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The investigators propose that post-exercise milk protein feeding will enhance the mitochondrial protein synthesis (biogenesis) response to an exercise-training program. In addition, the investigators propose that this stimulatory effect of protein feeding will overcome the potential blunting effect of metformin on exercise responses. The investigators will investigate these outcomes over a 12-week exercise-training program in older adults with pre-diabetes with or without metformin treatment.
This is a randomized, placebo controlled, double blind study. 60 men and women over the age of 55 with indications of pre-diabetes will be recruited for participation and randomly assigned to one of four 12 week exercise training programs: 1)Supervised aerobic exercise 3 days per week followed by a carbohydrate drink along with daily oral administration of Metformin. 2) Supervised aerobic exercise 3 days per week followed by a protein drink along with daily oral administration of Metformin. 3) Supervised aerobic exercise 3 days per week followed by a carbohydrate drink along with daily oral administration of matching placebo. 4) Supervised aerobic exercise 3 days per week followed by a protein drink along with daily oral administration of placebo.
Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. The titration dosing scheme and taking metformin/placebo with meals will help reduce the most common side effects (i.e.,gastrointestinal discomfort). If participants experience gastrointestinal discomfort, the dose will be lowered to 1500 mg/day.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin/Carbohydrate | Experimental | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. The dose of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4. Supervised aerobic exercise 3 days per week followed by a carbohydrate drink along with daily oral administration of Metformin. |
|
| Placebo/Carbohydrate | Placebo Comparator | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Supervised aerobic exercise 3 days per week followed by a carbohydrate drink along with daily oral administration of matching placebo. |
|
| Metformin/Protein | Active Comparator | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. The dose of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week. Supervised aerobic exercise 3 days per week followed by a protein drink along with daily oral administration of Metformin |
|
| Placebo/Protein |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
| Measure | Description | Time Frame |
|---|---|---|
| Mitochondrial Function | Oxygen consumption was assessed via high-resolution mitochondrial respirometry in permeabilized skeletal muscle. This outcome was assessed via 2 different protocols; Protocol 1 was a substrate-uncoupler-inhibitor titration (SUIT) and Protocol 2 was an adenosine diphosphate (ADP) titration. These data are reported as the percent change from baseline compared to 12 weeks. | Baseline and 12 weeks |
| Protein Synthesis | Incorporation of deuterium into proteins to calculate cumulative synthesis rates. Protein synthesis was measured in sub cellular fractions of skeletal muscle including mixed, cytoplasmic and mitochondrial enriched fractions. These data are reported as the mean at 12 weeks. | 12 weeks |
| Body Composition | Dual energy x-ray absorptiometry was used to assess fat-free and fat mass. These data are reported as the mean at baseline (pre) and mean at 12 weeks (post). | Baseline and 12 weeks |
| Insulin Sensitivity | Oral glucose tolerance test was used to measure whole-body insulin sensitivity. These data are reported as the mean at baseline (pre) and the mean at 12 weeks (post). | Baseline and 12 weeks |
| Peak Aerobic Capacity | Indirect calorimetry was used to measure peak oxygen consumption during a maximal, graded exercise test. These data are reported as the percent change from baseline compared to 12 weeks. | Baseline and 12 weeks |
| DNA Synthesis | Incorporation of Deuterium Oxide into DNA will be measured before and after the 12 week interventions. |
| Measure | Description | Time Frame |
|---|---|---|
| Intracellular Signaling Proteins | Protein content of intracellular signaling proteins that are implicated in mitochondrial biogenesis, mitochondrial function and insulin sensitivity were measured by Western blotting. Densitometry results are reported as a ratio of protein divided by total amount of protein expressed. All proteins of interest are expressed as phosphorylated relative to total. These data are reported as the percent change from baseline compared to 12 weeks. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Colorado State University, Dept. of Health and Exercise Science | Fort Collins | Colorado | 80523-1582 | United States |
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| Label | URL |
|---|---|
| Lab website | View source |
| Final Publication | View source |
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Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin:Carbohydrate | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a isocaloric carbohydrate beverage. Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
| FG001 | Placebo:Carbohydrate | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of with post-exercise consumption of a protein beverage. The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Placebo: Daily administration of matching placebo during a 12 week exercise training program. |
| FG002 | Metformin:Protein | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a protein beverage. The dose of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4. |
| FG003 | Placebo: Carbohydrate | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a isocaloric carbohydrate beverage. The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
2 subjects were withdrawn from the Placebo: Carbohydrate group (1 subject's baseline data was analyzed). 2 subjects were withdrawn from the Metformin: Protein group (1 subject's baseline data was analyzed). 1 subject was withdrawn from the Placebo: Protein Group and baseline data was not analyzed.
