Anabolic resistance: a road map to malnutrition

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1 The Danish Society of Clinical Nutrition Annual Clinical Nutrition Meeting 212 Copenhagen, Denmark 8 June 212 Anabolic resistance: a road map to malnutrition Gianni Biolo Department of Medical Science - University of Trieste Department of Internal Medicine - AOUTS Trieste - Italy

$excretion 5 Nitrogen balance of a fractured patient of 34 years$

2 J Coll Gen Pract g Daily nitrogen intake Daily nitrogen excretion 5 Nitrogen balance of a fractured patient of 34 years receiving 1.5 g protein/kg/day (The Disturbance of Metabolism Produced by Bony and non-bony Injury. Biochem J. 193)

3 EFFECTS OF AMINO ACID INFUSION ON SKELETAL MUSCLE PROTEIN BALANCE IN SEVERELY BURNED PATIENTS Biolo & Wolfe, Clinical Nutrition (abstract) 21 MUSCLE PROTEIN BALANCE phenylalanine nmo ol/min/1 m 8-8 Healthy volunteers Burned patients # # Postabsorptive state Amino acid infusion, P<.5 vs. postabsorptive state #, P<.5 vs. healthy volunteers

5 MODEL OF LEG MUSCLE AMINO ACID KINETICS F IN F V,A A V F M,A F V,M M F,M F M, F OUT JPEN 1992 AJPENDO 1995 THE ROLE OF TRANSMEMBRANE AMINO ACID TRANSPORT KINETICS IN ANABOLIC RESISTANCE

6 MODEL OF LEG MUSCLE AMINO ACID KINETICS F IN F M,A / F IN F V,A A F M,A M F,M V F V,M F M, F OUT JPEN 1992 AJPENDO 1995 impaired ability of transport systems and increased shunting of leg blood flow from artery to vein through non-nutritive routes

7 MODEL OF LEG MUSCLE AMINO ACID KINETICS F IN F V,A A V F M,A F V,M M F,M F M, F OUT JPEN 1992 AJPENDO 1995 Strategies to decrease anabolic resistance should include attempts to increase microvascular, nutritive muscle blood flow.

8 J. Clin. Invest. 95: , 1995 MUSCLE PROTEIN SYNTHESIS nmol /min x 1 ml leg vol INWARD AMINO ACID TRANSPORT (F M,A ) PHE LEU LYS ALA BASAL INSULIN ml/min/1ml leg vol. LEG BLOOD FLOW BAS INS

9 RELATIONSHIPS BETWEEN INSULIN-MEDIATED STIMULATION OF MUSCLE BLOOD FLOW AND PROTEIN SYNTHESIS (leg or forearm A-V balance technique combined with stable isotopes) Mean changes in muscle protein synthesis (nmol/min/1ml leg vol) R 2 = Mean changes in leg blood flow (ml/min/1ml leg vol) Moeller-Loswick et al., AJP 1994 Moeller-Loswick et al., AJP 1995 Zanetti et al., Cl Science 1999 Tessari et al., JCI 1991 Arfdisson et al., AJP 1991 Meek et al., Diabetes 1998 Denne et al., AJP 1991 Biolo et al., JCI 1995 Gelfand & Barrett, JCI 1987 Louard et al., JCI 1992 Biolo et al, Diabetes 1999

10 MUSCLE PROTEIN SYNTHESIS ml/min/1ml leg vol. LEG BLOOD FLOW BAS INS

EFFECT OF INSULIN-MEDIATED GLUCOSE CONTROL ON PROTEIN KINETICS µmol kg -1 min -1 Whole body 1.2.8.

11 EFFECT OF INSULIN-MEDIATED GLUCOSE CONTROL ON PROTEIN KINETICS µmol kg -1 min -1 Whole body Phe Ra from proteolysis -1 nmol 1cc -1 min Skeletal muscle Phe Rd to Phe Ra from Protein proteolysis synthesis 24-h HYPERGLYCEMIA (~18 mg/dl) 24-h EUGLYCEMIA (~11 mg/dl) CANCER PATIENTS AFTER MAJOR ABDOMINAL SURGERY ON TPN

