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

Study Overview
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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.

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

Conditions
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Insulin Resistance, Hypertriglyceridemia

Intervention / Treatment
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* Behavioral: Standardized Dinner
* Behavioral: Premeal exercise


Participation Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IR participants with standardized dinner<br>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. | Behavioral: Standardized Dinner<br>* De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner<br>|
| Experimental: IR participants with standardized dinner and premeal exercise<br>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. | Behavioral: Standardized Dinner<br>* De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner<br>Behavioral: Premeal exercise<br>* DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Baseline plasma triglycerides | Plasma triglycerides will be measured at the screening visit to determine eligibility for the study | baseline | 
| 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 | 
| 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. | Baseline |