Liver and Fat Regulation in Overweight Adolescent Girls (APPLE)

Assessment of Hepatic Glucose and Fat Regulation in Overweight Adolescent Girls

Women with polycystic ovarian syndrome (PCOS) have increased rates of hepatic steatosis compared to weight similar women with regular menses. It is unclear if this is related to high testosterone or insulin resistance. The investigators will assess hepatic glucose release, rates of lipolysis and hepatic de novo lipogenesis in the fasted and postprandial state to determine if alterations in the processes contribute to hepatic steatosis. Participants will be overweight, sedentary girls with or without PCOS. Those with PCOS will either be medication naive, or must be taking metformin or combined oral contraceptives (COCPs) for a period of at least 6 months prior to study procedures.

Study Overview

• Status: Completed
• Conditions: Obesity; Polycystic Ovarian Syndrome; Hepatic Steatosis
• Intervention / Treatment: Drug: Byetta 5Mcg Pen Injection

Detailed Description

Hepatic glucose release will be assessed with a stable isotope glycerol tracer, lipolysis with a glycerol tracer, and hepatic de novo lipogenesis with an acetate tracer. Data will be collected fasting and after a glucose challenge. The degree of hepatic steatosis and abdominal fat partitioning will be assessed with Magnetic Resonance Imaging (MRI), and total body composition with Dual-energy X-ray absorptiometry (DEXA).

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anshutz Medical Campus/Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Females
• 2 years post-menarche
• BMI percentile >90%

Exclusion Criteria:

• Type 2 diabetes
• Anemia
• Liver disease
• Medications known to effect insulin sensitivity
• Cause of oligomenorrhea or hirsutism other than PCOS,
• >3 hours a week of moderate exercise.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PCOS, medication naive + Byetta; PCOS, medication naive; 10 girls with PCOS will receive 2 doses of Byetta.	Drug: Byetta 5Mcg Pen Injection; 10 participants will receive 2 doses of Byetta, one at 7 PM the night prior to metabolic study and the second 30 min before ingestion of glucola; Other Names: Exenatide
No Intervention: Control; Up to 25 girls without PCOS
No Intervention: PCOS medication naive; Up to 45 girls with PCOS with no exposure to hormone therapy or metformin in the preceding 6 months.
No Intervention: PCOS on COCPs; Up to 10 girls with PCOS and 6 months of therapy with combined oral contraceptives (COCPs) prior to study procedures.
No Intervention: PCOS on metformin; Up to 10 girls with PCOS and 6 months of therapy with metformin prior to study procedures

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Glucose Release	Hepatic glucose release will be measured by the rate of appearance of a glucose tracer. Glucose rate of appearance reflects the amount of glucose being release by primarily the liver during fasting. A higher glucose rate of appearance is often seen with dysglycemia	Measured up to 4 months from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Fat Fraction	Amount of fat in the liver measured by MRI and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver.	Measured up to 4 months from enrollment
Hepatic Phosphate Concentrations	Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy. The ratio of the following will be reported over total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG)	Measured up to 4 months from enrollment
Rates of Lipolysis	Rate of lipolysis will be measured by the rate of appearance of a glycerol tracer. Glycerol rate of appearance reflects the amount of glycerol being released into the blood stream as a results of lipolysis. Higher rates of lipolysis are thought to be associated with insulin resistance.	Measured up to 4 months from enrollment
Hepatic de Novo Lipogenesis	Hepatic de novo lipogenesis will be measured by with an acetate tracer by mass spectroscopy. De novo lipogenesis can contribute to non-alcoholic fatty liver disease, so having a lower value is better.	Measured up to 4 months from enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Duration	Sleep duration will be assessed using home actigraphy using the Philips Actigraph wrist-worn watch, and collects 7 days of data.	Measured up to 4 months from enrollment
Whole Body Insulin Sensitivity	Participants will undergo a 75 gram oral glucose tolerance test, and whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model using SAMM II software. This software uses participant weight, glucose and insulin concentrations at various time points during the oral glucose tolerance test to calculate the participant insulin sensitivity. The higher the Si value means more insulin sensitivity.	Measured up to 4 months from enrollment
Sleep Quality	Apnea Hypopnea Index (AHI) will be measured using WatchPAT. In children and adolescents the scale that will be used is AHI>5 is considered mild sleep apnea. The higher the AHI, indicates more severe sleep apnea. The AHI is the number of times you have apnea or hypopnea during one night, divided by the hours of sleep. Normal sleep: An AHI of fewer than five events, on average, per hour Mild sleep apnea: An AHI of five to 14 events per hour Moderate sleep apnea: An AHI of 15 to 29 events per hour Severe sleep apnea: An AHI of 30 or more events per hour	Measured up to 4 months from enrollment

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Melanie Cree Green, MD, PhD, Department of Endocrinology

Publications and helpful links

General Publications

• Carreau AM, Pyle L, Garcia-Reyes Y, Rahat H, Vigers T, Jensen T, Scherzinger A, Nadeau KJ, Cree-Green M. Clinical prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic ovary syndrome (PCOS-HS index). Clin Endocrinol (Oxf). 2019 Oct;91(4):544-552. doi: 10.1111/cen.14062. Epub 2019 Aug 16.
• Simon SL, McWhirter L, Diniz Behn C, Bubar KM, Kaar JL, Pyle L, Rahat H, Garcia-Reyes Y, Carreau AM, Wright KP, Nadeau KJ, Cree-Green M. Morning Circadian Misalignment Is Associated With Insulin Resistance in Girls With Obesity and Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3525-3534. doi: 10.1210/jc.2018-02385.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: June 4, 2014
• First Submitted That Met QC Criteria: June 4, 2014
• First Posted (Estimated): June 6, 2014

Study Record Updates

• Last Update Posted (Estimated): June 4, 2024
• Last Update Submitted That Met QC Criteria: May 31, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Liver Diseases; Overnutrition; Nutrition Disorders; Body Weight; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Fatty Liver; Overweight; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Glucagon-Like Peptide-1 Receptor Agonists; Exenatide
• Other Study ID Numbers: 14-0542; UL1TR001082 (U.S. NIH Grant/Contract); K23DK107871 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will only be shared with IRB approved personnel.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No