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

Phase 2

Completed

Conditions: Physical Activity

Interventions: Drug: Placebo
Drug: Metformin
Dietary Supplement: Carbohydrate Beverage
Dietary Supplement: Protein Beverage

Registration Number: NCT02552355

Lead Sponsor: Colorado State University

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metformin/Carbohydrate	Carbohydrate Beverage	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	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.
Placebo/Carbohydrate	Carbohydrate Beverage	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	Metformin	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
Metformin/Protein	Protein Beverage	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	Placebo	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/Protein	Protein Beverage	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.
Metformin/Carbohydrate	Metformin	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.

Primary Outcome Measures

Name	Time	Method
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).
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.
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.
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).
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.
DNA Synthesis	Baseline and 12 weeks	Incorporation of Deuterium Oxide into DNA will be measured before and after the 12 week interventions.
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

Name	Time	Method
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.
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) .