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| ID | Title | Description |
|---|---|---|
| BG000 | Metformin: Carbohydrate | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. Immediately after each exercise session, participants consumed a standardized beverage that consisted of carbohydrates (82g) plus protein (2g). Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mitochondrial Function | Oxygen consumption was assessed via high-resolution mitochondrial respirometry in permeabilized skeletal muscle. This outcome was assessed via 2 different protocols; Protocol 1 was a substrate-uncoupler-inhibitor titration (SUIT) and Protocol 2 was an adenosine diphosphate (ADP) titration. These data are reported as the percent change from baseline compared to 12 weeks. | The number analyzed differs from the overall number due to subject withdrawal from study and/or limited muscle sample. | Posted | Mean | Standard Error | percent change in pmol/s/mg tissue | Baseline and 12 weeks |
|
From the start of the intervention period through the 12 week intervention period.
Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Metformin: Carbohydrate | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a isocaloric carbohydrate beverage. Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea/Nausea/Stomach Cramps | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Manager of Research Operations | Colorado State University | 9704912242 | Laurie.Biela@colostate.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 4, 2018 | Nov 5, 2018 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 20, 2017 | Nov 5, 2018 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.
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Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. The dose of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week. Supervised aerobic exercise 3 days per week followed by a protein drink along with daily oral administration of placebo. |
|
|
| Placebo | Drug | Daily administration of matching placebo during a 12 week exercise training program. |
|
| Carbohydrate Beverage | Dietary Supplement | Supervised aerobic exercise 3 days per week followed by a carbohydrate drink |
|
| Protein Beverage | Dietary Supplement | Supervised aerobic exercise 3 days per week followed by a protein drink |
|
| Baseline and 12 weeks |
| Glucose Tolerance | Oral glucose tolerance test was used to measure glucose tolerance. These data are reported as the mean at baseline (pre) and the mean at 12 weeks (post). | Baseline and 12 weeks |
| Baseline and 12 weeks |
| Glucose Profiles From Real-Time Continuous Glucose Monitoring | Data derived from Continuous Glucose Monitoring was used to calculate mean glucose and mean average glucose excursions (MAGE). These data are reported as the percent change at baseline (pre), 6-8 weeks (Mid), and 12 weeks (post) . | Baseline, Weeks 6-8, 12 weeks |
| Withdrawal by Subject |
|
| BG001 | Placebo: Carbohydrate | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Immediately after each exercise session, participants consumed a standardized beverage that consisted of carbohydrates (82g) plus protein (2g). |
| BG002 | Metformin: Protein | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training. Immediately after each exercise session, participants consumed a standardized beverage that consisted of carbohydrate (63g) plus protein (20g). Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
| BG003 | Placebo: Protein | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Immediately after each exercise session, participants consumed a standardized beverage that consisted of carbohydrates (63 g) plus protein (20g). |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo:Carbohydrate | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Placebo: Daily administration of matching placebo during a 12 week exercise training program with post-exercise consumption of a carbohydrate beverage. |
| OG002 | Metformin: Protein | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a protein beverage. Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. |
| OG003 | Placebo: Protein | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Placebo: Daily administration of matching placebo during a 12 week exercise training program with post-exercise consumption of a protein beverage. |
|
|
| Primary | Protein Synthesis | Incorporation of deuterium into proteins to calculate cumulative synthesis rates. Protein synthesis was measured in sub cellular fractions of skeletal muscle including mixed, cytoplasmic and mitochondrial enriched fractions. These data are reported as the mean at 12 weeks. | The number analyzed differs from the over all number due to subject withdrawal from study and/or limited muscle sample. | Posted | Mean | Standard Error | % of protein synthesis rate per day | 12 weeks |
|
|
|
