Insulin Resistance in Adolescents

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.

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.

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.

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.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Wechsler Abbreviated Scale of Intelligence (WASI) for Verbal IQ is composed of 2 of the 4 WASI subtests: 31-item Vocabulary and 24-item Similarities. The total range of possible scores is 40-160; the higher the score, the higher the Verbal IQ.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Wechsler Abbreviated Scale of Intelligence (WASI) for Performance IQ is composed of 2 of the 4 WASI subtests: 13-item Block Design and 30-item Matrix Reasoning. The total range of possible scores is 40-160, the higher the score, the higher the Performance IQ.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The NIH Toolbox (List Learning) Test assesses working memory by having participants sort images by size order. The total range of possible score is 0-28, with higher scores indicating more improved working memory.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The NIH Toolbox (Oral Symbol Digit Test) assesses processing speed. The total range of possible scores is 0-144, the higher the score, the faster the processing speed.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The NIH Toolbox (Flanker Inhibitory Control and Attention) assess executive attention. It is a visual display using a central arrow flanked by arrows either pointing in the same direction or different that the central arrow. The participant is to indicate the direction of the central arrow when they are all pointing in the same direction. Scoring is algorithm derived and based on accuracy and reaction time, with a total range of possible scores 0-10 with higher scores indicating increased executive attention.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The NIH Toolbox (Pattern Completion) assesses processing speed by asking participants to indicate if visual stimuli are the same or not the same. This test is scored by the total number of correct responses in 90 seconds (maximum score is 130). The higher the score, the better the processing speed.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The NIH Toolbox (Picture Sequence) assesses episodic memory. Participants are shown a series of pictures one at a time, related to a single theme. After the last picture is shown, the participants is asked to place the pictures in the demonstrated sequence. The total number of correct placements across 3 trials provides the score, up to a maximum of 48. The higher the score, the better the episodic memory.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Wide Range Assessment of Memory and Learning (WRAML) (Picture Memory Recognition) assesses visual memory function by asking participants to recall altered information from 4 pictures. Scoring is based on the number of correct items, up to a maximum of 51. The higher the score, the better the visual memory.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Delis-Kaplan Executive Function System (D-KEFS) (Color-Word Interference) test assesses executive function and consists of 4 parts: color naming, word reading, inhibition, and inhibition/switching. Test performance is measured by completion time and errors on each part. Raw scores are converted to norm-referenced scaled scores adjusted for age and education. These scores are aligned with a population mean of 10, and standard deviation of 3. Higher scores indicate better executive function.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Delis-Kaplan Executive Function System (D-KEFS) (Trail Making Test) assesses executive function using visual scanning, number sequencing, letter sequencing, number-letter switching, and motor speed. Performance time is measured, with lower times indicative of higher executive function.

Participants will undergo a series of cognitive tests to evaluate intelligence, memory, speed function, executive function, and psychiatric quality of life. The results of these test will be scored and reported individually. The Pediatric Quality of Life Inventory (PedsQL) is a 23-item survey assessing 4 functional dimensions: Physical, Emotional, Social, and School. Each item is scored on a 5-point Likert scale where 0 is 'not at all' and 4 is 'almost always'. Items are reversed scored (0=100, 1=75, 2=50, 3=25, 4=0) and linearly transformed to a 1-100 scale, where the higher the score, the better the Quality of Life.

Following relationships will be tested via linear regression: insulin resistance and cerebral blood flow; cerebral blood flow and cognitive tests; and insulin resistance and cognitive tests with cerebral blood flow as the mediator

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