Milk Protein Feeding After Aerobic Exercise in Older Adults With Pre-diabetes Taking the Biguanide Metformin

• Sponsor: Colorado State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02552355
• Collaborator: (none)
• Enrollment: 56
• Location: 1
• Arms: 4
• Actual Duration (Months): 24
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Physical Activity	Drug: Metformin; Drug: Placebo; Dietary Supplement: Carbohydrate Beverage; Dietary Supplement: Protein Beverage	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Milk Protein Feeding After Aerobic Exercise in Older Adults With Pre-diabetes Taking the Biguanide Metformin
• Actual Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin/Carbohydrate 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.	Drug: 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.; Other Names: Glumetza Fortamet Glucophage Riomet ; Dietary Supplement: Carbohydrate Beverage; Supervised aerobic exercise 3 days per week followed by a carbohydrate drink
Placebo Comparator: 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. Supervised aerobic exercise 3 days per week followed by a carbohydrate drink along with daily oral administration of matching placebo.	Drug: Placebo; Daily administration of matching placebo during a 12 week exercise training program.; Dietary Supplement: Carbohydrate Beverage; Supervised aerobic exercise 3 days per week followed by a carbohydrate drink
Active Comparator: Metformin/Protein 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	Drug: 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.; Other Names: Glumetza Fortamet Glucophage Riomet ; Dietary Supplement: Protein Beverage; Supervised aerobic exercise 3 days per week followed by a protein drink
Active Comparator: Placebo/Protein 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.	Drug: Placebo; Daily administration of matching placebo during a 12 week exercise training program.; Dietary Supplement: Protein Beverage; Supervised aerobic exercise 3 days per week followed by a protein drink

Outcome Measures

Primary Outcome Measures

1. Mitochondrial Function [Baseline and 12 weeks]

   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.

2. Protein Synthesis [12 weeks]

   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.

3. Body Composition [Baseline and 12 weeks]

   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).

4. Insulin Sensitivity [Baseline and 12 weeks]

   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).

5. Peak Aerobic Capacity [Baseline and 12 weeks]

   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.

6. DNA Synthesis [Baseline and 12 weeks]

   Incorporation of Deuterium Oxide into DNA will be measured before and after the 12 week interventions.

7. Glucose Tolerance [Baseline and 12 weeks]

   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).

Secondary Outcome Measures

1. Intracellular Signaling Proteins [Baseline and 12 weeks]

   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.

2. Glucose Profiles From Real-Time Continuous Glucose Monitoring [Baseline, Weeks 6-8, 12 weeks]

   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) .

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• 55 years or older

• Individuals with Prediabetes defined as impaired fasting glucose (100 to 126 mg/dl), HbA1c (5.7-6.4%), and/or impaired glucose tolerance defined as 2 hour postprandial blood glucose of 140 to 200 mg/dl.

Exclusion Criteria:

• Medications contraindicated with Metformin (Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine)

• Recent (less than 6 weeks) or planned imaging that requires IV contrast,

• Renal dysfunction creatinine ≥ 1.3 mg/dL in men or ≥ 1.2 mg/dL in women

• Alanine Aminotransferase (ALT) levels exceed 52 IU/L

• Heart, Kidney or Liver Disease

• Type I or Type II Diabetes

• Anti-coagulant therapy (warfarin/heparin)

• Lung/respiratory dysfunction

• Medications affecting primary outcomes

• Lactose Intolerant

• Tobacco Use

• Heavy Alcohol Use

• Cancer

• Lidocaine Allergy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Colorado State University, Dept. of Health and Exercise Science	Fort Collins	Colorado	United States	80523-1582

Sponsors and Collaborators

• Colorado State University

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 4, 2018
• Informed Consent Form - May 20, 2017

More Information

Additional Information:

• Lab website
• Final Publication

Publications

None provided.

• Responsible Party: Benjamin Miller, Associate Professor, Colorado State University
• ClinicalTrials.gov Identifier: NCT02552355
• Other Study ID Numbers: 15-8573H
• First Posted: Sep 17, 2015
• Last Update Posted: Apr 30, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Prediabetic State; Metformin

Study Results

Participant Flow

Pre-assignment Detail	Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.

Arm/Group Title	Metformin:Carbohydrate	Placebo:Carbohydrate	Metformin:Protein	Placebo: Carbohydrate
Arm/Group Description	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.	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.	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.	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.
Period Title: Overall Study
STARTED	14	13	14	15
COMPLETED	14	11	12	14
NOT COMPLETED	0	2	2	1

Baseline Characteristics

Arm/Group Title	Metformin: Carbohydrate	Placebo: Carbohydrate	Metformin: Protein	Placebo: Protein	Total
Arm/Group Description	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.	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).	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.	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).	Total of all reporting groups
Overall Participants	14	12	13	14	53
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	12 100%	13 100%	14 100%	53 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	11 78.6%	10 83.3%	10 76.9%	11 78.6%	42 79.2%
Male	3 21.4%	2 16.7%	3 23.1%	3 21.4%	11 20.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	14 100%	12 100%	13 100%	14 100%	53 100%
Region of Enrollment (participants) [Number]
United States	14 100%	12 100%	13 100%	14 100%	53 100%

Outcome Measures

1. Primary Outcome

Title	Mitochondrial Function
Description	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.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

The number analyzed differs from the overall number due to subject withdrawal from study and/or limited muscle sample.

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	13	14
SUIT	7.1 (12.8)	43.2 (15.5)	15.6 (7.6)	13.8 (6.9)
ADP titration	3.4 (8.2)	42.3 (12.9)	4.7 (11.7)	16 (9.4)

2. Primary Outcome

Title	Protein Synthesis
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The number analyzed differs from the over all number due to subject withdrawal from study and/or limited muscle sample.

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	12	14
Mixed	1.24 (0.06)	1.15 (0.04)	1.1 (0.04)	1.14 (0.04)
Cytoplasmic	1.15 (0.07)	1.00 (0.05)	1.05 (0.03)	1.06 (0.05)
Mitochondrial	1.09 (0.09)	0.97 (0.08)	1.03 (0.04)	0.95 (0.07)

3. Primary Outcome

Title	Body Composition
Description	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).
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	13	14
Pre Fat Free Mass	48 (3)	48 (3)	50 (2)	46 (2)
Post Fat Free Mass	47 (2)	48 (2)	50 (3)	46 (2)
Pre Fat Mass	34 (3)	35 (3)	33 (3)	33 (4)
Post Fat Mass	32 (3)	34 (2)	31 (3)	32 (4)

4. Primary Outcome

Title	Insulin Sensitivity
Description	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).
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	13	14
Pre 2 hour Insulin	86 (20)	57 (14)	39 (7)	56 (13)
Post 2 hour Insulin	91 (34)	51 (8)	32 (7)	55 (15)

5. Primary Outcome

Title	Peak Aerobic Capacity
Description	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.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	13	13
Mean (Standard Error) [percent change of Liters/Minute]	3 (2.1)	4.7 (3.8)	4.9 (2.8)	8.5 (2.9)

6. Primary Outcome

Title	DNA Synthesis
Description	Incorporation of Deuterium Oxide into DNA will be measured before and after the 12 week interventions.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

No data was collected.

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	0	0	0	0

7. Secondary Outcome

Title	Intracellular Signaling Proteins
Description	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.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Proteins were analyzed in a subset of participants due to limited tissue availability.

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	10	8	13
Ratio of AKT S473 phospho/total)	154.3 (46.7)	677.5 (187.5)	321.1 (147.4)	106.9 (28.8)
ratio of AKT T308 phospho /total)	151.8 (43.2)	563.2 (230.1)	477.3 (148.2)	94.0 (25.4)
RPS6 ratio of phospho/total	16.6 (12.6)	-2.2 (25.4)	47.0 (16.5)	-15.6 (15.4)
4EBP1 ratio of phospho/total	35 (25.2)	57 (42)	122 (76)	13.5 (13.9)

8. Secondary Outcome

Title	Glucose Profiles From Real-Time Continuous Glucose Monitoring
Description	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) .
Time Frame	Baseline, Weeks 6-8, 12 weeks

Outcome Measure Data

Analysis Population Description

Only a subset of subjects were studied.