| Primary | Body Composition | Dual energy x-ray absorptiometry was used to assess fat-free and fat mass. These data are reported as the mean at baseline (pre) and mean at 12 weeks (post). | Posted | Mean | Standard Deviation | Kilograms | Baseline and 12 weeks |
|
|
|
| Primary | Insulin Sensitivity | Oral glucose tolerance test was used to measure whole-body insulin sensitivity. These data are reported as the mean at baseline (pre) and the mean at 12 weeks (post). | Posted | Mean | Standard Deviation | microInternational units/mL | Baseline and 12 weeks |
|
|
|
| Primary | Peak Aerobic Capacity | Indirect calorimetry was used to measure peak oxygen consumption during a maximal, graded exercise test. These data are reported as the percent change from baseline compared to 12 weeks. | Posted | Mean | Standard Error | percent change of Liters/Minute | Baseline and 12 weeks |
|
|
|
| Primary | DNA Synthesis | Incorporation of Deuterium Oxide into DNA will be measured before and after the 12 week interventions. | No data was collected. | Posted | Baseline and 12 weeks |
|
|
| Secondary | Intracellular Signaling Proteins | Protein content of intracellular signaling proteins that are implicated in mitochondrial biogenesis, mitochondrial function and insulin sensitivity were measured by Western blotting. Densitometry results are reported as a ratio of protein divided by total amount of protein expressed. All proteins of interest are expressed as phosphorylated relative to total. These data are reported as the percent change from baseline compared to 12 weeks. | Proteins were analyzed in a subset of participants due to limited tissue availability. | Posted | Mean | Standard Error | percent change of densitometry ratio | Baseline and 12 weeks |
|
|
|
| Secondary | Glucose Profiles From Real-Time Continuous Glucose Monitoring | Data derived from Continuous Glucose Monitoring was used to calculate mean glucose and mean average glucose excursions (MAGE). These data are reported as the percent change at baseline (pre), 6-8 weeks (Mid), and 12 weeks (post) . | Only a subset of subjects were studied. | Posted | Mean | Standard Error | percent change of milligrams/deciliter | Baseline, Weeks 6-8, 12 weeks |
|
|
|
| Primary | Glucose Tolerance | Oral glucose tolerance test was used to measure glucose tolerance. These data are reported as the mean at baseline (pre) and the mean at 12 weeks (post). | Posted | Mean | Standard Deviation | mg/dL | Baseline and 12 weeks |
|
|
|
| 0 |
| 14 |
| 0 |
| 14 |
| 5 |
| 14 |
| EG001 | Placebo: Carbohydrate | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Placebo: Daily administration of matching placebo during a 12 week exercise training program with post-exercise consumption of an isocaloric carbohydrate beverage. | 0 | 13 | 0 | 13 | 5 | 13 |
| EG002 | Metformin: Protein | Daily oral administration of Metformin with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training with post-exercise consumption of a protein beverage. Metformin: Daily administration of Metformin will begin as one 500 mg tablet for the first week and will increase by 500 mg/day/week until reaching 2000 mg/day by week 4 during a 12 week exercise training program. | 0 | 14 | 0 | 14 | 9 | 14 |
| EG003 | Placebo:Protein | Daily oral administration of matching placebo with a 12-week exercise training program consisting of 3 days per week of aerobic exercise training The dose of matching placebo will begin as one tablet for the first week and will increase by one tablet/day/week until reaching 4 tablets by week 4. Placebo: Daily administration of matching placebo during a 12 week exercise training program with post-exercise consumption of a protein beverage. | 0 | 15 | 0 | 15 | 8 | 15 |
| Leg Cramps/Muscle Soreness | General disorders | Non-systematic Assessment |
|
| insomnia | General disorders | Non-systematic Assessment |
|
| Fatigue | General disorders | Non-systematic Assessment |
|
| High blood Pressure | General disorders | Non-systematic Assessment |
|
| High Creatine | Endocrine disorders | Non-systematic Assessment |
|
| Rash | General disorders | Non-systematic Assessment |
|
| Eye Infection/Pressure | General disorders | Non-systematic Assessment |
|
| Hair Loss | General disorders | Non-systematic Assessment |
|
| Common Cold | General disorders | Non-systematic Assessment |
|
| Headaches/Dizziness | General disorders | Non-systematic Assessment |
|
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| Title | Measurements |
|---|---|
|
|
| Cytoplasmic |
|
|
| Mitochondrial |
|
|
| Post Fat Free Mass |
|
| Pre Fat Mass |
|
| Post Fat Mass |
|
| Post 2 hour Insulin |
|
|
| ratio of AKT T308 phospho /total) |
|
|
| RPS6 ratio of phospho/total |
|
|
| 4EBP1 ratio of phospho/total |
|
|
| Mean Glucose- Mid |
|
| Mean Glucose-Post |
|
| MAGE- Pre |
|
| MAGE- Mid |
|
| MAGE- Post |
|
| Post 2 hour Glucose |
|