Cardiometabolic Disease and Substrate Metabolism (CAP)

Cardiometabolic Disease, Substrate Metabolism, and Abnormal Placental Pathology: a Multimodal Maternal-Fetal Study

This study's primary purpose is to determine the potential relationship between cardiometabolic disease, specifically insulin resistance (HOMA-IR), and maternal lipid oxidation.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Pregnancy Complications; Pregnancy; Preeclampsia; Gestational Diabetes; Gestational Diabetes Mellitus in Pregnancy; Placental Dysfunction; Gestational Diabetes Mellitus (GDM); Preeclampsia (PE); Cardiometabolic Diseases; Gestational Complications; Preeclampsia (PE) Risk

Detailed Description

Cardiometabolic disease such as pre-eclampsia (PreE) and gestational diabetes (GDM) affect close to 15% of pregnancies and are a major cause of maternal and neonatal morbidity and mortality. Much of the clinical data surrounding these disorders focuses on management during pregnancy and counseling regarding risks of continued cardiometabolic dysfunction after pregnancy. Data are much more limited regarding assessing and managing cardiometabolic dysfunction leading into or early in pregnancy. Furthermore, there are even less data describing metabolic dysfunction outside of GDM and PreE as relate to future cardiometabolic risk.

The standard of care of assessing metabolic dysfunction during pregnancy, specifically gestational diabetes, is a two-step glucose challenge approach. Outside of pregnant populations, metabolic dysfunction is assessed from a more holistic approach including assessment of insulin, lactate, triglycerides, HDL, LDL, VDRL, cholesterol and free fatty acids.

Data are currently lacking on substrate metabolism other than glucose in pregnancy. There are some data that describe maternal lipid metabolism in pregnancy, but most of these data focus on lipid metabolism as it relates to fetal growth and fat mass, but none describe substrate metabolism as it relates to development of maternal disease such as insulin resistance.

Additionally, the placenta is an extremely metabolically active organ that responds to changes in maternal stress. There is evidence in animal studies that the placenta can alter transportation of carbohydrates, lipids and amnio acids in response to changes in heat, undernutrition, hypoglycemia and glucocorticoid administration.

Traditional hypotheses regarding development of cardiometabolic disease in pregnancy surrounded topics such as abnormal placentation, dysfunctional spiral arteries and hormones such as human placental lactogen. Outside of pregnancy, studies have shown that endothelial dysfunction has been linked to cardiometabolic disease due to its role in regulating vascular tone and glycolysis. Furthermore, there is evidence to support that gestational diabetes is a risk factor for development of endothelial dysfunction; however, in vivo endothelial dysfunction in GDM is not well explored. While there are data that describe endothelial dysfunction in pregnancy as it relates to pre-eclampsia, most studies describe indirect measures of endothelial dysfunction using proteins such as VEGF, PLGF, and SFLT1.

The metabolic profiles in pregnant people at risk for cardiometabolic disease has not been explored heavily. By assessing both maternal substrate metabolism as well as placental function and pathology, we hope to better understand disease from the lens of not just the maternal but also the fetal and placental unit. Therefore, this study seeks to evaluate the relationship between substrate metabolism of pregnant individuals as it relates to their development of cardiometabolic disease in pregnancy with hopes for more translational research to design better targeted therapies.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Jill M Maples, PhD; Phone Number: 865-305-9367; Email: jmaples1@utmck.edu
• Study Contact Backup: Name: Hana O El-Messidi, BS; Phone Number: 865-305-5592; Email: hel1@utmck.edu

Study Locations

• United States
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Recruiting
      • University of Tennessee Graduate School of Medicine
      • Contact: Jill M Maples, PhD; Phone Number: 865-305-9367; Email: jmaples1@utmck.edu
      • Contact: Hana O El-Messidi, BS; Phone Number: 865-305-5592; Email: hel1@utmck.edu
      • Principal Investigator: Jacklyn Locklear, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Pregnant individuals at risk for preeclampsia

Description

Inclusion Criteria:

• Age 18-45
• Any pre-pregnancy BMI
• At least one high risk OR one moderate risk factor for pre-eclampsia based on ACOG and USPSTF guidelines
• Willingness to adhere to aspirin therapy
• Willingness to undergo 2h OGTT for serum collection in addition to survey collection, indirect calorimetry, body composition measures, neonatal measures, etc.
• Gestational age at enrollment <18 weeks
• Ability to speak, read, and communicate via English

Exclusion Criteria:

