Potential Association of a Common L-FABP Polymorphism With Lipid-induced Hepatic Insulin Resistance

Study Overview
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Brief Summary
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The investigators hypothesise that a common A277G polymorphism of the liver fatty acid binding protein (L-FABP) gene, which leads to an amino acid exchange, may be associated with alterations of lipid-induced hepatic insulin resistance. In the present study the investigators will investigate potential differences in lipid-induced hepatic insulin resistance, and in the relation between glycogenolysis and gluconeogenesis, in healthy subjects with the A277G polymorphism vs. subjects carrying the wildtype.

Detailed Description
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Liver fatty acid binding protein (L-FABP) is an abundant cytosolic lipid-binding protein that regulates lipid transport and metabolism. Only one common non-synonymous polymorphism (A227G) leading to an amino-acid exchange in the exonic region of the L-FABP gene has been previously identified. Experimental elevations of free fatty acids (FFAs) have been shown to impair insulin mediated suppression of endogenous glucose production (EGP). Deletion of the L-FABP gene shows no obvious phenotype in mice receiving a low fat chow diet, but leads to decreased hepatic triglyceride accumulation in the prolonged fasted state, which exposes mice to an increased fatty acid flux to the liver. The function of the L-FABP gene may be altered by polymorphisms in coding regions of the gene, probably leading to modifications in hepatic triglyceride accumulation and hepatic insulin resistance.We hypothesize that carriers of the A277G SNP, when compared to matched wild-type subjects, may show altered responses of hepatic glucose production upon exposure to increased peripheral fatty acid concentrations, as achieved by lipid / heparin infusions. Because it is known that free fatty acids potently increase insulin secretion, we use somatostatin clamps in our experiments, followed by replacement of postabsorptive insulin and glucagon concentrations.

Conditions
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Wildtype, Polymorphism Liver FABP

Intervention / Treatment
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* Procedure: measurement of lipid-induced hepatic insulin resistance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy subjects with normal glucose tolerance (NGT) Exclusion Criteria: any severe cardiac, liver, or kidney diseases pregnant or lactating women, menstrual irregularities cortisone, antidiabetic drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Diagnostic
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: measurement of lipid-induced hepatic insulin resistance|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| lipid-induced hepatic insulin resistance(WT vs.SNP L-FABP) |  |  | 
| changes in the relation GNG to GL |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in peripheral plasma glucose and lipid responses |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lipid induced hepatic insulin resistance, polymorphisms liver fatty-acid-binding-protein, gluconeogenesis, glycogenolysis, endogenous glucose production