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
Is MRSI a promising treatment for type 2 diabetes?Yes, MRSI is a promising treatment for type 2 diabetes because it helps measure changes in brain glucose levels and neurotransmitters, which are important for understanding and managing the disease.247810
What safety data is available for the use of MRSI in brain glucose studies?The studies reviewed indicate that MRSI, including its variants like 1H-MRSI, is a non-invasive and safe method for measuring brain glucose metabolism. It has been used in various settings, such as monitoring glucose concentration changes in the hypothalamus, examining the effects of insulin on cerebral glucose concentrations, and studying glucose metabolism in neurological disorders. These studies suggest that MRSI is a feasible and safe technique for brain glucose transport studies, with no reported adverse effects in the human and animal studies mentioned.156811
What data supports the idea that Brain Glucose Transport Study for Type 2 Diabetes is an effective treatment?The available research does not provide direct evidence that the Brain Glucose Transport Study for Type 2 Diabetes is an effective treatment. The studies focus on measuring brain glucose levels and other brain chemicals in different conditions, but they do not show how this treatment improves health outcomes for people with type 2 diabetes. For example, one study measured brain glucose in people with poorly controlled diabetes and found no significant difference compared to healthy individuals. Another study looked at changes in brain chemicals in type 2 diabetes patients but did not link these changes to treatment effectiveness. Therefore, there is no clear data supporting the effectiveness of this treatment for type 2 diabetes.348910
Do I need to stop my current medications for this trial?The trial protocol does not specify if you need to stop your current medications. However, you must be willing to intensify your diabetes regimen, which might involve changes to your current treatment.
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 between 18 and 60 years old.
My HbA1c is above 7.5% and my BMI is 18 or higher.
Exclusion Criteria
I am not pregnant, trying to get pregnant, or breastfeeding.
I have a diagnosed neurological disorder.
My high blood pressure is not under control.
I have a thyroid condition that hasn't been treated.
I have been diagnosed with cancer.
I have used steroids in the last 3 months.
I have a bleeding disorder.
Treatment Details
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.
1Treatment groups
Experimental Treatment
Group I: Brain Glucose Levels in Participants with Type 2 DiabetesExperimental Treatment1 Intervention
Intensification of diabetes management
MRSI is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Magnetic Resonance Spectroscopy Imaging for:
- Diagnostic imaging for various conditions including brain disorders
🇪🇺 Approved in European Union as Magnetic Resonance Spectroscopy Imaging for:
- Diagnostic imaging for various conditions including neurological disorders
🇨🇦 Approved in Canada as Magnetic Resonance Spectroscopy Imaging for:
- Diagnostic imaging for various conditions including brain disorders
Find a clinic near you
Research locations nearbySelect from list below to view details:
Yale New Haven Hospital (YNHH) Research Unit (HRU)New Haven, CT
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Who is running the clinical trial?
Yale UniversityLead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
References
The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. [2019]The continuous delivery of glucose to the brain is critically important to the maintenance of normal metabolic function. However, elucidation of the hormonal regulation of in vivo cerebral glucose metabolism in humans has been limited by the lack of direct, noninvasive methods with which to measure brain glucose. In this study, we sought to directly examine the effect of insulin on glucose concentrations and rates of glucose transport/metabolism in human brain using (1)H-magnetic resonance spectroscopy at 4 Tesla. Seven subjects participated in paired hyperglycemic (16.3 +/- 0.3 mmol/l) clamp studies performed with and without insulin. Brain glucose remained constant throughout (5.3 +/- 0.3 micromol/g wet wt when serum insulin = 16 +/- 7 pmol/l vs. 5.5 +/- 0.3 micromol/g wet wt when serum insulin = 668 +/- 81 pmol/l, P = NS). Glucose concentrations in gray matter-rich occipital cortex and white matter-rich periventricular tissue were then simultaneously measured in clamps, where plasma glucose ranged from 4.4 to 24.5 mmol/l and insulin was infused at 0.5 mU. kg(-1). min(-1). The relationship between plasma and brain glucose was linear in both regions. Reversible Michaelis-Menten kinetics fit these data best, and no differences were found in the kinetic constants calculated for each region. These data support the hypothesis that the majority of cerebral glucose uptake/metabolism is an insulin-independent process in humans.
Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy. [2006]Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p
Insights into the acute cerebral metabolic changes associated with childhood diabetes. [2016]Type 1 diabetes is a prevalent chronic disease in childhood with the commonest single cause of death being cerebral oedema in the context of diabetic ketoacidosis (DKA). The nature of the alterations in cerebral metabolism that may result in vulnerability to neuronal injury remains unknown. The aim of this study was to analyse the magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain data from eight children with diabetes following acute presentation with hyperglycaemia with or without ketoacidosis, to determine the nature and timing of any alterations in cerebral structure and metabolism.
Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy. [2022]Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% +/- 1.7%, mean +/- SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 +/- 0.9 vs 5.3 +/- 1.1 micromol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 micromol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects.
Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla. [2018]Proton magnetic resonance spectroscopy ((1)H-MRS) studies showing increased lactate during neural activation support a broader role for lactate in brain energy metabolism than was traditionally recognized. Proton MRS measures of brain lactate responses have been used to study regional brain metabolism in clinical populations. This study examined whether variations in blood glucose influence the lactate response to visual stimulation in the visual cortex. Six subjects were scanned twice, receiving either saline or 21% glucose intravenously. Using (1)H-MRS at 1.5 Tesla with a long echo time (TE=288 ms), the lactate doublet was visible at 1.32 ppm in the visual cortex of all subjects. Lactate increased significantly from resting to visual stimulation. Hyperglycemia had no effect on this increase. The order of the slice-selective gradients for defining the spectroscopy voxel had a pronounced effect on the extent of contamination by signal originating outside the voxel. The results of this preliminary study demonstrate a method for observing a consistent activity-stimulated increase in brain lactate at 1.5 T and show that variations in blood glucose across the normal range have little effect on this response.
1H-MRSI pattern perturbation in a mouse glioma: the effects of acute hyperglycemia and moderate hypothermia. [2010]MR spectroscopic Imaging (MRSI), with PRESS localization, is used here to monitor the effects of acute hyperglycemia in the spectral pattern of 11 mice bearing GL261 gliomas at normothermia (36.5-37.5 degrees C) and at hypothermia (28.5-29.5 degrees C). These in vivo studies were complemented by ex vivo high resolution magic angle spinning (HR-MAS) analysis of GL261 tumor samples from 6 animals sacrificed by focused microwave irradiation, and blood glucose measurements in 12 control mice. Apparent glucose levels, monitored by in vivo MRSI in brain tumors during acute hyperglycemia, rose to an average of 1.6-fold during hypothermia (p
Metabolite differences in the lenticular nucleus in type 2 diabetes mellitus shown by proton MR spectroscopy. [2021]Previous studies by using proton MR spectroscopy found metabolite abnormalities in the cerebral cortex and white matter of patients with type 2 diabetes mellitus. The present study was undertaken to detect metabolite differences in the lenticular nuclei and thalamus in patients with T2DM.
Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T. [2018]To evaluate the feasibility of using a clinical magnetic resonance (MR) system and MR spectroscopy (MRS) to measure glucose concentration changes in the human hypothalamus, a structure central to whole-body glucose regulation.