12 Am J Physiol Mar;268(3 Pt 1):E Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR. Department of Internal Medicine, University of Texas Medical Branch, Galveston. RELATIONSHIP BETWEEN LEG BLOOD FLOW (BF) AND MUSCLE PROTEIN SYNTHESIS (FSR) AFTER EXERCISE,2 FSR (% pe er hour),16,12,8,4 R 2 = BF (ml/min x 1ml leg vol.) Exercise increases microvascular, nutritive muscle blood flow

13 AJPENDO 1997 F IN F V,A A F M,A M F,M BASAL nmol /min x 1 ml leg vol. % per hour ,18,15,12,9,6,3, INWARD AMINO ACID TRANSPORT (FM,A) PHE LEU LYS ALA FRACTIONAL SYNTHESIS RATE OF MUSCLE PROTEIN Fractional Synthesis rate (% per hour) V F OUT F M, F V,M.8 R 2 = Inward Transport (nmol/min x 1 ml) HYPERAMINOACIDEMIA AT REST HYPERAMINOACIDEMIA AFTER EXERCISE

14 Regulation of muscle protein balace in the fasting and postprandial states at rest and after exercise nmol PHE/min x 1 ml leg vol REST POST-EXERCISE RECOVERY FASTING NS INSULIN + GLUCOSE AMINO ACIDS POST-PRANDIAL STATE : P<.5 RECOVERY VS. REST AJPENDO 1995 AJPENDO 1997 Diabetes 1999

Resistance training to counteract the catabolism of a low-protein diet and reduce the malnutrition-inflammation complex syndrome of chronic kidney disease Castaneda et al.

15 Resistance training to counteract the catabolism of a low-protein diet and reduce the malnutrition-inflammation complex syndrome of chronic kidney disease Castaneda et al. Ann Int Med 21; Am J Kidney Dis 24 Patients with chronic kidney disease, not on dialysis therapy n = 26 Randomized, Controlled Trial 12 weeks low-protein diet (.6 g/kg/d) low-protein diet (.6 g/kg/d) + resistance exercise training CRP (mg/l) changes p<.5 2 IL-6 (pg/ml)changes p<.1 3 Total body K (kg) changes 3 P=.1 Muscle strength (kg) changes 1 P=

16 EXERCISE INCREASED ANABOLIC EFFICIENCY INACTIVITY? ANABOLIC RESISTANCE

18 anabolic resistance CONTROLS CIRRHOTIC PATIENTS CHANGES VERSUS BASELINE AFTER INSULIN, GLUCOSE AND AMINO ACID INFUSION

19 Metabolic Effects of Very Low Calorie Weight Reduction Diets L.J. Hoffer, B.R. Bistrian, V.R. Young, G.L. Blackburn, and D.E. Matthews J Clin Invest ± 39 kcal.8 g protein/kg ideal BW 559 ± 79 kcal 1.5 g protein/kg ideal BW NITROGEN WEIGHT LOSS p = NS BALANCE p <.1

20 CHRONIC CONDITIONS WITH ANABOLIC RESISTANCE Sarcopenia of aging Cancer cachexia Chronic renal failure Rheumatoid arthritis Osteoarthritis HIV/AIDS COPD Anorexia Male hypogonadism Obesity (weight loss) Corticosteroid administration (transplant, autoimmune disease) Coronary artery disease Congestive heart failure Liver Cirrhosis Type 1 and 2 diebetes mellitus Hip fracture Disuse atrophy (spinal cord injury, bed rest, microgravity)

21 MUSCLE WASTING IN CHRONIC DISEASES AND AGING MUSCL LE MASS NORMAL NUTRITIONAL STATUS ACUTE STRESS COMPLICATIONS MORTALITY TIME

22 PREOPERATIVE INSULIN RESISTANCE AND THE IMPACT OF FEEDING ON POSTOPERATIVE PROTEIN BALANCE. A STABLE ISOTOPE STUDY Francesco Donatelli, Davide Corbella, Marta Di Nicola, Franco Carli, Luca Lorini, Roberto Fumagalli, Gianni Biolo. Ospedali Riuniti di Bergamo, Italy; McGill University Health Centre, Montreal, Quebec, Canada; University of Trieste, Italy J Clin Endocrinol Metab 211 Delta in phenylal lanine protein balance (micromo/kg/ /min) expressed as differences fed values minus fast ANABOLIC EFFICIENCY OF FEEDING Normal insulin sensititivity Preoperative insulin resistance PRE-SURGERY POST-SURGERY Well-nourished patients with coronary artery disease Elective coronary by-pass surgery, p=.4, surgery effect of; p=.2, group effect; p<.1 group x surgery interaction

