Effects of Metformin on Hepatic FFA Metabolism

Phase 4

Completed

• Conditions: Type 2 Diabetes; Dyslipidemia
• Interventions: Drug: Metformin; Drug: Placebo

• Registration Number: NCT01729156
• Lead Sponsor: Lars Christian Gormsen

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-11-13
• Study First Submitted QC: 2012-11-13
• Study First Posted: 2012-11-20
• Study Start: 2013-01
• Primary Completion: 2017-05-05
• Study Completion: 2017-05-05
• Status Verified: 2019-09
• Results First Submitted: 2019-09-24
• Results First Submitted QC: 2019-09-24
• Last Update Submitted: 2019-09-24
• Results First Posted: 2019-10-15
• Last Update Posted: 2019-10-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

• Recently diagnosed type 2 diabetes
• Age 50-70 years
• BMI<40

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Healthy controls	Metformin	Healthy controls receiving 1000 mg metformin twice daily for 3 months
Placebo	Placebo	Placebo
Metformin	Metformin	Metformin "Sandoz", 1000 mg twice daily for 3 months

Primary Outcome Measures

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

Secondary Outcome Measures

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