Dyslipidemia, Type 2 Diabetes
Conditions
Keywords
Type 2 diabetes, Hepatic fatty acid oxidation, Dyslipidemia, Metformin
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
Interventions
DRUGMetformin
1000 mg metformin twice daily in 3 months
DRUGPlacebo
2 tablets twice daily in 3 months
Sponsors
Lars Christian Gormsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 70 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Fatty Acid Reesterification | 90 days | Hepatic fatty acid reesterification 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 |
| Hepatic Fatty Acid Oxidation | 90 days | Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET |
| Hepatic Fatty Acid Uptake | 90 days | Hepatic fatty acid uptake assessed by C11-palmitate PET |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| VLDL-TG Oxidation | 90 days | VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath |
| Fatty Acid Turnover | 90 days | Fatty acid turnover assessed as whole body C11-palmitate turnover |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Healthy controls receiving 1000 mg metformin twice daily for 3 months
Metformin: 1000 mg metformin twice daily in 3 months | 12 |
| Placebo Placebo
Placebo: 2 tablets twice daily in 3 months | 12 |
| Metformin Metformin Teva, 1000 mg twice daily for 3 months
Metformin: 1000 mg metformin twice daily in 3 months | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Healthy Controls | Placebo | Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 6 | 60 years STANDARD_DEVIATION 5 | 64 years STANDARD_DEVIATION 5 | 62 years STANDARD_DEVIATION 5 |
| BMI | 27.3 kg/m2 STANDARD_DEVIATION 4.1 | 31.2 kg/m2 STANDARD_DEVIATION 4.3 | 30.3 kg/m2 STANDARD_DEVIATION 5.7 | 29.6 kg/m2 STANDARD_DEVIATION 4.7 |
| HbA1C | 37 mmol/mmol STANDARD_DEVIATION 3 | 45 mmol/mmol STANDARD_DEVIATION 6 | 51 mmol/mmol STANDARD_DEVIATION 6 | 44 mmol/mmol STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 12 Participants | 12 Participants | 36 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 6 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 1 / 12 | 1 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Hepatic Fatty Acid Oxidation
Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Hepatic Fatty Acid Oxidation | 0.052 micromol/ml/min | Standard Deviation 0.024 |
| Placebo | Hepatic Fatty Acid Oxidation | 0.045 micromol/ml/min | Standard Deviation 0.024 |
| Metformin | Hepatic Fatty Acid Oxidation | 0.042 micromol/ml/min | Standard Deviation 0.017 |
Primary
Hepatic Fatty Acid Reesterification
Hepatic fatty acid reesterification assessed by C11-palmitate PET
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Hepatic Fatty Acid Reesterification | 0.134 micromol/ml/min | Standard Deviation 0.056 |
| Placebo | Hepatic Fatty Acid Reesterification | 0.091 micromol/ml/min | Standard Deviation 0.035 |
| Metformin | Hepatic Fatty Acid Reesterification | 0.113 micromol/ml/min | Standard Deviation 0.025 |
Primary
Hepatic Fatty Acid Uptake
Hepatic fatty acid uptake assessed by C11-palmitate PET
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Hepatic Fatty Acid Uptake | 0.186 micromol/ml/min | Standard Deviation 0.067 |
| Placebo | Hepatic Fatty Acid Uptake | 0.137 micromol/ml/min | Standard Deviation 0.051 |
| Metformin | Hepatic Fatty Acid Uptake | 0.155 micromol/ml/min | Standard Deviation 0.029 |
Primary
VLDL-TG Secretion
Hepatic VLDL-TG secretion assessed by \[1-14C\] VLDL tracer
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | VLDL-TG Secretion | 48 micromol/min | Standard Deviation 30 |
| Placebo | VLDL-TG Secretion | 83 micromol/min | Standard Deviation 49 |
| Metformin | VLDL-TG Secretion | 71 micromol/min | Standard Deviation 31 |
Primary
Whole Body Glucose Rd
Whole body basal glucose metabolism assessed by \[3-3H\]glucose tracer kinetics
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Whole Body Glucose Rd | 1.74 mg/kg/min | Standard Deviation 0.29 |
| Placebo | Whole Body Glucose Rd | 1.30 mg/kg/min | Standard Deviation 0.31 |
| Metformin | Whole Body Glucose Rd | 1.78 mg/kg/min | Standard Deviation 0.43 |
Secondary
Fatty Acid Turnover
Fatty acid turnover assessed as whole body C11-palmitate turnover
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Fatty Acid Turnover | 464 micromol/min | Standard Deviation 127 |
| Placebo | Fatty Acid Turnover | 476 micromol/min | Standard Deviation 149 |
| Metformin | Fatty Acid Turnover | 559 micromol/min | Standard Deviation 295 |
Secondary
VLDL-TG Oxidation
VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | VLDL-TG Oxidation | 29 percentage of 14C-VLDL | Standard Deviation 5 |
| Placebo | VLDL-TG Oxidation | 30 percentage of 14C-VLDL | Standard Deviation 7 |
| Metformin | VLDL-TG Oxidation | 27 percentage of 14C-VLDL | Standard Deviation 9 |