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

Primary Purpose

Insulin Resistance, Hypertriglyceridemia

Status
Not yet recruiting
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Standardized Dinner
Premeal exercise
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Insulin Resistance

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • AMC Amsterdam

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

IR participants with standardized dinner

IR participants with standardized dinner and premeal exercise

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Effect of tissue-specific insulin resistance on contribution of DNL to plasma triglyceride
The amount of de novo lipogenesis (DNL) in VLDL-triglycerides after a standard meal will be measured in plasma from whole blood. Relationship between DNL and 1) whole body (skeletal muscle) insulin resistance and 2) white adipose tissue insulin resistance will be assessed individually.
Change in DNL in VLDL-triglycerides after a standard meal compared to a standard meal with premeal exercise.
The amount of de novo lipogenesis (DNL) in VLDL-triglycerides after a standard meal vs after a standard meal with premeal exercise will be measured in plasma from whole blood.

Secondary Outcome Measures

Change in plasma triglycerides after a standard meal compared to a standard meal with premeal exercise
Plasma triglycerides will be measured under both conditions.
Baseline plasma triglycerides
Plasma triglycerides will be measured at the screening visit to determine eligibility for the study
Adipose insulin sensitivity
Both nonesterified fatty acids and insulin will be measured in the plasma at baseline to calculate Adipo-IR, a measure of adipose tissue insulin sensitivity.
Skeletal muscle/whole-body insulin sensitivity assessed by oral glucose tolerance test (OGTT)
Matsuda index will be used to evaluate whole body physiological insulin sensitivity from the data obtained by OGTT. Insulin sensitivity as calculated by the Matsuda index: [10,000 / √glucose minute 0 x insulin minute 0) (mean glucose (OGTT) x mean insulin OGTT)]. A higher result indicates less IR.

Full Information

First Posted
February 15, 2023
Last Updated
July 13, 2023
Sponsor
Yale University
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT05743868
Brief Title
Metabolic Heterogeneity Underlying Hypertriglyceridemia: Hepatic Triglyceride Biosynthesis in Humans With Different Insulin Resistance Phenotypes
Official Title
Metabolic Heterogeneity Underlying Hypertriglyceridemia: Hepatic Triglyceride Biosynthesis in Humans With Different Insulin Resistance Phenotypes
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 2023 (Anticipated)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
August 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Resistance, Hypertriglyceridemia

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
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.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
IR participants with standardized dinner
Arm Type
Experimental
Arm Description
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.
Arm Title
IR participants with standardized dinner and premeal exercise
Arm Type
Experimental
Arm Description
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.
Intervention Type
Behavioral
Intervention Name(s)
Standardized Dinner
Intervention Description
De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner
Intervention Type
Behavioral
Intervention Name(s)
Premeal exercise
Intervention Description
DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner
Primary Outcome Measure Information:
Title
Effect of tissue-specific insulin resistance on contribution of DNL to plasma triglyceride
Description
The amount of de novo lipogenesis (DNL) in VLDL-triglycerides after a standard meal will be measured in plasma from whole blood. Relationship between DNL and 1) whole body (skeletal muscle) insulin resistance and 2) white adipose tissue insulin resistance will be assessed individually.
Time Frame
Baseline
Title
Change in DNL in VLDL-triglycerides after a standard meal compared to a standard meal with premeal exercise.
Description
The amount of de novo lipogenesis (DNL) in VLDL-triglycerides after a standard meal vs after a standard meal with premeal exercise will be measured in plasma from whole blood.
Time Frame
study visit 1 and study visit 2, up to 8 weeks
Secondary Outcome Measure Information:
Title
Change in plasma triglycerides after a standard meal compared to a standard meal with premeal exercise
Description
Plasma triglycerides will be measured under both conditions.
Time Frame
study visit 1 and study visit 2, up to 8 weeks
Title
Baseline plasma triglycerides
Description
Plasma triglycerides will be measured at the screening visit to determine eligibility for the study
Time Frame
baseline
Title
Adipose insulin sensitivity
Description
Both nonesterified fatty acids and insulin will be measured in the plasma at baseline to calculate Adipo-IR, a measure of adipose tissue insulin sensitivity.
Time Frame
Baseline
Title
Skeletal muscle/whole-body insulin sensitivity assessed by oral glucose tolerance test (OGTT)
Description
Matsuda index will be used to evaluate whole body physiological insulin sensitivity from the data obtained by OGTT. Insulin sensitivity as calculated by the Matsuda index: [10,000 / √glucose minute 0 x insulin minute 0) (mean glucose (OGTT) x mean insulin OGTT)]. A higher result indicates less IR.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Daniel F Vatner, MD, PhD
Phone
203 785 5934
Email
daniel.vatner@yale.edu
Facility Information:
Facility Name
AMC Amsterdam
City
Amsterdam
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kasper ter Horst, MD, PhD
Email
k.w.terhorst@amsterdamumc.nl

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
By reasonable request, PI can be reached by email, and individual participant data (OGTT results, fasting plasma data, DNL data) will be provided electronically.
IPD Sharing Time Frame
Data will be available when data collection ends until 36 months after publication.

Learn more about this trial

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

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