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

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.

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.