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Type1diabetesNCT05355285

Type 1 Diabetes and Depression: Role of Brain Glutamate

A study testing Glucose Clamp in people with Type1diabetes and Depressive Symptoms, run by Beth Israel Deaconess Medical Center.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The goal of this study is to examine the effect of chronic and acute hyperglycemia in type 1 diabetes mellitus (T1DM) on brain glutamate levels using magnetic resonance spectroscopy (MRS), and associations of brain glutamate with symptoms of depression. Read more about this study

Who is it for?
Ages 18 to 50 yearsHealthy volunteers can take part
What is being tested?
Glucose Clamp
Could I receive a placebo?
No, everyone receives an active treatment
How many people
68 participants
Where
No sites listed yet
Study dates
Jan 2011to Nov 2014
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 10-25 years duration of T1DM.
  • Relatively low levels of complications from diabetes.
  • No history of T1DM or Major Depressive Disorder.
  • Normal fasting blood glucose, HbA1c and hematocrit levels.
  • History of at least one episode of major depression.
  • A 17-item HAM-D (HAMD-17) score ≥ 10 and ≤ 27

Who cannot join

  • Type 2 diabetes and/or gestational diabetes.
  • Other major clinical conditions such as cancer, symptomatic coronary artery disease, (e.g., prior myocardial infarction), stroke, proliferative diabetic retinopathy requiring a laser treatment, clinically significant diabetic nephropathy as evidenced by urinary albumin levels > 300 mg/day and/or serum creatinine > 1.5 mg/dl for men and > 1.4 mg/dl for women, painful or symptomatic neuropathy, and/or diagnosed gastroparesis.
  • Current or past history of attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, panic disorder, substance dependence or schizophrenia.
  • Ethanol dependence and/or nicotine dependence according to Diagnostic and Statistical Manual-IV criteria and heavy smokers according to the Epidemiology of Diabetes Interventions and Complications scale 57.
  • Control Subjects:
  • Known chronic medical illness such as rheumatoid arthritis or major cardiac, kidney or liver disease or anemia.
Show all 30Show fewer
  • Current or past history of attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, panic disorder, substance dependence or schizophrenia.
  • Past history of a major depressive episode, as well as with current symptoms of depression as defined by a HAMD-17 score ≥ 10.
  • Subjects with depressive history and current depressive symptoms:
  • Current or past history of attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, panic disorder, substance dependence or schizophrenia.
  • Subjects under current treatment with antidepressant medication.
  • Subjects with acute severe depression or acute suicidal ideation, who in the opinion of the psychiatrist are clinically inappropriate for participation in the study.
  • Subjects who in the opinion of the psychiatrist are clinically inappropriate for a one-week delay in antidepressant medication treatment.
  • HAMD-17 score > 27.
  • All Subjects:
  • Participants who have metal in their body, suffer from claustrophobia or panic disorder or women who are pregnant, or who are currently breast-feeding cannot participate in this research study.
  • Additional MR exclusion criteria include people with:
  • Cardiac pacemakers
  • Metal clips on blood vessels (also called stents)
  • Artificial heart valves
  • Artificial arms, hands, legs, etc.
  • Brain stimulator devices
  • Implanted drug pumps
  • Ear implants
  • Eye implants or known metal fragments in eyes
  • Exposure to shrapnel or metal filings (wounded in military combat, sheet metal workers, welders, and others)
  • Other metallic surgical hardware in vital areas
  • Certain tattoos with metallic ink (subjects are requested to inform the investigator if they have a tattoo)
  • Certain transdermal (skin) patches such as NicoDerm (nicotine for tobacco dependence), Transderm Scop (scopolamine for motion sickness), or Ortho Evra (birth control).
  • Claustrophobia

About this study

The goal of this study is to examine the effect of chronic and acute hyperglycemia in type 1 diabetes mellitus (T1DM) on brain glutamate levels using magnetic resonance spectroscopy (MRS), and associations of brain glutamate with symptoms of depression.

Read the detailed description

The research of this study is focused on elucidating the relationship between the perturbations in glucose metabolism associated with T1DM and the higher prevalence of major depressive episodes in this patient population. Converging evidence associating high brain levels of glutamate with T1DM and depression leads to the hypothesis that the link between diabetes-related glucose metabolic disorders and depression is excessive brain glutamate. The overarching aim of the study is to examine the effect of chronic and acute hyperglycemia in T1DM on brain glutamate levels. Four subject groups were studied and characterized: T1DM patients with and without concurrent depressive symptoms, and non-diabetic subjects with and without concurrent depressive symptoms. Two brain regions were examined : the anterior cingulate cortex (ACC), known to play an essential role in the regulation of emotions, and a control occipital cortex region. Regional brain glutamate concentrations were measured using high-field (3 Tesla) localized multidimensional magnetic resonance spectroscopy (MRS), regional indices of brain function were assessed using functional magnetic resonance imaging (fMRI), concurrent depression symptom severity and depression history were evaluated using psychiatric assessment, extensive medical evaluation of patients was performed including evaluation of glycemic control (HbA1c), evaluation of behavioral performance on emotional and cognitive tasks and evaluation of regional brain cortical thickness using high-resolution structural MRI. For all subjects, MRS brain glutamate was assessed during basal euglycemia and, for a subset of subjects per group, during an acute hyperglycemic clamp. To control for potential confounding effects of hyperinsulinemia, brain glutamate was also assessed during a euglycemic hyperinsulinemic clamp in a subset of healthy controls without diabetes or depressive symptoms.

