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

The Hospital for Sick Children52 enrolled

Overview

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.

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.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Obesity PreDiabetes Adolescent Obesity Inflammation Metabolic Problems Insulin Resistance

Eligibility

Sex: ALLMin age: 12 YearsMax age: 18 Years

Medical Language ↔ Plain English

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: 1. Known type 2 diabetes 2. Diabetes secondary to medication or surgery 3. Antibodies suggestive of type 1 diabetes 4. Pregnancy 5. Were born by C-section 6. Developmental delay precluding assent/consent 7. Acute illness within the past 3 days (chills, fever, vomiting \> 1x, or diarrhea \> 3x) 8. Taking medications that influence glucose (e.g., steroids, metformin) or lipids (e.g., statins) 9. Have taken prescribed medicine/antibiotics in the three months prior to clinic or study visit 10. Significant chronic illness (e.g., Cushing's Disease, Craniopharyngioma, Hypothalamic Obesity, etc.) 11. Lactose intolerance and/or milk allergy (Study Visit Day 2 Only) 12. Bariatric surgery

Outcomes

Primary Outcomes

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 / √ \[(fasting glucose x fasting insulin) x (mean glucose x mean insulin)\].

Time frame: 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.

Time frame: 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.