Type 1 Diabetes and Depression: Role of Brain Glutamate

NCT05355285 | Completed

• 1 other identifier: NIH R01-DK084202
• Study Type: interventional
• Target: 68
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Type1diabetes; Depressive Symptoms; Major Depressive Disorder

Keywords

Hyperglycemia; Euglycemic hyperinsulinemic clamp; Euglycemia; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging; Glutamate

Outcome Measures

Primary Outcomes (2)

• Anterior cingulate cortex glutamate concentration during Baseline Euglycemia

  mmol/kg wet weight of brain tissue

  Baseline Euglycemia

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

  mmol/kg wet weight of brain tissue

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

Secondary Outcomes (15)

• Change in anterior cingulate cortex glutamate concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

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

• Change in occipital lobe glutamate concentration from Baseline Euglycemia to Hyperglycemia

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

• Change in occipital lobe glutamate concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia

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

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

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

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

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

Other Outcomes (8)

• Hamilton Depression rating (HAM-D)

  Baseline

• Revised Symptom Checklist rating (SCL-90-R)

  Baseline

• Wechsler Abbreviated Scale of Intelligence - intelligence quotient (WASI-IQ)

  Baseline

Study Arms (3)

Baseline Euglycemia

EXPERIMENTAL

Subjects 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).

Procedure: Glucose Clamp

Hyperglycemic Clamp

EXPERIMENTAL

Subjects 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.

Procedure: Glucose Clamp

Hyperinsulinemic Euglycemic Clamp

EXPERIMENTAL

Subjects 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.

Procedure: Glucose Clamp

Interventions

Glucose Clamp PROCEDURE

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

Also known as: Hyperglycemic, Euglycemic, or Hyperinsulinemic Euglycemic Clamp

Baseline Euglycemia; Hyperglycemic Clamp; Hyperinsulinemic Euglycemic Clamp

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• years duration of T1DM.
• Relatively low levels of complications from diabetes.

You may not qualify if:

• 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:
• No history of T1DM or Major Depressive Disorder.
• Normal fasting blood glucose, HbA1c and hematocrit levels.
• Known chronic medical illness such as rheumatoid arthritis or major cardiac, kidney or liver disease or anemia.
• 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:
• History of at least one episode of major depression.
• A 17-item HAM-D (HAMD-17) score ≥ 10 and ≤ 27
• 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.

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead

Related Publications (2)

• 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.

  PMID: 32295804 RESULT

• 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.

  PMID: 35417272 RESULT

MeSH Terms

Conditions

Depression; Depressive Disorder, Major; Hyperglycemia

Interventions

Glucose Clamp Technique

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Depressive Disorder; Mood Disorders; Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Nicolas R Bolo, PhD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Neuroimaging in Psychiatry

Model Details: 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).

Study Record Dates

• First Submitted: April 20, 2022
• First Posted: May 2, 2022
• Study Start: January 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: May 5, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share