Metabolic Heterogeneity Underlying Hypertriglyceridemia: Hepatic Triglyceride Biosynthesis in Humans With Different Insulin Resistance Phenotypes

NCT ID: NCT05743868

Last Updated: 2026-01-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

40 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-11-16

Study Completion Date

2026-06-30

Brief Summary

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The focus of this cross-sectional study is to determine the effects of tissue-specific (adipose tissue or muscle) vs global (combined) insulin resistance (IR) on hepatic triglyceride biosynthesis in humans, and to determine differential effects of an acute exercise intervention on hepatic triglyceride biosynthesis in these groups.

Detailed Description

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Hypothesis: Patients who primarily have muscle IR will have a greater percentage of lipids derived from de novo lipogenesis (DNL) than patients with combined muscle and adipose IR, and these subjects will respond more robustly to the effects of premeal exercise.

With this study, the investigators will demonstrate that the mechanisms that drive triglyceride overproduction in insulin-resistant humans are dependent on which tissues are insulin resistant. To this end, investigators will determine whether subjects with muscle insulin resistance and adipose tissue insulin resistance utilize different mechanisms of triglyceride biosynthesis to assemble hepatic very low density lipoprotein (VLDL), as compared with individuals with muscle insulin resistance but relative adipose tissue insulin sensitivity. Additionally, investigators will see if adipose tissue insulin sensitivity predicts exercise responsiveness of hepatic triglyceride production.

Main study parameters/endpoints: Difference in %DNL between subjects with global vs muscle-only insulin resistance as well as the differential effects of premeal exercise on %DNL in these groups.

Conditions

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Insulin Resistance Hypertriglyceridemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Glucose tolerance, skeletal muscle/whole-body insulin sensitivity and adipose tissue insulin sensitivity will be evaluated prior to intervention. Plasma deuterium will be allowed to wash out over several weeks, and the 2nd deuterated water study will be performed.

Randomized crossover within group design.
Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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IR participants with standardized dinner

Participants with global IR and tissue-specific IR. Participants with global IR (in both skeletal muscle and adipose tissue) and tissue-specific IR (in adipose tissue). Glucose tolerance, skeletal muscle/whole-body insulin sensitivity and adipose tissue insulin sensitivity will be evaluated prior to intervention.

Contribution of DNL to hepatic VLDL will be measured using a deuterated water drink, to be ingested prior to the standardized dinner. Blood will be drawn the following morning for the measurement of deuterium incorporation into triglycerides. Plasma deuterium will be allowed to wash out over several weeks, and the 2nd deuterated water study will be performed.

Group Type EXPERIMENTAL

Standardized Dinner

Intervention Type BEHAVIORAL

De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner

IR participants with standardized dinner and premeal exercise

Participants with global IR and tissue-specific IR. Participants with global IR (in both skeletal muscle and adipose tissue) and tissue-specific IR (in adipose tissue). Glucose tolerance, skeletal muscle/whole-body insulin sensitivity and adipose tissue insulin sensitivity will be evaluated prior to intervention.

DNL will be assessed in all participants after a single day with short bouts of premeal exercise with a standardized dinner.

Contribution of DNL to hepatic VLDL will be measured using a deuterated water drink, to be ingested prior to the standardized dinner. Blood will be drawn the following morning for the measurement of deuterium incorporation into triglycerides. Plasma deuterium will be allowed to wash out over several weeks, and the 2nd deuterated water study will be performed.

Group Type EXPERIMENTAL

Standardized Dinner

Intervention Type BEHAVIORAL

De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner

Premeal exercise

Intervention Type BEHAVIORAL

DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner

Interventions

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Standardized Dinner

De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner

Intervention Type BEHAVIORAL

Premeal exercise

DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner

Intervention Type BEHAVIORAL

Eligibility Criteria

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Inclusion Criteria

* Ability to give informed consent
* Overweight, defined as BMI 25-30 kg/m2
* Modest hypertriglyceridemia, defined as fasting plasma triglycerides 1.5-3.0mM
* High risk of insulin resistance, defined as fasting plasma insulin \>64pM
* Stable weight for at least 3mo prior to participation

Exclusion Criteria

* Active or chronic liver disease, kidney disease, congestive heart failure, unstable angina, history of acute cardiovascular events within 6mo of screening, history of seizures or syncope, or an active infection requiring antimicrobial therapy;
* Use of insulin, thiazolidinediones, SGLT2 inhibitors, or sulfonylureas;
* Use of fibrates, omega 3 (fish oil), niacin, or PCSK9 antagonists;
* Use of systemic glucocorticoids within 60d prior to participation;
* Hematocrit \<35%;
* Pregnancy of breastfeeding;
* Active tobacco use, excessive alcohol intake (\>14U/wk), or history of drug abuse.
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Amsterdam UMC

OTHER

Sponsor Role collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role collaborator

Yale University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Daniel F Vatner, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

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AMC Amsterdam

Amsterdam, , Netherlands

Site Status RECRUITING

Countries

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Netherlands

Central Contacts

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Daniel F Vatner, MD, PhD

Role: CONTACT

203 785 5934

Facility Contacts

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Kasper ter Horst, MD, PhD

Role: primary

Other Identifiers

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Vatner 012523

Identifier Type: -

Identifier Source: org_study_id

NL83166.018.22

Identifier Type: OTHER

Identifier Source: secondary_id

R01DK124272

Identifier Type: NIH

Identifier Source: secondary_id

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