Type 2 Diabetes and the Brain in Adolescents

Study Overview
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Brief Summary
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This study evaluates differences in brain function and cognitive performance in adolescents with type 2 diabetes (T2D) compared to non diabetic controls (both obese and lean) and correlates these changes with obesity, insulin resistance, and glycemic control in youth with T2D.

Detailed Description
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This is a cross-sectional study examining neurocognitive function and brain activity in resting state and during working memory and executive function tasks using blood oxygen level dependent (BOLD) functional MRI (fMRI) during hyperinsulinemic euglycemic and hyperglycemic clamps in obese adolescents with T2D compared to non-diabetic obese and lean controls. The investigators will measure glycemic control (acute hyperglycemia during clamps and glycemic variability) and insulin resistance to examine their association with neurocognitive metrics and brain functional activity. There will be one screening visit and three study visits for subjects with T2D. One visit will consist of neurocognitive testing and dual energy X-ray absorptiometry (DEXA) of the whole body to assess body composition including fat mass. In the other two visits, subjects with T2D will undergo normal and high glucose clamps during fMRI. Obese and lean control subjects will have one screening visit and two study visits, one for neurocognitive testing and DEXA and another for fMRI without glucose clamps. All subjects will have a blood sample obtained at the screening visit. Only adolescents with type 2 diabetes will wear a continuous glucose monitor (CGM) for 6 days prior to neuroimaging to determine glycemic variability. A1C will be assessed at baseline. Parents of subjects will also have abbreviated IQ testing.

Official Title
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Dysglycemia & Obesity: Impact on the Brain in Adolescents With Type 2 Diabetes

Conditions
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Dysglycemia, Hyperglycemia, Type 2 Diabetes Mellitus, Obesity, Pediatric Obesity, Insulin Resistance

Intervention / Treatment
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* Procedure: Hyperglycemic clamp
* Procedure: Hyperinsulinemic Euglycemic clamp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes: BMI ≥85th percentile A1c ≥ 8% Pubertal Healthy Controls: BMI ≥85th percentile for Obese Controls BMI < 85th percentile for Lean Controls Pubertal Normal A1c & Fasting glucose Exclusion Criteria: Significant developmental delay or learning disability Significant visual or auditory deficits Born <34 weeks gestation Neurologic disease Psychiatric disease requiring inpatient treatment Significant head trauma Malignancy Pregnancy Weight > 350lb (MRI weight limit) Metal in the body (including dental braces)

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Type 2 Diabetes<br>Hyperglycemic clamp and Hyperinsulinemic Euglycemic clamp | Procedure: Hyperglycemic clamp<br>* Subjects with T2D will receive IV Dextrose infusion to maintain plasma glucose at  250 mg/dL during fMRI.<br>Procedure: Hyperinsulinemic Euglycemic clamp<br>* Subjects with T2D will receive IV Dextrose and Insulin infusion to maintain plasma glucose at approximately 90 mg/dL during fMRI.<br>|
| No Intervention: Lean Control<br>Controls do not undergo Hyperglycemic clamp and Hyperinsulinemic Euglycemic clamp | |
| No Intervention: Obese Control<br>Controls do not undergo Hyperglycemic clamp and Hyperinsulinemic Euglycemic clamp | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Activity using functional MRI (fMRI) | The investigators will examine functional connectivity of brain networks during cross sectional resting-state and task-related (working memory and response inhibition) BOLD-fMRI activation. fMRI activation in adolescents with T2D will be compared to age- and sex- matched, non-diabetic, healthy lean and obese controls. | Baseline | 
| Neurocognitive battery metrics including IQ as well as executive function and visual-spatial memory | The investigators will evaluate cognitive performance by examining test scores from neurocognitive metrics which reflect global IQ, spatial recognition, episodic memory, executive function (includes response inhibition, working memory), academic achievement, and processing speed. Adolescents with T2D will be compared to controls to determine whether these differences are associated with glycemic control, obesity, and insulin resistance. | Baseline | 
| fMRI performance in relation to dysglycemia | In adolescents with T2D, the investigators will examine BOLD-fMRI brain activation in relation to acute hyperglycemia during glucose clamping, chronic hyperglycemia, glycemic variability, and insulin resistance. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, MRI, Functional MRI, Pediatric Obesity, Type 2 Diabetes Mellitus, Adolescents, Continuous Glucose Monitoring, Insulin Clamp