23 AGING LOW PROTEIN ENERGY INTAKE MECHANISMS OF ANABOLIC RESISTANCE IN CHRONIC CONDITIONS CHRONIC CONDITIONS WITH ANABOLIC RESISTANCE CANCER CACHECTIC FACTORS HORMONE DEFICIENCY OR EXCESS Sarcopenia of aging Cancer cachexia Chronic renal failure Rheumatoid arthritis Osteoarthritis HIV/AIDS COPD Anorexia Male hypogonadism Obesity (weight loss) Corticosteroid administration (transplant, autoimmune disease) Coronary artery disease Congestive heart failure Liver Cirrhosis Type 1 and 2 diebetes mellitus Hip fracture Disuse atrophy (spinal cord injury, denervation, bed rest, microgravity) LOW PHYSICAL ACTIVITY HYPOPERFUSION HYPOXIA OXIDATIVE STRESS AND CHRONIC INFLAMMATION

24 Inactivity Amplifies the Catabolic Response of Skeletal Muscle to Cortisol Ferrando et al., J Clin Endocrinol & Metab, h hydrocortisone infusion (12 microg/kg/h) Ambulatory 5-days Bed rest 14-days MUSCLE PROTEIN BALANCE nmol phenylalanine/ /min/1 ml leg vol Activity Inactivity -75 P<.5

25 CHANGES IN LEAN MASS (DEXA).2 Eucaloric Ambulatory Eucaloric Bed Rest Hypocaloric Ambulatory Hypocaloric Bed Rest kg percent 5 25 Meal-induced stimulation of protein synthesis AMB BR Eucaloric diet AMB BR Hypocaloric diet micromol leucine/kh/min Protein catabolism in the fasting state AMB BR Eucaloric diet AMB BR Hypocaloric diet

26 MALNUTRITION IN PATIENTS WITH CANCER OR CHRONIC DISEASES Anabolic resistance muscle atrophy CACHEXIA SARCOPENIC OBESITY ANOREXIA ADEQUATE OR INCREASED NUTRIENT INTAKE

percent 4 3 2 1 PREVALENCE OF OBESITY IN COPD PATIENTS

27 percent PREVALENCE OF OBESITY IN COPD PATIENTS Body Mass Index (kg/m 2 ) (BMI) Low (<21) Normal (21-25) High (25-3) Obese (>3) 628 elderly patients with moderate to severe COPD (61% male) Breyer et al., Clin Nutr 29

28 (kj/d) time effect P =.2. REDUCED ENERGY REQUIREMENT IN CANCER PATIENTS RMR Weight and Body Composition Changes during and after Adjuvant Chemotherapy in Women with Breast Cancer J Clin Endocrinol Metab 24 PHYSICAL ACTIVITY PRE CHEMOTHERAPY 2 wk 6 wk 43 time effect P <.5 24 time effect P <.5 kg kg 23 ENERGY INTAKE 4 39 LEAN MASS FAT MASS

29 Changes in fat mass (bioimpedence) 3 EFFECTS OF POSITIVE ENERGY BALANCE ON BED REST-MEDIATED MUSCLE ATROPHY (kg) 2 1 Changes in vastus lateralis thickness (ultrasounds) (cm) Positive Energy Balance -.5 Near-neutral Energy Balance, p<.5 significant different from zero;, p<.5 versus near-neutral energy balance Changes in fat-free mass (bioimpedence) (kg)

30 STEPS/DAY Metabolic Responses to Reduced Daily Steps in Healthy Nonexercising Men JAMA 28 2 PRE 2 wk, P<.5 INSULIN RESISTANCE kg 15 TOTAL FAT ABDOMINAL FAT ml OGTT - Insulin AUC pmol/l/3h

31 CRP LEPTIN Changes in fat mass (bioimpedence) (%) 1 5 (%) (kg) Positive Energy Balance Near-neutral Energy Balance (%) ERYTHOCYTE GLUTATHIONE SYNTHESIS RATE 2 15, p<.5 significant different from zero;, p<.5 versus lower energy balance -1 PLASMA MYELOPEROXIDASE (%) 1 5-5

