Clinical trial NCT04751916: Nutritional Stimulation of Muscle Protein Synthesis and Metabolic Rate After Bariatric Surgery
Official title: Nutritional Stimulation of Muscle Protein Synthesis and Metabolic Rate After Bariatric Surgery
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Weight Loss
Keywords: bariatric surgery
muscle synthesis
weight loss
essential amino acids
protein supplementation
total energy expenditure
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: The Amino Company, LLC
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-02-12
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double-blinded randomized clinical trial
Primary purpose: TREATMENT

Brief summary: Bariatric surgery is an effective treatment for severe obesity but results in loss of muscle mass. The investigators will test the hypothesis that consumption of an Essential Amino Acid-based nutritional formulation will maintain muscle mass while stimulating fat loss after bariatric surgery.

Detailed description: 1. Objectives

   Bariatric surgery has become a common treatment for severe obesity, and results in a loss of fat mass. However, muscle mass is also lost following bariatric surgery. It is the investigators' overarching premise that consumption of the Essential Amino Acid-based nutritional formulation following bariatric surgery will preserve muscle mass by stimulating muscle protein synthesis. As a result, the energy utilization associated with the combination of maintained muscle mass and stimulated muscle protein synthesis will counter the decrease in metabolic rate that normally occurs in hypocaloric circumstances. Maintenance of a higher total energy expenditure by Essential Amino Acid consumption will accelerate loss of body fat, as well as accelerate loss of body weight. The investigators further propose that consumption of an Essential Amino Acid-based nutritional formulation will reduce muscle intra-cellular lipid accumulation, which will translate to greater improvements in glucose homeostasis and muscle protein metabolism. The loss of muscle mass in those with obesity undergoing rapid weight loss post-bariatric surgery, is not in itself, a disease or a medical condition.

   The following aims will test specific hypotheses related to the scientific premise:

   Aim 1. Supplementation of the usual diet following bariatric surgery with a proprietary Essential Amino Acid-based nutritional formulation twice per day for 6 months will maintain muscle mass and reduce fat mass more than supplementation of the diet with an isonitrogenous amount of whey protein. Muscle mass will be directly measured using a novel tracer-dilution technique using deuterium-labeled creatine. Fat mass and lean body mass will be measured by Dual-energy X-ray absorptiometry.

   Aim 2. Muscle protein fractional synthetic rate and total muscle protein synthesis (muscle mass x fractional synthetic rate) will decline less from pre-surgery values in participants consuming the Essential Amino Acid-based nutritional formulation as compared to whey protein. Muscle protein fractional synthetic rate will be measured by the novel "virtual biopsy" method, which provides an integrated value over three weeks.

   Aim 3. The pre-surgery rate of total energy expenditure will be better maintained in participants consuming the Essential Amino Acid-based nutritional formulation as opposed to whey protein. Change in total energy expenditure will be measured over 10-day intervals using the doubly-labeled water technique, before to 6 months following surgery.

   Aim 4. Six months after bariatric surgery muscle intra-cellular lipid accumulation will be reduced from the pre-surgery value to a greater extent in participants consuming the Essential Amino Acid-based nutritional formulation than whey protein. Muscle intra-cellular lipid accumulation will be measured by means of magnetic resonance spectroscopy and magnetic resonance imaging. The investigators anticipate that a greater reduction in intra-cellular lipid accumulation will be related to greater improvement in insulin sensitivity in terms of glucose homeostasis and also in terms of muscle protein synthesis.

   Positive results of this study will support the value of the Essential Amino Acid-based nutritional formulation in terms of increasing the rate of fat loss and improving body composition changes following bariatric surgery.
2. Background

   Despite successful weight loss and improvement of comorbidities after bariatric surgery, most patients with severe obesity remain overweight. Patients also experience variation in treatment response. Up to 30% patients experience sub-optimal weight loss or significant weight regain. Amount of weight lost and its maintenance are important because they are what lead to improvement/remission of comorbidities (diabetes, heart disease, etc.), and to decreased mortality from cardiovascular disease or cancer. One of the keys to optimal weight loss from a calorie restricted diet, and subsequent weight-loss maintenance, is losing fat without losing muscle (aka lean body mass). It is decreased energy expenditure from decreased muscle mass after weight loss which contributes significantly to weight regain. Muscle mass is the key driver of energy metabolism favoring the burning of food as fuel rather than its storage as fat. Since muscle provides a reservoir of amino acids to maintain protein synthesis essential for survival, its mass quantity is always at risk under conditions of inadequate dietary intake. Skeletal muscle, under the caloric restriction of weight-loss diets, catabolizes to provide the body's unmet protein needs. It becomes challenging to maintain muscle in conditions of severe calorie restriction such as after bariatric surgery.

