Evaluating the Influence of Diet-induced Weight Loss on Fat (Adipose) Tissue's Insulin Sensitivity and Testosterone Synthesis in Women With Overweight or Obesity, Insulin Resistance, and Hyperandrogenemia (WAIST)

The Interplay Between Androgens, Insulin, and Adipose Tissue Metabolism

The investigators will measure plasma concentrations of the hormones insulin and testosterone as well as measures of insulin sensitivity in women with overweight or obesity who have insulin resistance (IR). Women who meet these criteria that also have elevated total or free testosterone will be eligible to participate in the diet intervention. The dietary intervention is designed to produce a 5% reduction in starting body weight to test whether weight loss will acutely lower fasting insulin and testosterone concentrations.

Study Overview

• Status: Active, not recruiting
• Conditions: Insulin Resistance; Overweight and Obesity; Hyperandrogenemia
• Intervention / Treatment: Behavioral: Mediterranean-based, carbohydrate restricted, calorie reduced diet

Detailed Description

The investigators will measure the efficacy of a diet-induced weight loss intervention to reduce blood concentrations of the hormone's insulin and testosterone over the course of 2 months in women who have overweight or obesity and evidence of IR. Women meeting the eligibility criteria that have biochemical evidence or clinical manifestations of hyperandrogenemia (HA), or elevated blood androgens - testosterone or free testosterone - will be eligible for the dietary intervention arm of the study. A Mediterranean-based, calorie reduced, carbohydrate restricted diet will be employed to produce a 5% weight loss over the 8 weeks of the intervention. Participants will be provided with a full menu of meals and snacks for 4 of the 8 weeks in the study and will meet with a registered, licensed dietitian routinely for nutrition counseling and to ensure dietary compliance. Those in the dietary intervention will undergo 6 clinical visits at the Clinical and Translational Science's Unit whereas the control group (no dietary intervention or nutrition counseling) will undergo 2 clinical visits. Of the 6 study visits, 4 will include an adipose tissue biopsy and an oral glucose tolerance test. All visits will include DEXA measurement of body composition and collection of fasting blood samples. The control group's 2 study visits will occur at the start and end of the 8-week period and will include all study measurements (i.e., adipose tissue biopsies, oral glucose tolerance tests, DEXA scans, and fasting blood samples). Adipose tissue samples will be cultured and used to assess adipose-level insulin sensitivity. Area under the curve for insulin, glucose, and non-esterified fatty acids (NEFA) will be calculated from the samples collected during the oral glucose tolerance test. Additionally, the fasting HOMA-IR, Matsuda Index, QUICKI value, 2-hour blood glucose concentration, and NEFA suppression will be measured during the oral glucose tolerance test.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65211
      • University of Missouri

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women (female sex, premenopausal)
• Age 21-45y
• Overweight/obesity with BMI ≥25.0 or ≤50.0 kg/m2
• Prediabetic (fasting glucose between 100-125 mg/dL,HbA1c between 5.7-6.4%, blood glucose ≥ 140 mg/dL, but ≤ 200 mg/dL at 2 hours into OGTT) or diabetic with a fasting glucose <200 mg/dL, stably treated with metformin for 2 months or longer

• Alternatively: if not prediabetic as evidenced by abnormal fasting blood glucose or glucose tolerance, evidence of insulin resistance such as fasting insulin value ≥ 10 µU/mL, elevated HOMA-IR or elevated QUICKI may be substituted

  o Prediabetes and diabetes are associated with insulin resistance and excess body weight. Our study seeks to improve impaired insulin signaling through weight loss from dietary restriction. Therefore, insulin resistance in the presence of normal glucose tolerance may still be improved through this intervention.

• Plasma testosterone concentration <200 ng/dL, as measured at screening visit
• Weight stable: No fluctuations in body weight of greater than 4 kg in the last 2 months (see exclusion criteria for undergoing weight loss)
• Presence of central (android) obesity as defined by WHR > 0.8 or waist circumference > 80 cm

• No use or active use of hormonal contraceptives (IUD, oral contraceptive pill, Nexplanon)

  o Hormonal contraceptives are not expected to alter the outcomes of this study; therefore, their use is not prohibited. However, it is not a requirement that women use hormonal contraception to be part of this study.

• Willingness to consume a defined diet (Intervention arm - Weight loss)

Exclusion Criteria:

• Pregnant or trying to become pregnant
• Postmenopausal as testosterone naturally increases with menopause
• BMI of <25.0 or >50.0 kg/m2

• Use of tobacco, cannabis, or other recreational drug products.

  o Tobacco and other recreational drugs products are excluded as they known to increase adipose lipolysis. Cannabis products are excluded as they are fat soluble compounds and could alter the adipose gene and protein expression.

