Mechanisms of Inflammation, Immunity, Islet Cell and Intestinal Hormone Changes in Youth at Risk for Diabetes

Study Overview
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Brief Summary
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This study intends to assess the role of inflammation in insulin resistant conditions (i.e., obesity and pre-diabetes) and the subsequent development of disease, such as type 2 diabetes (T2D) and cardiovascular disease (CVD), in the adolescent population.

Detailed Description
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This study proposes to characterize inflammatory biomarkers, insulin resistance and fecal microbiome composition in obese/pre-diabetic adolescents after glucose ingestion, followed by an oral fat tolerance test on a separate visit. Lipoprotein abnormalities and intestinal biomarkers, post-lipid ingestion, will also be evaluated. The primary aim is to assess the role of inflammation in insulin resistant conditions (i.e., obesity and pre-diabetes) and the subsequent development of disease, such as type 2 diabetes (T2D) and cardiovascular disease (CVD), in the adolescent population.

Official Title
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Mechanisms of Inflammation, Immunity, Islet Cell and Intestinal Hormone Changes in Youth at Risk for Diabetes (MI4D)

Conditions
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Obesity, PreDiabetes, Adolescent Obesity, Inflammation, Metabolic Problems, Insulin Resistance, Gut Microbiome, Immunity, Beta Cell Dysfunction, Gut Hormones

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Adolescents aged 12 - 18 years old with obesity (defined as body mass index (BMI) >97th percentile based on their age- and sex-specific World Health Organization growth chart) Exclusion Criteria: Known type 2 diabetes Diabetes secondary to medication or surgery Antibodies suggestive of type 1 diabetes Pregnancy Were born by C-section Developmental delay precluding assent/consent Acute illness within the past 3 days (chills, fever, vomiting > 1x, or diarrhea > 3x) Taking medications that influence glucose (e.g., steroids, metformin) or lipids (e.g., statins) Have taken prescribed medicine/antibiotics in the three months prior to clinic or study visit Significant chronic illness (e.g., Cushing's Disease, Craniopharyngioma, Hypothalamic Obesity, etc.) Lactose intolerance and/or milk allergy (Study Visit Day 2 Only) Bariatric surgery

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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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body insulin sensitivity index | Multiple measurements from a 2-hour oral glucose tolerance will be aggregated to arrive at one reported value (ie., insulin in uU/mL units and glucose values in mg/dL units which are measured at baseline, 30 min, 60 min, 90 min, and 120 min during the oral glucose tolerance test will be combined to calculate whole body insulin sensitivity index). There is no unit of measure for whole body insulin sensitivity index. Whole body insulin sensitivity index will be calculated using the following equation: whole body insulin sensitivity index = 10,000 / √ [(fasting glucose x fasting insulin) x (mean glucose x mean insulin)]. | Through study completion, an average of 2 years. | 
| Microbiome Composition | We will perform microbiome 16S ribosomal ribonucleic acid (rRNA) sequencing in fecal samples from study participants. | Through study completion, an average of 3 years. | 
| Inflammatory markers | Cytokines will be measured in plasma and fecal water with Bio-PlexTM arrays providing biomarkers of type 1 diabetes and/or type 2 diabetes progression. As indices of gut microbial translocation, serum lipopolysaccharides (LPS), macrophage secreted cluster of differentiation 14 (CD14) that binds LPS and LPS binding protein (LBP) will be examined. | Through study completion, an average of 3 years. |