   Protein supplementation has been shown to protect against muscle loss experienced in weight loss, but only if supplementation is sufficient. The standard of care approach to maintain muscle mass during rapid, significant weight loss after bariatric surgery has been dietary whey protein supplementation. After bariatric surgery, protein supplementation is limited by the inability of patients to take in sufficient calories. This can be further hindered by typical perioperative complications which limit intake, such as nausea, vomiting, and early satiety. Therefore, despite standard of care supplementation with whey protein post bariatric surgery, only marginal gains in preventing muscle loss have been made. Essential Amino Acid, the intervention supplement in this study, is a patented formula scientifically shown to be far more anabolic than whey protein in free-living elderly and young healthy adults undergoing bedrest. The Essential Amino Acid supplement stimulates protein synthesis 3-5 times as effectively as whey protein, with negligible non-protein calories.

   The importance of the role of muscle in weight loss and its maintenance cannot be overemphasized. Muscle, crucial to energy metabolism, is responsible for the majority of total energy expenditure (equivalent to physical activity energy expenditure, resting energy expenditure, and diet induced thermogenesis - calories required to digest food). Both physical activity, and muscle protein synthesis comprise a significant portion of energy expenditure. Through its function in physical activity and protein synthesis, muscle largely determines the caloric expenditure underlying the ability to 'use up' food eaten rather than store it as fat.

   Obesity, is not just increased body fat, but also increased intramuscular fat. The intramuscular fat associated with obesity impairs the muscle function of providing normal glucose homeostasis. Fortunately, when fat stored in muscle decreases, insulin sensitivity improves. Also impaired under conditions of increased intramuscular fat, is the function of providing amino acids to maintain essential protein synthesis. Impaired muscle mitochondria-stimulated protein synthesis potentially decreases resting energy expenditure, and diet induced thermogenesis. Adequate protein supplementation can counter muscle mitochondrial protein synthesis impairment, and in theory, lead to decreased intramuscular fat improving both energy expenditure and insulin sensitivity.
3. Study Design

This is a double-blinded randomized clinical trial in which the responses to consumption of one of two different dietary supplements following bariatric surgery will be determined. A variety of factors related to body composition and muscle metabolism will be quantified in participants with obesity before and approximately 6 months after bariatric surgery. This interval of time was selected because additional body weight changes are generally relatively small 6 months after surgery; most of the weight loss occurs in the first 6 months. Participants will be assigned randomly by computer to receive either an Essential Amino Acid based nutritional supplement (intervention) or a commercially-available whey protein supplement (Beneprotein®).

Eligibility criteria: Inclusion Criteria:

* A determination to proceed with bariatric surgery
* Roux-en-Y gastric bypass or sleeve gastrectomy
* Absence of any exclusion

Exclusion Criteria:

* Contraindications to Magnetic Resonance Spectroscopy/Magnetic Resonance Imaging
* greater than 450 pounds (scan table limit)
* Renal Failure requiring dialysis
* Liver disease as indicated by bilirubin \>2 or Fibrosis-4 score ≥6
* Cardiac disease such as Left Ventricular Assist Device requirement
* Uncontrolled diabetes as indicated by Hemoglobin A1c \>8
* Positive pregnancy test (for participants in whom pregnancy is possible)
* Any other exclusion per indication of clinical surgeon
* Refusal to consume study formula

