Insulin Resistance in Adolescents

Not Applicable

Completed

• Conditions: Insulin Resistance
• Interventions: Other: Oral Glucose Tolerance Test (OGTT); Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Cognitive Tests

• Registration Number: NCT04089332
• Lead Sponsor: University of Wisconsin, Madison

Brief Summary

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.

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 Timeline

• Study First Submitted: 2019-09-03
• Study First Submitted QC: 2019-09-12
• Study First Posted: 2019-09-13
• Study Start: 2019-10-04
• Primary Completion: 2022-07-31
• Study Completion: 2022-07-31
• Status Verified: 2022-08
• Last Update Submitted: 2022-08-03
• Last Update Posted: 2022-08-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Enrolled, eligible	Oral Glucose Tolerance Test (OGTT)	Single arm for eligible subjects
Enrolled, eligible	3 Tesla MRI	Single arm for eligible subjects
Enrolled, eligible	Intravenous Catheter	Single arm for eligible subjects
Enrolled, eligible	Cognitive Tests	Single arm for eligible subjects

Primary Outcome Measures

Name	Time	Method
Linear Relationship Between HOMA-IR and Cognitive Function (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)	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).
Change in Cerebral Blood Flow (CBF) as Determined by MRI (mL/100g/Min)	1 study visit, measured at baseline and peak insulin (45-60 minutes after baseline)	CBF will be measured via MRI before OGTT (baseline) and after OGTT at Peak insulin.
Linear Relationship Between Cerebral Blood Flow and Cognitive Function (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	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).
Mediation Analysis of the Indirect Effect of Cerebral Blood Flow on Insulin Resistance and Cognitive Function	through study completion (up to 2 years)	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.

Trial Locations

Locations (1)

University of Wisconsin-Madison; 🇺🇸 Madison, Wisconsin, United States