• Type 2 Diabetes Mellitus
• Type 1 Diabetes Mellitus
• Current gestational diabetes mellitus
• Current/active platelet disorder or bleeding diathesis (thrombocytopenia of any etiology, idiopathic thrombocytopenic purpura/ITP, thrombotic thrombocytopenic purpura/TTP, von Willebrand disease, etc.)
• Thrombophilia
• Current use of NSAID for other indication (indomethacin, ibuprofen, etc.)
• Current use of other immune-modulating agents and biologics (hydroxychloroquine, azathioprine, 6-mercaptopurine, IL-6 inhibitors, etc.)
• Current or recent use of steroids
• Current use of prophylactic or therapeutic anticoagulation
• Medical contraindication to aspirin therapy
• Molar pregnancy
• Renal disease
• Inability or unwillingness to give informed consent
• Current psychiatric illness/social situation that would limit compliance with study requirements, as determined by the principal investigators

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Pregnant individuals at risk for cardiometabolic disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Pregnancy Fasting Insulin (mIU/mL)	Early pregnancy fasting insulin level (mIU/mL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Homeostatic Model Assessment for Insulin Resistance	Approximates early pregnancy insulin resistance.	Calculated from fasting insulin and fasting glucose collected at the start of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Lipid Oxidation Rate (g/min)	Early pregnancy fasting lipid oxidation rate measures whole body lipid oxidation, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 12-18 weeks gestational age
Late Pregnancy Fasting Insulin (mIU/mL)	Late pregnancy fasting insulin level (mIU/mL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Homeostatic Model Assessment for Insulin Resistance	Approximates late pregnancy insulin resistance.	Calculated from fasting insulin and fasting glucose collected at the start of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Lipid Oxidation Rate (g/min)	Fasting late pregnancy lipid oxidation rate measures whole body lipid oxidation, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 26-30 weeks gestational age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Pregnancy Fasting Resting Metabolic Rate (kcal/day)	Early pregnancy resting metabolic rate describes whole body caloric expenditure, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Resting Respiratory Quotient	Early pregnancy resting respiratory quotient describes whole body caloric expenditure, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Carbohydrate Oxidation Rate (g/min)	Early pregnancy fasting carbohydrate oxidation rate measures whole body carbohydrate oxidation, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Glucose (mg/dL)	Early pregnancy fasting glucose level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Lactate (mmol/L)	Early pregnancy fasting lactate level (mmol/L) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Triglycerides (mg/dL)	Early pregnancy fasting triglycerides level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting High Density Lipoprotein (mg/dL)	Early pregnancy fasting high density lipoprotein level (HDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Very Low Density Lipoprotein (mg/dL)	Early pregnancy fasting very low density lipoprotein level (VLDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Low Density Lipoprotein (mg/dL)	Early pregnancy fasting low density lipoprotein level (LDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Cholesterol (mg/dL)	Early pregnancy fasting cholesterol level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Early Pregnancy Fasting Free Fatty Acids (mEq/L)	Early pregnancy fasting free fatty acids (FFA) (mEq/L) in venous blood	Fasting, at the beginning of a single study visit between 12-18 weeks gestational age
Late Pregnancy Fasting Resting Metabolic Rate (kcal/day)	Late pregnancy resting metabolic rate describes whole body caloric expenditure, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Resting Respiratory Quotient	Late pregnancy resting respiratory quotient describes whole body caloric expenditure, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Carbohydrate Oxidation Rate (g/min)	Late pregnancy fasting carbohydrate oxidation rate measures whole body carbohydrate oxidation, which is assessed using indirect calorimetry	Measured at the start of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Glucose (mg/dL)	Late pregnancy fasting glucose level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Lactate (mmol/L)	Late pregnancy fasting lactate level (mmol/L) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Triglycerides (mg/dL)	Late pregnancy fasting triglycerides level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting High Density Lipoprotein (mg/dL)	Late pregnancy fasting high density lipoprotein level (HDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Very Low Density Lipoprotein (mg/dL)	Late pregnancy fasting very low density lipoprotein level (VLDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Low Density Lipoprotein (mg/dL)	Late pregnancy fasting low density lipoprotein level (LDL) (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Cholesterol (mg/dL)	Late pregnancy fasting cholesterol level (mg/dL) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age
Late Pregnancy Fasting Free Fatty Acids (mEq/L)	Late pregnancy fasting free fatty acids (FFA) (mEq/L) in venous blood	Fasting, at the beginning of a single study visit between 26-30 weeks gestational age

Collaborators and Investigators

• Sponsor: University of Tennessee Graduate School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: April 27, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Insulin resistance; Preeclampsia; Gestational Diabetes; Substrate metabolism; HOMA-IR; Cardiometabolic disease; Lipid oxidation; Placental dysfunction; Chorangiosis
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Hypertension, Pregnancy-Induced; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes, Gestational; Pre-Eclampsia; Pregnancy Complications; Insulin Resistance
• Other Study ID Numbers: 5483

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Reasonable requests will be considered on a case-by-case basis.
• IPD Sharing Time Frame: We anticipate publishing the study protocol within the next 2 years
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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