The Bone-Fat-Pancreas Axis in Children

November 21, 2019 updated by: Krista Casazza, University of Alabama at Birmingham

The Bone-Fat-Pancreas Axis in Children: Establishing a Role for Undercarboxylated Osteocalcin in Energy Homeostasis

The overarching hypothesis of this proposal is that obesity and positive energy balance in children promote both low bone mass accrual and risk for diabetes through events that are mechanistically associated and that involve bone as an endocrine organ. Recent studies conducted in mice have uncovered the presence of a unique "bone-fat-pancreas" axis that regulates energy homeostasis, coordinates energy partitioning between bone and adipose tissue, and impacts insulin sensitivity. The adipocyte-derived hormone leptin, elevated levels of which reflect both adiposity and positive energy balance, inhibits bone formation via sympathetic activation. Decreased bone formation in turn depresses insulin sensitivity and secretion via decreased production of undercarboxylated osteocalcin (unOC), a novel bone-derived hormone. Although data from mice are compelling, this novel pathway has not been widely tested in humans. Sparse data from adult men and women suggest that this axis is active in humans, and that unOC is regulated in part by exercise. No data are available regarding the bone-fat-pancreas axis in children. Because the foundations of body composition trajectories and metabolic "programming" are established early in the life course, childhood, particularly during early stages of growth and development, is an especially salient time period for evaluating the bone-fat-pancreas axis. With this pilot grant, we propose to gather evidence that these interrelationships exist in children. The data from this project will be used to prepare an NIH R01 proposal to conduct a lifestyle-based intervention in children aimed both at reducing risk for osteoporosis and type 2 diabetes, and at identifying the role of unOC in metabolism and tissue partitioning.

Hypothesis 1: Obesity and positive energy balance in children decrease bone mass via elevated leptin.

Specific Aim 1: Determine the association between bone mass by DXA and serum leptin concentration in lean and obese children. We predict that body weight will be positively associated with bone mass, but that at any given body weight, bone mass will be lower in obese children, and that this difference will be explained by leptin.

Hypothesis 2: Leptin-mediated suppression of unOC decreases insulin secretion through action on the β-cell, and decreases insulin sensitivity by inhibiting secretion of adiponectin from adipose tissue.

Specific Aim 2: Determine the association between insulin secretion during oral glucose tolerance test (OGTT; from C-peptide modeling) and serum unOC in lean and obese children. Determine the association between insulin sensitivity during OGTT (derived from mathematical modeling) and serum unOC in lean and obese children. Obese children are less insulin sensitive, and in an absolute sense, secrete more insulin. However, we predict that at any given degree of insulin sensitivity, insulin secretion will be lower in obese children, and that this difference will be explained by unOC. unOC will be inversely associated with serum leptin, and will be positively associated with adiponectin and insulin sensitivity.

Hypothesis 3: Physical activity prevents leptin suppression of unOC and partitions energy towards bone mineral at the expense of bone marrow adipose tissue.

Specific Aim 3: Assess the interrelationships among physical activity using accelerometry, bone mass using DXA and bone marrow adipose tissue using magnetic resonance imaging. We predict that at any given level of serum leptin, active children will have greater unOC. Further, we predict that at any given body weight, active children will have greater bone mass and lesser bone marrow adipose tissue than inactive children.

Study Overview

Study Type

Observational

Enrollment (Actual)

28

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Alabama
      • Birmingham, Alabama, United States, 35294
        • UAB

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 years to 10 years (Child)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Healthy European American (Caucasian) girls aged five to ten years

Description

Inclusion Criteria:

  • Female
  • Self-identified as European American (Caucasian) of African American
  • Aged 5 to 10 years
  • Healthy, not under the care of a doctor
  • Not taking medications known to affect body composition or metabolism
  • Pre-pubertal

Exclusion Criteria:

  • Not meeting above criteria

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Evaluate the role of undercarboxylated osteocalcin on body composition and insulin homeostasis
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Krista Casazza, PhD, University of Alabama at Birmingham

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2009

Primary Completion (Actual)

December 1, 2011

Study Completion (Actual)

December 1, 2011

Study Registration Dates

First Submitted

December 30, 2009

First Submitted That Met QC Criteria

December 31, 2009

First Posted (Estimate)

January 1, 2010

Study Record Updates

Last Update Posted (Actual)

November 25, 2019

Last Update Submitted That Met QC Criteria

November 21, 2019

Last Verified

November 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Bone Mineral Density

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