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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
40
De novo lipogenesis (DNL) will be assessed in all participants with a standardized dinner
DNL will be assessed in all participants with short bouts of premeal exercise with a standardized dinner
AMC Amsterdam
Amsterdam, Netherlands
RECRUITINGEffect 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.
Time frame: 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.
Time frame: study visit 1 and study visit 2, up to 8 weeks
Change in plasma triglycerides after a standard meal compared to a standard meal with premeal exercise
Plasma triglycerides will be measured under both conditions.
Time frame: 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
Time frame: 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.
Time frame: 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.
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Time frame: Baseline