Effects of Metformin on Hepatic FFA Metabolism

Overview[ - collapse ][ - ]

Purpose 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 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 healthy controls will receive metformin for 3 months. Hypothesis: Metformin lowers VLDL-TG secretion and circulating triglycerides by increasing hepatic fatty acid oxidation
ConditionType 2 Diabetes
Dyslipidemia
InterventionDrug: Metformin
Drug: Placebo
PhasePhase 4
SponsorLars Christian Gormsen
Responsible PartyUniversity of Aarhus
ClinicalTrials.gov IdentifierNCT01729156
First ReceivedNovember 13, 2012
Last UpdatedNovember 26, 2012
Last verifiedNovember 2012

Tracking Information[ + expand ][ + ]

First Received DateNovember 13, 2012
Last Updated DateNovember 26, 2012
Start DateJanuary 2013
Estimated Primary Completion DateApril 2016
Current Primary Outcome Measures
  • Hepatic fatty acid oxidation [Time Frame: 06/01/2015] [Designated as safety issue: No]Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET
  • Hepatic fatty acid reesterification [Time Frame: 06/01/2015] [Designated as safety issue: No]Hepatic fatty acid reesterification assessed by C11-palmitate PET
  • Hepatic fatty acid uptake [Time Frame: 06/01/2015] [Designated as safety issue: No]Hepatic fatty acid uptake assessed by C11-palmitate PET
  • VLDL-TG secretion [Time Frame: 06/01/2015] [Designated as safety issue: No]Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer
Current Secondary Outcome Measures
  • Weight loss [Time Frame: 06/01/2015] [Designated as safety issue: No]Weight loss after metformin treatment
  • Fatty acid turnover [Time Frame: 06/01/2015] [Designated as safety issue: No]Fatty acid turnover assessed as whole body C11-palmitate turnover
  • VLDL-TG oxidation [Time Frame: 06/01/2015] [Designated as safety issue: No]VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath

Descriptive Information[ + expand ][ + ]

Brief TitleEffects of Metformin on Hepatic FFA Metabolism
Official TitleEffects of Metformin on Hepatic Free Fatty Acid Metabolism in Patients Diagnosed With Type 2 Diabetes: A C11 PET Study
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 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 healthy controls will
receive metformin for 3 months.

Hypothesis: Metformin lowers VLDL-TG secretion and circulating triglycerides by increasing
hepatic fatty acid oxidation
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science
Condition
  • Type 2 Diabetes
  • Dyslipidemia
InterventionDrug: Metformin
Other Names:
Metformin "Sandoz" 500 mgDrug: Placebo
Study Arm (s)
  • Other: Healthy controls
    Healthy controls receiving 1000 mg metformin twice daily for 3 months
  • Placebo Comparator: Placebo
    Placebo
  • Active Comparator: Metformin
    Metformin "Sandoz", 1000 mg twice daily for 3 months

Recruitment Information[ + expand ][ + ]

Recruitment StatusNot yet recruiting
Estimated Enrollment36
Estimated Completion DateApril 2016
Estimated Primary Completion DateJuly 2015
Eligibility Criteria
Inclusion Criteria:

- Newly diagnosed type 2 diabetes (>3 and <12 months)

- Age 50-70 years

- BMI<40

Exclusion Criteria:

- Metformin treatment >6 months

- 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)
GenderBoth
Ages50 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsContact: Lars C Gormsen, MD PhD
+4578456205
lars.christian.gormsen@ki.au.dk
Location CountriesNot Provided

Administrative Information[ + expand ][ + ]

NCT Number NCT01729156
Other Study ID NumbersC11palmitatMetformin
Has Data Monitoring CommitteeYes
Information Provided ByUniversity of Aarhus
Study SponsorLars Christian Gormsen
CollaboratorsNot Provided
Investigators Principal Investigator: Lars C Gormsen, MD PhD Aarhus University Hospital
Verification DateNovember 2012