Insulin Resistance in Adolescents

Insulin Resistance, Cognitive Health, and Perfusion of the Adolescent Brain

The growing population of adolescents with insulin resistance (IR) is predicted to create a large public health burden in the next few decades. This study examines the function of brain blood vessels and cognitive function, to test if increasing severity of IR in adolescents is related to reduced cognitive function and reduced brain blood vessel function. Findings from this study may help create treatments to delay or prevent some of the negative effects of IR on cognitive and vascular health.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance
• Intervention / Treatment: Other: Cognitive Tests; Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Oral Glucose Tolerance Test (OGTT)

Detailed Description

One in five American adolescents is obese. Up to half of those are already exhibiting insulin resistance (IR), a hallmark of metabolic syndrome and diabetes linked to serious life-altering health disorders, including cardiovascular and cerebrovascular disease. In adults, IR negatively affects brain structure and function and is reflected in lower regional brain volumes, perfusion, increased white matter hyperintensities and abnormal neuropsychological status, especially affecting memory and attention-all changes associated with accelerated cognitive and brain aging and increased risk of dementia. In an analogous fashion, a limited set of literature suggests adolescents with IR exhibit similar brain changes during maturation. The investigators hypothesize that the brains of obese adolescents are more susceptible to insults of IR during rapid brain development, positioning them on an abnormal cognitive trajectory, and predisposing them to issues related to learning, behavioral stress responses, and depression.

While the metabolic consequences of IR are well described in adolescence, the impact of IR on their neurocognitive status (intelligence, memory, attention, executive function, processing speed) and cerebrovascular function and their interactions remains largely unexplored. This is important since in addition to its classic role as a metabolic hormone, insulin acts as a vasodilator and supports neurotrophic signaling in healthy humans. Therefore, dysfunctional insulin signaling may hold tremendous influence over brain health in adolescents during this vital period of brain development. New insight is required to understand where, when, and how IR negatively transforms brain health, including whether a dose-response exists between IR severity and anomalies in brain and cognition.

The long-term goal of this research program is to determine the influence of IR on brain development in adolescents through the relationships between neurocognition and cerebral blood supply. The primary goal of the current project is to quantify fundamental neurocognitive and cerebrovascular function in relation to the severity of IR. The central hypothesis is that as IR worsens: a) subtle but meaningful neurocognitive declines emerge; b) regional brain perfusion is reduced primarily in areas linked to learning and memory despite preserved resting global cerebral blood flow (CBF); c) acute insulin surges exacerbate regional hypoperfusion, and d) cognitive scores will be lower, mediated in part by insulin-stimulated hypoperfusion.

Participants will be recruited primarily from pediatric and pediatric endocrinology clinics via our collaborator, Dr. Aaron Carrel, and his staff in UWHC Pediatric Endocrinology. Additionally, participants will be recruited from the greater Madison, WI community.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin-Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 12-18 years inclusive
• Typically developing and cognitively intact

Exclusion Criteria:

• Diabetes (≥126 mg dL-1 fasting glucose)
• Insulin treatment or sensitizing drugs
• Diagnosis of kidney, pulmonary, or heart disease
• Current smoking (defined as use of nicotine >5 times in the past month)
• Pregnancy
• Neurological or developmental disorders (e.g., intellectual disability, autism)
• Significant head injury or medical conditions (e.g., concussion, encephalopathy, seizure disorder)
• Inability to undergo the MRI procedure
• Weight less than 94.5 lbs (42.9 kg) to adhere to safety guidelines regarding blood sampling and OGTT administration
• Tanner Stage <3
• Any other circumstance deemed by the PI not addressed above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Enrolled, eligible; Single arm for eligible subjects

Other: Cognitive Tests; A battery of cognitive tests will be completed by the subject.; Device: 3 Tesla MRI; A 3 Tesla MRI will be used to assess brain structure, quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.; Other Names: MRI; Device: Intravenous Catheter; A blood sampling IV catheter will be used to draw blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin.; Other Names: Cath; Other: Oral Glucose Tolerance Test (OGTT); Eligible subjects will undergo MRI scanning before and after oral glucose tolerance test.; Other Names: OGTT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Linear Relationship Between HOMA-IR and Cognitive Function (R-squared)	HOMA-IR was measured from each participant at baseline (up to 1 hour visit) and a battery of cognitive instruments (listed here) were measured at a different study visit (2-3 hours of time). A relationship between individual HOMA-IR and Cognitive Function was hypothesized and a measured via Linear Regression (R-squared).	data collected at baseline visit (HOMA-IR) and one other study visit (Cognitive Function Tests) (up to 4 hours total time of data collection over two visits - data collection not temporally dependent)
Change in Cerebral Blood Flow (CBF) as Determined by MRI (mL/100g/Min)	CBF will be measured via MRI before OGTT (baseline) and after OGTT at Peak insulin.	1 study visit, measured at baseline and peak insulin (45-60 minutes after baseline)
Linear Relationship Between Cerebral Blood Flow and Cognitive Function (R-squared)	Cerebral Blood Flow was measured from each participant at baseline (without OGTT MRI Visit) and a battery of cognitive instruments (those listed below) were measured at a different study visit. A relationship between individual Cerebral Blood Flow and Cognitive Function was hypothesized and a measured via Linear Regression (R-squared).	data collected at baseline (CBF - up to 1 hour) and Cognitive Function data collected at another study visit (up to 3 hours), data collection over 2 study visits up to 4 hours total, data collection not temporally dependent
Mediation Analysis of the Indirect Effect of Cerebral Blood Flow on Insulin Resistance and Cognitive Function	Mediation analysis is a statistical method used to explain the influence of an outside variable (mediator) that may modify the direct relationship between the Independent (X) and Dependent variable (Y). (X - Mediator - Y) Mediation analysis was used to explore the impact of cerebral blood flow on the relationship between HOMA-IR and cognitive function. This analysis was conducted on 11 separate cognitive function tests, looking at verbal skills, memory, executive function, and self-reported quality of life rating. In the first set of analyses, the mediator was "grey matter baseline", which is the cerebral blood flow in the resting state. The second set of analyses, the mediator was "grey matter change with OGTT", which is the cerebral blood flow changing from rest to response from Oral Glucose Tolerance Test (OGTT). Positive/negative effect numbers indicated that the total effect of the relationship was positive/negative.	through study completion (up to 2 years)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: William Schrage, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2019
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: September 3, 2019
• First Submitted That Met QC Criteria: September 12, 2019
• First Posted (Actual): September 13, 2019

Study Record Updates

• Last Update Posted (Estimated): September 5, 2024
• Last Update Submitted That Met QC Criteria: August 28, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 2019-0361 (Other Identifier: M D Anderson Cancer Center); A176000 (Other Identifier: UW Madison); EDUC/KINESIOLOGY/KINESIOLOG (Other Identifier: UW Madison); 1R21HD097510-01A1 (U.S. NIH Grant/Contract); 19PRE34450141 (Other Grant/Funding Number: American Heart Association); Protocol Version 9/24/2021 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No