Primary outcomes:
measure: Lean body mass
timeFrame: Baseline (before bariatric surgery)
measure: Lean body mass
timeFrame: 6 months after bariatric surgery
measure: Total energy expenditure
timeFrame: Baseline (before bariatric surgery)
measure: Total energy expenditure
timeFrame: 6 months after bariatric surgery
measure: Muscle mass
timeFrame: Baseline (before bariatric surgery)
measure: Muscle mass
timeFrame: 6 months after bariatric surgery
Secondary outcomes:
measure: Liver fat mass
timeFrame: Baseline (before bariatric surgery)
measure: Liver fat mass
timeFrame: 6 months after bariatric surgery
measure: Visceral fat mass
timeFrame: Baseline (before bariatric surgery)
measure: Visceral fat mass
timeFrame: 6 months after bariatric surgery
measure: Subcutaneous fat mass
timeFrame: Baseline (before bariatric surgery)
measure: Subcutaneous fat mass
timeFrame: 6 months after bariatric surgery
measure: Whole body fat mass
timeFrame: Baseline (before bariatric surgery)
measure: Whole body fat mass
timeFrame: 6 months after bariatric surgery
measure: Weight
timeFrame: Baseline (before bariatric surgery)
measure: Weight
timeFrame: 6 months after bariatric surgery
measure: Resting energy expenditure
timeFrame: Baseline (before bariatric surgery)
measure: Resting energy expenditure
timeFrame: 6 months after bariatric surgery
measure: Diet induced thermogenesis
timeFrame: Baseline (before bariatric surgery)
measure: Diet induced thermogenesis
timeFrame: 6 months after bariatric surgery
measure: Glucose
timeFrame: Baseline (before bariatric surgery)
measure: Glucose
timeFrame: 6 months after bariatric surgery
measure: Insulin
timeFrame: Baseline (before bariatric surgery)
measure: Insulin
timeFrame: 6 months after bariatric surgery
measure: Essential amino acids
timeFrame: Baseline (before bariatric surgery)
measure: Essential amino acids
timeFrame: 6 months after bariatric surgery
measure: Dietary intake (Objective)
timeFrame: Baseline (before bariatric surgery)
measure: Dietary intake (Objective)
timeFrame: 6 months after bariatric surgery
measure: Physical activity (Objective)
timeFrame: Baseline (before bariatric surgery)
measure: Physical activity (Objective)
timeFrame: 6 months after bariatric surgery
measure: Percent muscle fat
timeFrame: Baseline (before bariatric surgery)
measure: Percent muscle fat
timeFrame: 6 months after bariatric surgery
measure: Muscle protein synthetic rate
timeFrame: Baseline (before bariatric surgery)
measure: Muscle protein synthetic rate
timeFrame: 6 months after bariatric surgery
measure: Muscle protein fractional synthetic rate
timeFrame: Baseline (before bariatric surgery)
measure: Muscle protein fractional synthetic rate
timeFrame: 6 months after bariatric surgery
Other outcomes:
measure: Physical activity (Subjective)
timeFrame: Baseline (before bariatric surgery)
measure: Physical activity (Subjective)
timeFrame: 1 month after bariatric surgery
measure: Physical activity (Subjective)
timeFrame: 2 months after bariatric surgery
measure: Physical activity (Subjective)
timeFrame: 3 months after bariatric surgery
measure: Physical activity (Subjective)
timeFrame: 4 months after bariatric surgery
measure: Physical activity (Subjective)
timeFrame: 5 months after bariatric surgery
measure: Physical activity (Subjective)
timeFrame: 6 months after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: Baseline (before bariatric surgery)
measure: Dietary Intake (Subjective)
timeFrame: 1 month after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: 2 months after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: 3 months after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: 4 months after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: 5 months after bariatric surgery
measure: Dietary Intake (Subjective)
timeFrame: 6 months after bariatric surgery
Locations:
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
Study officials:
affiliation: Oregon Health and Science University
name: Nancy Puzziferri, MD MSCS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Courcoulas AP, King WC, Belle SH, Berk P, Flum DR, Garcia L, Gourash W, Horlick M, Mitchell JE, Pomp A, Pories WJ, Purnell JQ, Singh A, Spaniolas K, Thirlby R, Wolfe BM, Yanovski SZ. Seven-Year Weight Trajectories and Health Outcomes in the Longitudinal Assessment of Bariatric Surgery (LABS) Study. JAMA Surg. 2018 May 1;153(5):427-434. doi: 10.1001/jamasurg.2017.5025.
citation: Lent MR, Hu Y, Benotti PN, Petrick AT, Wood GC, Still CD, Kirchner HL. Demographic, clinical, and behavioral determinants of 7-year weight change trajectories in Roux-en-Y gastric bypass patients. Surg Obes Relat Dis. 2018 Nov;14(11):1680-1685. doi: 10.1016/j.soard.2018.07.023. Epub 2018 Jul 30.
