Acute Effects of an Oral Fat Load on Skeletal Muscle and Hepatic Insulin Sensitivity

Study Overview
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Brief Summary
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The development of type 2 diabetes is based on a combination of insulin resistance and beta cell dysfunction. In the last years, elevated FFA were recognized as a key players in the pathogenesis of insulin resistance and type 2 diabetes. The study compares the acute effects of an oral lipid bolus on insulin sensitivity and hepatic glucose metabolism in healthy humans.

Detailed Description
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A dysregulation of lipid metabolism with increased levels of free fatty acids (FFA) represents one key mechanism in the pathogenesis of insulin resistance, which contributes to the development of type 2 diabetes (T2D). In most cases, dyslipidemia is related to obesity and the metabolic syndrome. Not only skeletal muscle glucose uptake, but also hepatic glucose fluxes are altered in insulin resistant states. In obese and T2D subjects, rates of gluconeogenesis (GNG) are increased, but in obese normoglycemic subjects endogenous glucose production (EGP) remains constant because of downregulation of glycogenolysis (GL). However, in T2D subjects, both GNG and GL are elevated, contributing to fasting and postprandial hyperglycemia. Therefore, elevated GNG rates may represent an early event in the pathophysiology of insulin resistance and T2D. Preliminary studies of our institute show that intravenous lipid infusion with subsequent elevation of FFA results in increased GNG rates without alteration of EGP in lean, non-diabetic subjects. In another recent study we investigated the effects of an oral fat load on hepatic insulin sensitivity. As expected, we did not find any alterations in EGP; however, rates of GNG and GL have not been assessed. The aim of this study is to analyze the effects of an oral fat load with transiently elevated levels of circulating lipids on hepatic glucose fluxes, especially GNG and GL, to elucidate the role of dietary fat in the induction of insulin resistance in healthy humans. In this randomized, controlled cross-over study, effects of oral palm oil and canola oil ingestion will be investigated in young, healthy lean subjects. Hepatic glucose fluxes will be assessed by two independent methods, in vivo magnet resonance spectroscopy (MRS) and the deuterated water/acetaminophen method, which also allows for the determination of glycogen cycling rates. Furthermore, hepatic phosphorus metabolites and liver fat content will be monitored by MRS.

Official Title
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Acute Effects of an Oral Fat Load on Skeletal Muscle and Hepatic Insulin Sensitivity (FLAME-study)

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Biological: fat orally


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy male and female subjects age 20-40 BMI 20-25 kg/m2 Exclusion Criteria: hyperlipidemia smoking pregnancy allergy against paracetamol/palm oil/canola oil contraindication for MRI investigations anaemia taking drugs influencing lipid or glucose metabolism, the immune system or antihypertensive treatment M. Meulengracht Hepatitis/HIV chronic diseases

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Palm oil orally<br>oral fat load | Biological: fat orally<br>* Oral ingestion of palm oil or canola oil or water at timepoint zero<br>* Other names: water orally;|
| Active Comparator: Canola oil orally<br>Oral fat load | Biological: fat orally<br>* Oral ingestion of palm oil or canola oil or water at timepoint zero<br>* Other names: water orally;|
| Placebo Comparator: Water orally<br>oral water administration as control | Biological: fat orally<br>* Oral ingestion of palm oil or canola oil or water at timepoint zero<br>* Other names: water orally;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in rate of glucose disappearance (Rd) | Measurement of whole body insulin sensitivity in a hyperinsulinamic euglicamic clamp with deuterated glucose kinetics | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in rate of hepatic endogenous glucose production (EGP) | Measurement of hepatic EGP in a hyperinsulinamic euglicamic clamp with deuterated glucose kinetics | 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oral fat, insulin sensitivity