Type1diabetes, Depressive Symptoms, Major Depressive Disorder
Conditions
Keywords
Hyperglycemia, Euglycemic hyperinsulinemic clamp, Euglycemia, Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging, Glutamate
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.
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.
Interventions
PROCEDUREGlucose Clamp
Subjects receive variable rates of glucose or insulin infusions to adjust and maintain desired plasma glucose or insulin levels.
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
T1DM Subjects: Inclusion Criteria: * 10-25 years duration of T1DM. * Relatively low levels of complications from diabetes.
Exclusion criteria
* 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: Inclusion Criteria: * No history of T1DM or Major Depressive Disorder. * Normal fasting blood glucose, HbA1c and hematocrit levels.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anterior cingulate cortex glutamate concentration during Baseline Euglycemia | Baseline Euglycemia | mmol/kg wet weight of brain tissue |
| Change in anterior cingulate cortex glutamate concentration from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | mmol/kg wet weight of brain tissue |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | mmol/kg wet weight of brain tissue |
| Change in Intrinsic Neuronal Activity from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | Fractional amplitude of low frequency fluctuations (fALFF) of fMRI signal |
| Change in Intrinsic Neuronal Activity from Baseline Euglycemia to Hyperinsulinemic Euglycemia | During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes | Fractional amplitude of low frequency fluctuations (fALFF) of fMRI signal |
| Change in Functional Connectivity from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | Correlation strength of fMRI signal fluctuations between brain regions |
| Change in Functional Connectivity from Baseline Euglycemia to Hyperinsulinemic Euglycemia | During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes | Correlation strength of fMRI signal fluctuations between brain regions |
| Change in plasma glucose concentration from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | mmol/L |
| Change in plasma glucose concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia | During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes | mmol/L |
| Change in plasma insulin concentration from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | micro-Unit/mL |
| Change in plasma insulin concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia | During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes | micro-Unit/mL |
| 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 | mmol/kg wet weight of brain tissue |
| Change in occipital lobe glutamate concentration from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | mmol/kg wet weight of brain tissue |
| Change in occipital lobe myo-inositol concentration from Baseline Euglycemia to Hyperglycemia | During the MRI scanning visit with hyperglycemic clamp, up to 180 minutes | mmol/kg wet weight of brain tissue |
| 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 | mmol/kg wet weight of brain tissue |
| 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 | mmol/kg wet weight of brain tissue |
| Change in occipital lobe myo-inositol concentration from Baseline Euglycemia to Hyperinsulinemic Euglycemia | During the MRI scanning visit with hyperinsulinemic euglycemic clamp, up to 180 minutes | mmol/kg wet weight of brain tissue |
Other
| Measure | Time frame | Description |
|---|---|---|
| Grooved Pegboard task time | Baseline | seconds |
| HbA1c | Baseline | Percentage |
| BMI | Baseline | kg/m2 |
| Emotional Stroop Task response time | Baseline | milli-seconds |
| Self Referential Emotional Task (SRET) response time | Baseline | milli-seconds |
| Revised Symptom Checklist rating (SCL-90-R) | Baseline | Revised Symptom Checklist rating Score from 0 to 360. Higher scores indicate worse symptoms. |
| Hamilton Depression rating (HAM-D) | Baseline | Hamilton depression rating Score from 0 to 51. Higher scores indicate worse depression. |
| Wechsler Abbreviated Scale of Intelligence - intelligence quotient (WASI-IQ) | Baseline | Wechsler Abbreviated Scale of Intelligence - intelligence quotient Score from 40 to 160 (mean = 100, standard deviation = 15). Higher scores indicate better intellectual ability. |
Outcome results
None listed