during visual stimulation, indicating a broader role for lactate in brain energy metabolism.

Variations in blood glucose levels did not affect the lactate response during visual stimulation, suggesting that the brain's lactate response is stable across normal glucose ranges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla. Maddock, RJ., Buonocore, MH., Lavoie, SP., et al.[2018]

Proton magnetic resonance spectroscopic imaging (1H-MRSI) at 7T offers a safer and more effective way to study brain glucose metabolism compared to deuterium MRSI (2H-MRSI), with better sensitivity and spatial resolution.

In a study involving five volunteers, 1H-MRSI successfully differentiated various metabolites, including glutamate and glucose, which could enhance our understanding of glucose metabolism's role in neurological disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

1H magnetic resonance spectroscopic imaging of deuterated glucose and of neurotransmitter metabolism at 7 T in the human brain. Bednarik, P., Goranovic, D., Svatkova, A., et al.[2023]

In a study using 1H magnetic resonance spectroscopy on Zucker Diabetic Fatty rats, significant increases in hippocampal glucose, myo-inositol, and total creatine levels were observed, indicating metabolic changes associated with type 2 diabetes.

The findings suggest that elevated levels of glucose and myo-inositol in the brain may reflect similar changes seen in human patients with diabetes, highlighting potential metabolic markers for the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy. van der Graaf, M., Janssen, SW., van Asten, JJ., et al.[2006]

In a study involving 20 patients with type 2 diabetes mellitus (T2DM) and 22 control subjects, significant metabolic differences were found in the lenticular nuclei, with lower NAA/Cr ratios and higher Cho/Cr ratios in T2DM patients, indicating altered brain metabolism associated with the disease.

The study suggests that the lenticular nuclei are more affected by T2DM than the thalamus, as these metabolic changes were detected before any visible lesions appeared, highlighting the early impact of diabetes on brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolite differences in the lenticular nucleus in type 2 diabetes mellitus shown by proton MR spectroscopy. Lin, Y., Zhou, J., Sha, L., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Monitoring the Neurotransmitter Response to Glycemic Changes Using an Advanced Magnetic Resonance Spectroscopy Protocol at 7T. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy. [2022]

4. Scotland pubmed.ncbi.nlm.nih.gov

Changes in cerebral metabolites in type 2 diabetes mellitus: A meta-analysis of proton magnetic resonance spectroscopy. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Insights into the acute cerebral metabolic changes associated with childhood diabetes. [2016]

6. England pubmed.ncbi.nlm.nih.gov

1H-MRSI pattern perturbation in a mouse glioma: the effects of acute hyperglycemia and moderate hypothermia. [2010]

7. United States pubmed.ncbi.nlm.nih.gov

The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. [2019]

8. Ireland pubmed.ncbi.nlm.nih.gov

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla. [2018]

9. England pubmed.ncbi.nlm.nih.gov

1H magnetic resonance spectroscopic imaging of deuterated glucose and of neurotransmitter metabolism at 7 T in the human brain. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy. [2006]

11. United States pubmed.ncbi.nlm.nih.gov

Metabolite differences in the lenticular nucleus in type 2 diabetes mellitus shown by proton MR spectroscopy. [2021]