Changes in cerebral metabolites in type 2 diabetes mellitus: A meta-analysis of proton magnetic resonance spectroscopy. [2018]To investigate whether there were differences and consistent patterns that highlight and consolidate the metabolite changes in type 2 diabetes mellitus (T2DM), a meta-analysis of proton magnetic resonance spectroscopy (MRS) was conducted. PubMed, Web of Science, and Embase databases were searched up to August 2016 for collecting the relevant studies. After an inclusion and exclusion criteria, the data was extracted. The data was analyzed using Stata software v.12.0. The weight mean difference (MD) and 95% confidence interval (CI) were used to compare continuous variables. A total of 10 studies (with a total of 244 T2DM patients and 223 healthy controls) were included. N-Acetyl Aspartate (NAA)/creatine (Cr) levels were decreased in the frontal lobe (MD=-0.20, 95%CI=-0.33 to -0.06, P=0.005) and lenticular nucleus (MD=-0.14, 95%CI=-0.22 to -0.06, P=0.001); choline (Cho)/Cr levels were increased in the lenticular nucleus (MD=0.15, 95%CI=0.02-0.28, P=0.025); myo-inositol (MI)/Cr levels were increased in the in the occipital lobe (MD=0.11, 95%CI=0.02-0.19, P=0.017) and parietal lobe (MD=0.16, 95%CI=0.05-0.28, P=0.006); MI levels were increased in the frontal white matter (MD=0.52, 95%CI=0.14-0.90, P=0.008). The results of our meta-analysis indicated that metabolite levels were altered in different regions of brain, which may be shown with MRS and caused clinical symptoms in T2DM further.
Monitoring the Neurotransmitter Response to Glycemic Changes Using an Advanced Magnetic Resonance Spectroscopy Protocol at 7T. [2022]>The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-quality data. Data were acquired with a semi-LASER sequence [repetition time/echo time (TR/TE) = 5,000/26 ms] from volumes of interest (VOIs) in the prefrontal cortex (PFC) and hypothalamus (HTL). Five healthy volunteers were scanned to evaluate the effect of the BaTiO3 pads on B 1 + distribution. Use of BaTiO3 padding resulted in a 60% gain in signal-to-noise ratio in the PFC VOI over the acquisition without the pad. The protocol was tested in six patients with type 1 diabetes during a clamp study where euglycemic (~100 mg/dL) and hypoglycemic (~50 mg/dL) blood Glc levels were maintained in the scanner. The new protocol allowed retention of all HTL data compared with our prior experience of having to exclude approximately half of the HTL data in similar clamp experiments in the 7T scanner due to subject motion. The advanced MRS protocol showed excellent data quality (reliable quantification of 11-12 metabolites) and stability (p > 0.05 for both signal-to-noise ratio and water linewidths) between euglycemia and hypoglycemia. Decreased brain Glc levels under hypoglycemia were reliably detected in both VOIs. In addition, mean Glu level trended lower at hypoglycemia than euglycemia for both VOIs, consistent with prior observations in the occipital cortex. This protocol will allow robust mechanistic investigations of the primary neurotransmitters, Glu and GABA, under changing glycemic conditions.
1H magnetic resonance spectroscopic imaging of deuterated glucose and of neurotransmitter metabolism at 7 T in the human brain. [2023]Impaired glucose metabolism in the brain has been linked to several neurological disorders. Positron emission tomography and carbon-13 magnetic resonance spectroscopic imaging (MRSI) can be used to quantify the metabolism of glucose, but these methods involve exposure to radiation, cannot quantify downstream metabolism, or have poor spatial resolution. Deuterium MRSI (2H-MRSI) is a non-invasive and safe alternative for the quantification of the metabolism of 2H-labelled substrates such as glucose and their downstream metabolic products, yet it can only measure a limited number of deuterated compounds and requires specialized hardware. Here we show that proton MRSI (1H-MRSI) at 7 T has higher sensitivity, chemical specificity and spatiotemporal resolution than 2H-MRSI. We used 1H-MRSI in five volunteers to differentiate glutamate, glutamine, γ-aminobutyric acid and glucose deuterated at specific molecular positions, and to simultaneously map deuterated and non-deuterated metabolites. 1H-MRSI, which is amenable to clinically available magnetic-resonance hardware, may facilitate the study of glucose metabolism in the brain and its potential roles in neurological disorders.