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

Insulin Resistance Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05743868
• Other study ID #: Vatner 012523
• Secondary ID: NL83166.018.22R0
• Status: Recruiting
• Phase: N/A
• Start date: November 16, 2023
• Est. completion date: August 2024

Study information

• Verified date: November 2023
• Source: Yale University
• Contact: Daniel F Vatner, MD, PhD
• Phone: 203 785 5934
• Email: daniel.vatner[@]yale.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypertriglyceridemia
• Insulin Resistance

Intervention

Behavioral:
• Standardized Dinner
De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner
• Premeal exercise
DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner

Locations

Country	Name	City	State
Netherlands	AMC Amsterdam	Amsterdam

Sponsors (3)

Lead Sponsor	Collaborator
Yale University	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Baseline
Primary	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.	study visit 1 and study visit 2, up to 8 weeks
Secondary	Change in plasma triglycerides after a standard meal compared to a standard meal with premeal exercise	Plasma triglycerides will be measured under both conditions.	study visit 1 and study visit 2, up to 8 weeks
Secondary	Baseline plasma triglycerides	Plasma triglycerides will be measured at the screening visit to determine eligibility for the study	baseline
Secondary	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.	Baseline
Secondary	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 / vglucose minute 0 x insulin minute 0) (mean glucose (OGTT) x mean insulin OGTT)]. A higher result indicates less IR.	Baseline