Microbiome Insulin Sensitivity Study (MISS)

Sex Differences in Youth-Onset Type 2 Diabetes: Exploring Mechanisms

The Microbiome Insulin Sensitivity Study "MISS" is a pilot study designed to study microbiome composition across puberty and how it relates to insulin sensitivity and secretion in obese girls, who are at increased risk for developing type 2 diabetes in puberty. The investigators will evaluate the gut microbiome composition in fecal samples of 57 obese girls in three groups: prepubertal (Tanner 1), early pubertal (Tanner 2-3), and late pubertal (Tanner 4-5). Insulin sensitivity will also be measured via an intravenous glucose tolerance test (IVGTT) in 18 prepubertal and late pubertal participants.

Study Overview

• Status: Completed
• Conditions: Obesity; Insulin Resistance; Type2 Diabetes

Detailed Description

Pediatric type 2 diabetes (T2D) is increasing in prevalence and its incidence is twice as high in girls as in boys. Pediatric onset of T2D occurs exclusively in obese youth and is tightly linked with puberty, suggesting a link with the physiologic insulin resistance of puberty. However, markers are as yet unavailable to identify those at highest risk for progression to T2D. Results from the Treatment Options for Diabetes in Youth (TODAY) Study demonstrate that pediatric T2D appears to progress rapidly in youth, forecasting poor quality of life and early complications. Therefore, identifying those most at risk and developing a better understanding of the pathophysiology of onset of T2D in youth are critical for preventing T2D, particularly in obese girls.

The investigators overarching hypothesis is that effects of obesity on metabolic and hormonal changes during puberty place obese girls at greatest risk for early T2D, similar to that which is seen in women with gestational diabetes. More specifically, sex steroid effects on insulin resistance, β-cell function, and body composition may contribute to both the pubertal increase in risk for T2D, as well as the disproportionately higher prevalence of T2D among girls. The investigators long-term goal is to design a focused intervention aimed to prevent progression to T2D during puberty. In order to do this it is necessary to: 1. Develop a better understanding of underlying mechanisms for β-cell failure in obese youth during puberty, and 2. Identify early markers for predicting which obese youth will progress to early T2D.

Alterations in gut microbiota appear to play an important role in mediating obesity and insulin resistance through poorly understood mechanisms. Current hypotheses are that shifts in the composition of the gut microbiome lead to dysregulation of complex polysaccharide metabolism, altered production of gut hormones regulating energy balance, and local and systemic inflammation. The gut microbiome composition has been reported to change during pregnancy and may play a role in metabolic changes during this time. As metabolic and hormonal changes in puberty parallel those in pregnancy, shifts in the microbiome may also accompany metabolic shifts during puberty. Currently, there are no published studies evaluating shifts in human gut microbiome composition during puberty. Consequently, the overall goal of this study is to collect cross-sectional preliminary data to inform feasibility of a future longitudinal study of metabolic and hormonal changes in lean and obese youth during the pubertal transition.

• Study Type: Observational
• Enrollment (Actual): 54

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 17 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

19 prepubertal (Tanner 1, [T1]), 19 early pubertal (T2-3), 19 late pubertal (T4-5) obese (BMI>95%ile) females, age >9 years.

Description

Inclusion Criteria:

• Female sex
• Obesity (BMI > 95th percentile for age)
• Age > 9 years, <18 years

Exclusion Criteria:

• Medications affecting glucose metabolism
• Known T2D
• Known polycystic ovarian syndrome
• Known fatty liver disease (ALT > 2x above the upper limit of normal)
• Chronic illness affecting glucose metabolism
• Antibiotic use in the previous 6 months

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
All subjects; Female sex, obese, aged 9-17 years, Tanner stages 1-5.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Firmicutes:Bacteroides ratio (F:B Ratio)	F:B ratio in prepubertal, early pubertal, and late pubertal obese girls by high-throughput 16S ribosomal ribonucleic acid (16 S rRNA) sequencing from stool samples.	Within 2 weeks of enrollment
Insulin sensitivity (Si)	Insulin sensitivity (Si) estimated from IV glucose tolerance testing using Bergman's minimal model	Within 2 weeks of enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary estradiol metabolites (E1c)	Measurement of estrogen metabolites in first morning urine sample and normalized to creatinine	Within 2 weeks of enrollment
Urinary luteinizing hormone (LH)	Measurement of LH in first morning urine sample and normalized to creatinine	Within 2 weeks of enrollment
Urinary follicle stimulating hormone (FSH)	Measurement of FSH in first morning urine sample and normalized to creatinine	Within 2 weeks of enrollment

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Children's Hospital Colorado; National Institutes of Health (NIH)
• Investigators: Principal Investigator: Megan M Kelsey, MD, MS, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2017
• Primary Completion (Actual): August 19, 2018
• Study Completion (Actual): August 19, 2018

Study Registration Dates

• First Submitted: April 14, 2017
• First Submitted That Met QC Criteria: April 14, 2017
• First Posted (Actual): April 19, 2017

Study Record Updates

• Last Update Posted (Estimated): October 10, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Microbiome; Insulin Sensitivity; Beta cell failure; Puberty
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: 16-2633; UL1TR001082 (U.S. NIH Grant/Contract)

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
• product manufactured in and exported from the U.S.: No