Clinical trial NCT05743868: 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
Overall status: RECRUITING
Phase: NA
Conditions: Insulin Resistance
Hypertriglyceridemia
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Amsterdam UMC
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2023-02-24
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: Effect of tissue-specific insulin resistance on contribution of DNL to plasma triglyceride
timeFrame: Baseline
measure: Change in DNL in VLDL-triglycerides after a standard meal compared to a standard meal with premeal exercise.
timeFrame: study visit 1 and study visit 2, up to 8 weeks
Secondary outcomes:
measure: Change in plasma triglycerides after a standard meal compared to a standard meal with premeal exercise
timeFrame: study visit 1 and study visit 2, up to 8 weeks
measure: Baseline plasma triglycerides
timeFrame: baseline
measure: Adipose insulin sensitivity
timeFrame: Baseline
measure: Skeletal muscle/whole-body insulin sensitivity assessed by oral glucose tolerance test (OGTT)
timeFrame: Baseline
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: AMC Amsterdam
Study officials:
affiliation: Yale University
name: Daniel F Vatner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: