Trial Outcomes & Findings for Milk Protein Feeding After Aerobic Exercise in Older Adults With Pre-diabetes Taking the Biguanide Metformin (NCT NCT02552355)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

56 participants

Primary outcome timeframe

Baseline and 12 weeks

Results posted on

2019-04-30

Participant Flow

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

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.
Overall Study STARTED	14	13	14	15
Overall Study COMPLETED	14	11	12	14
Overall Study NOT COMPLETED	0	2	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.	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.
Overall Study Adverse Event	0	2	2	0
Overall Study Withdrawal by Subject	0	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo: Carbohydrate n=12 Participants 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).	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=14 Participants 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 n=53 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants	14 Participants n=4 Participants	53 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	10 Participants n=7 Participants	10 Participants n=5 Participants	11 Participants n=4 Participants	42 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	11 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	14 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants	14 Participants n=4 Participants	53 Participants n=21 Participants
Region of Enrollment United States	14 participants n=5 Participants	12 participants n=7 Participants	13 participants n=5 Participants	14 participants n=4 Participants	53 participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks

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

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.

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=14 Participants 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.
Mitochondrial Function ADP titration	3.4 percent change in pmol/s/mg tissue Standard Error 8.2	42.3 percent change in pmol/s/mg tissue Standard Error 12.9	4.7 percent change in pmol/s/mg tissue Standard Error 11.7	16 percent change in pmol/s/mg tissue Standard Error 9.4
Mitochondrial Function SUIT	7.1 percent change in pmol/s/mg tissue Standard Error 12.8	43.2 percent change in pmol/s/mg tissue Standard Error 15.5	15.6 percent change in pmol/s/mg tissue Standard Error 7.6	13.8 percent change in pmol/s/mg tissue Standard Error 6.9

PRIMARY outcome

Timeframe: 12 weeks

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

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.

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=12 Participants 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.	Placebo: Protein n=14 Participants 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.
Protein Synthesis Mixed	1.24 % of protein synthesis rate per day Standard Error 0.06	1.15 % of protein synthesis rate per day Standard Error 0.04	1.1 % of protein synthesis rate per day Standard Error 0.04	1.14 % of protein synthesis rate per day Standard Error 0.04
Protein Synthesis Cytoplasmic	1.15 % of protein synthesis rate per day Standard Error 0.07	1.00 % of protein synthesis rate per day Standard Error 0.05	1.05 % of protein synthesis rate per day Standard Error 0.03	1.06 % of protein synthesis rate per day Standard Error 0.05
Protein Synthesis Mitochondrial	1.09 % of protein synthesis rate per day Standard Error 0.09	0.97 % of protein synthesis rate per day Standard Error 0.08	1.03 % of protein synthesis rate per day Standard Error 0.04	0.95 % of protein synthesis rate per day Standard Error 0.07

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=14 Participants 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.
Body Composition Pre Fat Mass	34 Kilograms Standard Deviation 3	35 Kilograms Standard Deviation 3	33 Kilograms Standard Deviation 3	33 Kilograms Standard Deviation 4
Body Composition Post Fat Mass	32 Kilograms Standard Deviation 3	34 Kilograms Standard Deviation 2	31 Kilograms Standard Deviation 3	32 Kilograms Standard Deviation 4
Body Composition Pre Fat Free Mass	48 Kilograms Standard Deviation 3	48 Kilograms Standard Deviation 3	50 Kilograms Standard Deviation 2	46 Kilograms Standard Deviation 2
Body Composition Post Fat Free Mass	47 Kilograms Standard Deviation 2	48 Kilograms Standard Deviation 2	50 Kilograms Standard Deviation 3	46 Kilograms Standard Deviation 2

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=14 Participants 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.
Insulin Sensitivity Pre 2 hour Insulin	86 microInternational units/mL Standard Deviation 20	57 microInternational units/mL Standard Deviation 14	39 microInternational units/mL Standard Deviation 7	56 microInternational units/mL Standard Deviation 13
Insulin Sensitivity Post 2 hour Insulin	91 microInternational units/mL Standard Deviation 34	51 microInternational units/mL Standard Deviation 8	32 microInternational units/mL Standard Deviation 7	55 microInternational units/mL Standard Deviation 15

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=13 Participants 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.
Peak Aerobic Capacity	3 percent change of Liters/Minute Standard Error 2.1	4.7 percent change of Liters/Minute Standard Error 3.8	4.9 percent change of Liters/Minute Standard Error 2.8	8.5 percent change of Liters/Minute Standard Error 2.9

PRIMARY outcome

Timeframe: Baseline and 12 weeks

Population: No data was collected.

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=12 Participants 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.	Metformin: Protein n=13 Participants 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.	Placebo: Protein n=14 Participants 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.
Glucose Tolerance Post 2 hour Glucose	133 mg/dL Standard Deviation 7	115 mg/dL Standard Deviation 7	112 mg/dL Standard Deviation 12	107 mg/dL Standard Deviation 10
Glucose Tolerance Pre 2 hour Glucose	131 mg/dL Standard Deviation 7	116 mg/dL Standard Deviation 7	108 mg/dL Standard Deviation 14	102 mg/dL Standard Deviation 7

SECONDARY outcome

Timeframe: Baseline and 12 weeks

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

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.

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=14 Participants 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.	Placebo:Carbohydrate n=10 Participants 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.	Metformin: Protein n=8 Participants 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.	Placebo: Protein n=13 Participants 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.
Intracellular Signaling Proteins RPS6 ratio of phospho/total	16.6 percent change of densitometry ratio Standard Error 12.6	-2.2 percent change of densitometry ratio Standard Error 25.4	47.0 percent change of densitometry ratio Standard Error 16.5	-15.6 percent change of densitometry ratio Standard Error 15.4
Intracellular Signaling Proteins 4EBP1 ratio of phospho/total	35 percent change of densitometry ratio Standard Error 25.2	57 percent change of densitometry ratio Standard Error 42	122 percent change of densitometry ratio Standard Error 76	13.5 percent change of densitometry ratio Standard Error 13.9
Intracellular Signaling Proteins Ratio of AKT S473 phospho/total)	154.3 percent change of densitometry ratio Standard Error 46.7	677.5 percent change of densitometry ratio Standard Error 187.5	321.1 percent change of densitometry ratio Standard Error 147.4	106.9 percent change of densitometry ratio Standard Error 28.8
Intracellular Signaling Proteins ratio of AKT T308 phospho /total)	151.8 percent change of densitometry ratio Standard Error 43.2	563.2 percent change of densitometry ratio Standard Error 230.1	477.3 percent change of densitometry ratio Standard Error 148.2	94.0 percent change of densitometry ratio Standard Error 25.4

SECONDARY outcome

Timeframe: Baseline, Weeks 6-8, 12 weeks

Population: Only a subset of subjects were studied.

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) .