citation: King WC, Hinerman AS, Belle SH, Wahed AS, Courcoulas AP. Comparison of the Performance of Common Measures of Weight Regain After Bariatric Surgery for Association With Clinical Outcomes. JAMA. 2018 Oct 16;320(15):1560-1569. doi: 10.1001/jama.2018.14433.
citation: Sjostrom L, Peltonen M, Jacobson P, Sjostrom CD, Karason K, Wedel H, Ahlin S, Anveden A, Bengtsson C, Bergmark G, Bouchard C, Carlsson B, Dahlgren S, Karlsson J, Lindroos AK, Lonroth H, Narbro K, Naslund I, Olbers T, Svensson PA, Carlsson LM. Bariatric surgery and long-term cardiovascular events. JAMA. 2012 Jan 4;307(1):56-65. doi: 10.1001/jama.2011.1914.
citation: Adams TD, Stroup AM, Gress RE, Adams KF, Calle EE, Smith SC, Halverson RC, Simper SC, Hopkins PN, Hunt SC. Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring). 2009 Apr;17(4):796-802. doi: 10.1038/oby.2008.610. Epub 2009 Jan 15.
citation: Maclean PS, Bergouignan A, Cornier MA, Jackman MR. Biology's response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R581-600. doi: 10.1152/ajpregu.00755.2010. Epub 2011 Jun 15.
citation: Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995 Mar 9;332(10):621-8. doi: 10.1056/NEJM199503093321001.
citation: Felig P, Owen OE, Wahren J, Cahill GF Jr. Amino acid metabolism during prolonged starvation. J Clin Invest. 1969 Mar;48(3):584-94. doi: 10.1172/JCI106017.
citation: Cahill GF Jr. Starvation in man. N Engl J Med. 1970 Mar 19;282(12):668-75. doi: 10.1056/NEJM197003192821209. No abstract available.
citation: Weijs PJM, Wolfe RR. Exploration of the protein requirement during weight loss in obese older adults. Clin Nutr. 2016 Apr;35(2):394-398. doi: 10.1016/j.clnu.2015.02.016. Epub 2015 Mar 6.
citation: Hector AJ, McGlory C, Damas F, Mazara N, Baker SK, Phillips SM. Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise. FASEB J. 2018 Jan;32(1):265-275. doi: 10.1096/fj.201700158RR. Epub 2017 Sep 12.
citation: Schollenberger AE, Karschin J, Meile T, Kuper MA, Konigsrainer A, Bischoff SC. Impact of protein supplementation after bariatric surgery: A randomized controlled double-blind pilot study. Nutrition. 2016 Feb;32(2):186-92. doi: 10.1016/j.nut.2015.08.005. Epub 2015 Sep 1.
citation: Dillon EL, Sheffield-Moore M, Paddon-Jones D, Gilkison C, Sanford AP, Casperson SL, Jiang J, Chinkes DL, Urban RJ. Amino acid supplementation increases lean body mass, basal muscle protein synthesis, and insulin-like growth factor-I expression in older women. J Clin Endocrinol Metab. 2009 May;94(5):1630-7. doi: 10.1210/jc.2008-1564. Epub 2009 Feb 10.
citation: Borsheim E, Bui QU, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr. 2008 Apr;27(2):189-95. doi: 10.1016/j.clnu.2008.01.001. Epub 2008 Mar 4.
citation: Paddon-Jones D, Sheffield-Moore M, Urban RJ, Sanford AP, Aarsland A, Wolfe RR, Ferrando AA. Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab. 2004 Sep;89(9):4351-8. doi: 10.1210/jc.2003-032159.
citation: Paddon-Jones D, Sheffield-Moore M, Katsanos CS, Zhang XJ, Wolfe RR. Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol. 2006 Feb;41(2):215-9. doi: 10.1016/j.exger.2005.10.006. Epub 2005 Nov 23.
citation: Kim IY, Park S, Smeets ETHC, Schutzler S, Azhar G, Wei JY, Ferrando AA, Wolfe RR. Consumption of a Specially-Formulated Mixture of Essential Amino Acids Promotes Gain in Whole-Body Protein to a Greater Extent than a Complete Meal Replacement in Older Women with Heart Failure. Nutrients. 2019 Jun 17;11(6):1360. doi: 10.3390/nu11061360.
citation: Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E381-7. doi: 10.1152/ajpendo.00488.2005. Epub 2006 Feb 28.
citation: Goodpaster BH, Theriault R, Watkins SC, Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism. 2000 Apr;49(4):467-72. doi: 10.1016/s0026-0495(00)80010-4.
citation: Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr. 2000 Apr;71(4):885-92. doi: 10.1093/ajcn/71.4.885.
citation: Petersen KF, Shulman GI. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. Am J Cardiol. 2002 Sep 5;90(5A):11G-18G. doi: 10.1016/s0002-9149(02)02554-7.
citation: Guillet C, Delcourt I, Rance M, Giraudet C, Walrand S, Bedu M, Duche P, Boirie Y. Changes in basal and insulin and amino acid response of whole body and skeletal muscle proteins in obese men. J Clin Endocrinol Metab. 2009 Aug;94(8):3044-50. doi: 10.1210/jc.2008-2216. Epub 2009 May 26.
citation: Liang C, Curry BJ, Brown PL, Zemel MB. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes. J Nutr Metab. 2014;2014:239750. doi: 10.1155/2014/239750. Epub 2014 Oct 7.
citation: Bohe J, Low JF, Wolfe RR, Rennie MJ. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids. J Physiol. 2001 Apr 15;532(Pt 2):575-9. doi: 10.1111/j.1469-7793.2001.0575f.x.