• Taking medications known to affect adipose tissue metabolism (steroids, niacin)
• Use of antiandrogen medications (spironolactone, flutamide, finasteride) within the last 3 months o These medications are designed to lower testosterone concentrations.
• Already undergoing weight loss. o As this study is investigating the impact of weight loss, the goal is to obtain samples before and after weight loss (intervention arm) or during weight stability (control arm).
• Diagnosis of congenital adrenal hyperplasia, or Cushing syndrome o These conditions are associated with significantly high androgens in need of medical treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dietary intervention; Group receiving the study diet and nutrition counseling.	Behavioral: Mediterranean-based, carbohydrate restricted, calorie reduced diet; Dietary intervention - calorie reduced (300-500 kcal/day below estimated energy needs), carbohydrate restricted (<100 grams of available carbohydrates per day), Mediterranean-based (high fat diet with an emphasis on the addition of healthy fats - nuts, avocados, olive oil, increasing whole grains, increasing fruit and vegetables, replacing red meats with fish and poultry, reducing dairy, and reducing added sugars) diet.
No Intervention: Control; Group that performs repeat measures over the span of 8 weeks without any intervention or influence from study team in the interim.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fasting hormone concentrations.	Fasting insulin (µU/mL) will be measured and compared to baseline values. Samples are sent to an external CLIA-compliant lab (Quest Diagnostics) for analysis.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.
Change in fasting hormone concentrations.	Fasting testosterone (ng/dL) will be measured and compared to baseline values. Samples are sent to an external CLIA-compliant lab (Quest Diagnostics) for analysis.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.
Change in body weight (kg).	Change from baseline values will be measured using a calibrated, standard, clinical scale.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.
Change in fasting blood biochemistries.	Fasting SHBG (nmol/L) will be measured and compared to baseline values. Samples are sent to an external CLIA-compliant lab (Quest Diagnostics) for analysis.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in whole body insulin sensitivity.	Participants will undergo an oral 75-gram glucose tolerance test. Insulin sensitivity will be assessed using HOMA-IR. This insulin sensitivity index is calculated as [(fasting insulin (µU/mL) x fasting glucose (mg/dL))/405].	Day 0, day 14, day 28, day 56 for the intervention group and day 0 and day 56 for the control group.
Indirect measure of change in adipose insulin sensitivity.	Change will be calculated relative to the fasting value as the percent suppression of free fatty acids in response to the oral glucose tolerance test. Plasma free fatty acids are measured in mmol/L.	Day 0, day 14, day 28, day 56 for the intervention group and day 0 and day 56 for the control group.
Direct measure of change in adipose insulin sensitivity.	Abdominal subcutaneous adipose tissue (~1 gram) is collected via biopsy. Primary cells are cultured. After differentiation to fully mature adipocytes, the cells are cultured in 1 of 6 media conditions - standard (10 nM insulin, 0 ng/dL testosterone), hyperinsulinemic (100 nM insulin, 0 ng/dL testosterone), hyperinsulinemic and low testosterone (20 ng/dL), hyperinsulinemic and high testosterone (40 ng/dL), standard and low testosterone, standard and high testosterone. Following 10 days of media treatment, adipocyte insulin sensitivity is assessed via a lipolysis assay. This assay measures the release of free fatty acid (mmol/L) from adipocytes in response to cAMP and the subsequent suppression when treated with insulin.	Day 0, day 14, day 28, day 56 for the intervention group and day 0 and day 56 for the control group.
Change in measures of biochemical hyperandrogenemia.	Fasting free testosterone concentrations (as a percentage (%) of total testosterone) will be estimated. Values will be compared to baseline.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.
Change in body composition.	Absolute (kg) and relative (percent of total body mass) fat-free and fat mass are measured using a DEXA at each study visit and compared to baseline values.	Day 0, day 7, day 14, day 28, day 42, and day 56 for the intervention group and day 0 and day 56 for the control group.
Change in average blood glucose concentrations.	Change in HbA1c % will be measured and compared to baseline values. Samples are sent to an external, CLIA compliant lab (Quest Diagnostics) for analysis.	Day 0 and day 56 for both the intervention and the control groups.

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Investigators: Principal Investigator: Elizabeth J Parks, PhD, University of Missouri-Columbia; Principal Investigator: Jean Ricci Goodman, MD, University of Missouri-Columbia

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2024
• Primary Completion (Actual): October 5, 2024
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 24, 2025
• First Submitted That Met QC Criteria: May 28, 2025
• First Posted (Actual): May 31, 2025

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Insulin resistance; Women; Weight loss; Mediterranean Diet; Overweight or Obesity; Hyperandrogenemia
• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Body Weight Changes; Glucose Metabolism Disorders; Hyperinsulinism; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity; Weight Loss; Insulin Resistance
• Other Study ID Numbers: 2095704

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data will be shared upon reasonable request to study's primary investigator, Elizabeth J. Parks, PhD.

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