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	4	4	4	5
Mean Glucose- Pre	116 (9.9)	116.7 (5.9)	113.3 (3.5)	107.1 (5.3)
Mean Glucose- Mid	105.3 (6.2)	104.7 (4.1)	93.7 (7.7)	95.2 (10.7)
Mean Glucose-Post	110.7 (2.7)	116.1 (6.2)	107.8 (3.7)	108.6 (2.0)
MAGE- Pre	61.3 (15)	49.5 (4.2)	41.1 (3.0)	46.4 (6.5)
MAGE- Mid	53.6 (6.9)	40.8 (3.1)	36.2 (2.5)	37.1 (4.9)
MAGE- Post	56.4 (8.4)	58.6 (7.1)	42.1 (2.9)	46.3 (5.5)

9. Primary Outcome

Title	Glucose Tolerance
Description	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).
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin: Carbohydrate	Placebo:Carbohydrate	Metformin: Protein	Placebo: Protein
Arm/Group Description	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 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.	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.	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.	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.
Measure Participants	14	12	13	14
Pre 2 hour Glucose	131 (7)	116 (7)	108 (14)	102 (7)
Post 2 hour Glucose	133 (7)	115 (7)	112 (12)	107 (10)

Adverse Events

Time Frame	From the start of the intervention period through the 12 week intervention period.
Adverse Event Reporting Description	Participants were assigned to either Metformin-Protein, Metformin-Carbohydrate, Placebo-Protein, and Placebo-Carbohydrate.
Arm/Group Title	Metformin: Carbohydrate		Placebo: Carbohydrate		Metformin: Protein		Placebo:Protein
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Metformin: Carbohydrate		Placebo: Carbohydrate		Metformin: Protein		Placebo:Protein
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)		0/14 (0%)		0/15 (0%)
Serious Adverse Events
	Metformin: Carbohydrate		Placebo: Carbohydrate		Metformin: Protein		Placebo:Protein
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)		0/14 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Metformin: Carbohydrate		Placebo: Carbohydrate		Metformin: Protein		Placebo:Protein
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/14 (35.7%)		5/13 (38.5%)		9/14 (64.3%)		8/15 (53.3%)
Endocrine disorders
High Creatine	0/14 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0	0/15 (0%)	0
General disorders
Diarrhea/Nausea/Stomach Cramps	5/14 (35.7%)	12	2/13 (15.4%)	2	5/14 (35.7%)	5	6/15 (40%)	8
Leg Cramps/Muscle Soreness	1/14 (7.1%)	1	0/13 (0%)	0	4/14 (28.6%)	4	3/15 (20%)	3
insomnia	0/14 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0	0/15 (0%)	0
Fatigue	0/14 (0%)	0	1/13 (7.7%)	1	1/14 (7.1%)	1	0/15 (0%)	0
High blood Pressure	0/14 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0	0/15 (0%)	0
Rash	0/14 (0%)	0	1/13 (7.7%)	1	1/14 (7.1%)	1	0/15 (0%)	0
Eye Infection/Pressure	2/14 (14.3%)	2	1/13 (7.7%)	1	0/14 (0%)	0	0/15 (0%)	0
Hair Loss	1/14 (7.1%)	1	0/13 (0%)	0	0/14 (0%)	0	0/15 (0%)	0
Common Cold	1/14 (7.1%)	1	0/13 (0%)	0	0/14 (0%)	0	0/15 (0%)	0
Headaches/Dizziness	0/14 (0%)	0	0/13 (0%)	0	1/14 (7.1%)	2	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.