Outcome measures

Outcome measures
Measure	Metformin: Carbohydrate n=4 Participants 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.	Placebo:Carbohydrate n=4 Participants 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.	Metformin: Protein n=4 Participants 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.	Placebo: Protein n=5 Participants 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.
Glucose Profiles From Real-Time Continuous Glucose Monitoring Mean Glucose- Pre	116 percent change of milligrams/deciliter Standard Error 9.9	116.7 percent change of milligrams/deciliter Standard Error 5.9	113.3 percent change of milligrams/deciliter Standard Error 3.5	107.1 percent change of milligrams/deciliter Standard Error 5.3
Glucose Profiles From Real-Time Continuous Glucose Monitoring Mean Glucose- Mid	105.3 percent change of milligrams/deciliter Standard Error 6.2	104.7 percent change of milligrams/deciliter Standard Error 4.1	93.7 percent change of milligrams/deciliter Standard Error 7.7	95.2 percent change of milligrams/deciliter Standard Error 10.7
Glucose Profiles From Real-Time Continuous Glucose Monitoring Mean Glucose-Post	110.7 percent change of milligrams/deciliter Standard Error 2.7	116.1 percent change of milligrams/deciliter Standard Error 6.2	107.8 percent change of milligrams/deciliter Standard Error 3.7	108.6 percent change of milligrams/deciliter Standard Error 2.0
Glucose Profiles From Real-Time Continuous Glucose Monitoring MAGE- Pre	61.3 percent change of milligrams/deciliter Standard Error 15	49.5 percent change of milligrams/deciliter Standard Error 4.2	41.1 percent change of milligrams/deciliter Standard Error 3.0	46.4 percent change of milligrams/deciliter Standard Error 6.5
Glucose Profiles From Real-Time Continuous Glucose Monitoring MAGE- Mid	53.6 percent change of milligrams/deciliter Standard Error 6.9	40.8 percent change of milligrams/deciliter Standard Error 3.1	36.2 percent change of milligrams/deciliter Standard Error 2.5	37.1 percent change of milligrams/deciliter Standard Error 4.9
Glucose Profiles From Real-Time Continuous Glucose Monitoring MAGE- Post	56.4 percent change of milligrams/deciliter Standard Error 8.4	58.6 percent change of milligrams/deciliter Standard Error 7.1	42.1 percent change of milligrams/deciliter Standard Error 2.9	46.3 percent change of milligrams/deciliter Standard Error 5.5

Adverse Events

Metformin: Carbohydrate

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo: Carbohydrate

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Metformin: Protein

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo:Protein

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Metformin: Carbohydrate n=14 participants at risk 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.	Placebo: Carbohydrate n=13 participants at risk 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.	Metformin: Protein n=14 participants at risk 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.	Placebo:Protein n=15 participants at risk 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.
General disorders Diarrhea/Nausea/Stomach Cramps	35.7% 5/14 • Number of events 12 • 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.	15.4% 2/13 • Number of events 2 • 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.	35.7% 5/14 • Number of events 5 • 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.	40.0% 6/15 • Number of events 8 • 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.
General disorders Leg Cramps/Muscle Soreness	7.1% 1/14 • Number of events 1 • 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.	0.00% 0/13 • 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.	28.6% 4/14 • Number of events 4 • 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.	20.0% 3/15 • Number of events 3 • 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.
General disorders insomnia	0.00% 0/14 • 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.	7.7% 1/13 • Number of events 1 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
General disorders Fatigue	0.00% 0/14 • 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.	7.7% 1/13 • Number of events 1 • 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.	7.1% 1/14 • Number of events 1 • 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.	0.00% 0/15 • 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.
General disorders High blood Pressure	0.00% 0/14 • 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.	7.7% 1/13 • Number of events 1 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
Endocrine disorders High Creatine	0.00% 0/14 • 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.	7.7% 1/13 • Number of events 1 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
General disorders Rash	0.00% 0/14 • 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.	7.7% 1/13 • Number of events 1 • 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.	7.1% 1/14 • Number of events 1 • 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.	0.00% 0/15 • 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.
General disorders Eye Infection/Pressure	14.3% 2/14 • Number of events 2 • 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.	7.7% 1/13 • Number of events 1 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
General disorders Hair Loss	7.1% 1/14 • Number of events 1 • 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.	0.00% 0/13 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
General disorders Common Cold	7.1% 1/14 • Number of events 1 • 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.	0.00% 0/13 • 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.	0.00% 0/14 • 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.	0.00% 0/15 • 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.
General disorders Headaches/Dizziness	0.00% 0/14 • 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.	0.00% 0/13 • 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.	7.1% 1/14 • Number of events 2 • 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.	0.00% 0/15 • 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.

Additional Information

Manager of Research Operations

Colorado State University

Phone: 9704912242

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place