Being tested
Glucose Clamp
Keywords
Hyperglycemia, Euglycemic hyperinsulinemic clamp, Euglycemia, Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging, Glutamate
Medical subject headings
Depression, Depressive Disorder, Major, Hyperglycemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Glucose ClampProcedure or surgery

    Also called Hyperglycemic, Euglycemic, or Hyperinsulinemic Euglycemic Clamp

    Subjects receive variable rates of glucose or insulin infusions to adjust and maintain desired plasma glucose or insulin levels.

Study groups in NCT05355285
Study groupRoleWhat they receive
Baseline EuglycemiaExperimentalSubjects with T1DM (Groups 1 and 2): 1) receive a low dose insulin infusion to reduce their plasma glucose to euglycemia; 2) receive a continuous infusion of insulin at the rate of 0.25 milli-Units/kg/min to maintain euglycemia during a Baseline MRI scanning period. Subjects without diabetes (Groups 3 and 4) are scanned during a Baseline MRI scanning period (no intervention is needed to maintain euglycemia in these subjects).
Receives: Procedure: Glucose Clamp
Hyperglycemic ClampExperimentalSubjects with T1DM (Groups 1 and 2): 1) receive a primed variable glucose infusion to attain a target increase in glycemic level of +5.5 mmol/L; 2) receive a continuous infusion of insulin at the rate of 0.25 milli-Units/kg/min. Subjects without diabetes (Groups 3 and 4): 1) receive a primed variable glucose infusion to attain a target increase in glycemic level of +5.5 mmol/L.
Receives: Procedure: Glucose Clamp
Hyperinsulinemic Euglycemic ClampExperimentalSubjects without diabetes or depression (Group 3) have a second study visit at least 15 days after the Hyperglycemic Clamp visit. They receive a variable insulin infusion to match individual insulin levels to the levels attained during the Hyperglycemic Clamp and they receive a variable glucose infusion to maintain euglycemia.
Receives: Procedure: Glucose Clamp

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Anterior cingulate cortex glutamate concentration during Baseline Euglycemia

    mmol/kg wet weight of brain tissue

    Measured: Baseline Euglycemia

  2. Change in anterior cingulate cortex glutamate concentration from Baseline Euglycemia to Hyperglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

Secondary outcomes (15)
  1. Change in anterior cingulate cortex glutamate concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  2. Change in occipital lobe glutamate concentration from Baseline Euglycemia to Hyperglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  3. Change in occipital lobe glutamate concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  4. Change in anterior cingulate cortex myo-inositol concentration from Baseline Euglycemia to Hyperglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  5. Change in anterior cingulate cortex myo-inositol concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  6. Change in occipital lobe myo-inositol concentration from Baseline Euglycemia to Hyperglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  7. Change in occipital lobe myo-inositol concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    mmol/kg wet weight of brain tissue

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  8. Change in Intrinsic Neuronal Activity from Baseline Euglycemia to Hyperglycemia

    Fractional amplitude of low frequency fluctuations (fALFF) of fMRI signal

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  9. Change in Intrinsic Neuronal Activity from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    Fractional amplitude of low frequency fluctuations (fALFF) of fMRI signal

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  10. Change in Functional Connectivity from Baseline Euglycemia to Hyperglycemia

    Correlation strength of fMRI signal fluctuations between brain regions

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  11. Change in Functional Connectivity from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    Correlation strength of fMRI signal fluctuations between brain regions

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  12. Change in plasma glucose concentration from Baseline Euglycemia to Hyperglycemia

    mmol/L

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  13. Change in plasma glucose concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    mmol/L

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

  14. Change in plasma insulin concentration from Baseline Euglycemia to Hyperglycemia

    micro-Unit/mL

    Measured: During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes

  15. Change in plasma insulin concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

    micro-Unit/mL

    Measured: During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2022
  2. Study startJan 2011
  3. Primary completionNov 2014
  4. Study completionNov 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
There are 4 subject groups for this study: 1) T1DM without current depressive symptoms with no history of major depressive disorder; 2) T1DM with current depressive symptoms and with a history of major depressive disorder; 3) Non-diabetic controls without current depressive symptoms and with no history of major depression; 4) Non-diabetic controls with current depressive symptoms and with major depression history. For all subjects, MRS brain glutamate is assessed during basal euglycemia, and for a subset of subjects per group, during an acute hyperglycemic clamp. To control for potential confounding effects of hyperinsulinemia, brain glutamate is also assessed during a euglycemic hyperinsulinemic clamp in a subset of controls (group 3).
Masking
None (open label)
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05355285
Sponsor's protocol ID
NIH R01-DK084202
Status last verified
Apr 2022
First submitted
20 Apr 2022
Last updated
5 May 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Bolo NR, Jacobson AM, Musen G, Keshavan MS, Simonson DC. Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes. Diabetes. 2020 Jul;69(7):1528-1539. doi: 10.2337/db19-0936. Epub 2020 Apr 15.

    PubMed 32295804
  • Bolo NR, Jacobson AM, Musen G, Simonson DC. Hyperglycemia and hyperinsulinemia effects on anterior cingulate cortex myoinositol-relation to brain network functional connectivity in healthy adults. J Neurophysiol. 2022 May 1;127(5):1426-1437. doi: 10.1152/jn.00408.2021. Epub 2022 Apr 13.

    PubMed 35417272

Questions about this trial

What is this clinical trial studying?

A study testing Glucose Clamp in people with Type1diabetes and Depressive Symptoms, run by Beth Israel Deaconess Medical Center.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 May 2022. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Anterior cingulate cortex glutamate concentration during Baseline Euglycemia (time frame: Baseline Euglycemia). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05355285, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2022.

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