Effects of Metformin on Hepatic FFA Metabolism

Study Overview
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Brief Summary
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Background: Metformin treatment has beneficial effects on both glucose and lipid metabolism. Whereas there is general agreement that the blood glucose lowering effect of metformin results from inhibition of hepatic gluconeogenesis, it is less clear exactly how the drug lowers blood triglyceride concentration. There are indications that it enhances hepatic free fatty acid (FFA) oxidation thus diminishing substrate for reesterification and resecretion as very-low-density-lipoprotein (VLDL) triglycerides (TG). However, the liver is not easily accessible for sampling in humans and data on the clinical effects of metformin in the liver are therefore lacking. This may change due to the increasing use of the positron emission tomography (PET) technique. Using PET isotopes (11C or 18F) coupled to either palmitate or a fatty acid analogue, it is possible to non-invasively measure hepatic fatty acid handling. Aim: To determine how 3 months metformin treatment (1000 mg twice daily) affects hepatic lipid and glucose metabolism in patients with newly diagnosed type 2 diabetes. Design: Randomized, placebo controlled, double-blind parallel study with patients receiving either metformin or placebo. A control group of BMI and age-matched non-diabetic individuals will receive metformin for 3 months. Hypothesis: Metformin lowers VLDL-TG secretion and circulating triglycerides by increasing hepatic fatty acid oxidation

Official Title
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Effects of Metformin on Hepatic Free Fatty Acid Metabolism in Patients Diagnosed With Type 2 Diabetes: A C11 PET Study

Conditions
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Type 2 Diabetes, Dyslipidemia

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recently diagnosed type 2 diabetes Age 50-70 years BMI<40 Exclusion Criteria: Insulin treatment NASH (non alcoholic steatohepatitis) Cancer Anemia HbA1C>8.5 % Chronic or acute pancreatitis Alcohol or medicine abuse Allergy towards metformin Claustrophobia Severe obesity (weight >130 kilogram)

Ages Eligible for Study
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Minimum Age: 50 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy controls<br>Healthy controls receiving 1000 mg metformin twice daily for 3 months | Drug: Metformin<br>* 1000 mg metformin twice daily in 3 months<br>* Other names: Metformin Sandoz 500 mg;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* 2 tablets twice daily in 3 months<br>|
| Active Comparator: Metformin<br>Metformin Sandoz, 1000 mg twice daily for 3 months | Drug: Metformin<br>* 1000 mg metformin twice daily in 3 months<br>* Other names: Metformin Sandoz 500 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic Fatty Acid Oxidation | Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET | 90 days | 
| Hepatic Fatty Acid Reesterification | Hepatic fatty acid reesterification assessed by C11-palmitate PET | 90 days | 
| Hepatic Fatty Acid Uptake | Hepatic fatty acid uptake assessed by C11-palmitate PET | 90 days | 
| VLDL-TG Secretion | Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer | 90 days | 
| Whole Body Glucose Rd | Whole body basal glucose metabolism assessed by [3-3H]glucose tracer kinetics | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatty Acid Turnover | Fatty acid turnover assessed as whole body C11-palmitate turnover | 90 days | 
| VLDL-TG Oxidation | VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, Hepatic fatty acid oxidation, Dyslipidemia, Metformin