ABDOMINAL PERIPHERAL HEPATIC MUSCULAR INSULIN RESISTANCE POSITIVE

32 THE VICIOUS CYCLE OF SARCOPENIC OBESITY DECREASED PHYSICAL ACTIVITY SYSTEMIC INFLAMMATORY RESPONSE INCREASED FAT DEPOSITION ABDOMINAL PERIPHERAL HEPATIC MUSCULAR INSULIN RESISTANCE POSITIVE ENERGY BALANCE ANABOLIC RESISTANCE TO AMINO ACID AND PROTEIN MUSCLE ATROPHY

33 2115 cancer patients SURVIVAL 15% obesity 15% sarcopenic obesity

34 1 CROSS-SECTIONAL STUDY 252 healthy subjects with normal body mass index, 35 to 65 years BODY WEIGHT AND COMPOSITION IN AGING kg Age (years) BODY WEIGHT LEAN MASS FAT MASS Clinica Medica University of Trieste

36 Long-term bed-rest (6 days) in healthy female volunteers WISE 25 (Women International Space Simulation for Exploration) ESA/CNES/NASA/CSA N = 8 N = 6 ADAPTATION (2 days) Ambulatory conditions Ambulatory conditions EXPERIMENTAL PERIOD (6 days) Bed Rest - Eucaloric diet 1 g protein / (kg day) non-protein calories to nitrogen ratio 134±3 kcal/g Bed Rest - Eucaloric diet 1.4 g protein / (kg day).16 g BCAA / (kg day) non-protein calories to nitrogen ratio 86±2 kcal/g REABILITATION (2 days) Ambulatory conditions Ambulatory conditions y mass Percent loss of lean bod BR BR BR BR 15 days 31 days 43 days 6 days Control High-protein diet Bed rest effect: p =.1; bed rest diet interaction: p =.1 (repeated measures ANCOVA) High-protein CARDIAC ATROPHY (MRI) Dorfman et al., J Appl Physiol 27 SKELETAL MUSCLE ATROPHY (DEXA)

37 Strength improvements from 6 to 24 wk, a significant difference was apparent between groups: nutrient group, 9±3% vs. control, 1±2%(P <.5). Adjusting for covariates (age at inclusion, BMI at inclusion, and BMD of the femoral neck at inclusion) a significant (P <.5) difference was seen in the response to training of bone mineral density between the two groups.

38 The majority of sick elderly patients require at least 1 g protein/kg/day and around 3 kcal/kg/day of energy, depending on their activity.

40 A 5-Year Cohort Study of the Effects of High Protein Intake on Lean Mass and Bone Mineral Content in Elderly Postmenopausal Women J Bone Miner Res. 29 relationship between baseline protein intake and lean mass and bone mineral content (DEXA) 862 elderly postmenopausal women (mean age: 75 yrs) 5 years follow-up whole body lean mass whole body bone mineral density Percent differences between the lowest (< 66 g/d), and the highest (> 87 g/d) tertile of protein intake A higher protein intake is associated with long term beneficial effects on muscle mass and size and bone mass in elderly women

41 PROTEIN REQUIREMENT IN CRITICAL ILLNESS AT ADEQUATE ENERGY INTAKE Wolfe et al., Ann Surg 1983; Ishibashi et al., Crit Care Med 1998 Hoffer Am J Clin Nutr 23 g protein / kg IBW per day Whole-body protein loss (kg / 2 weeks)

42 Protein/amino acid requirement g/kg ideal body weight per day in conjunction with an adequate energy supply (Grade B) 29 ESPEN Guidelines

43 Medications and nutraceuticals to counteract anabolic resistance

45 8 weeks supplementation CLAMP = INSULIN+GLUCOSE+AMINO ACID INFUSION

46 9-day strength training increased muscle strength in elderly women. The inclusion of fish oil supplementation caused greater improvements in muscle strength and functional capacity. Fish oil Fish oil Fish oil Fish oil

47 Critical illness ANABOLIC RESISTANCE Chronic diseases Aging Inactivity COUNTERACTING ANABOLIC RESISTANCE Increase microvascular, nutritive muscle blood flow (exercise) Definition of optimal protein intake in each condition Control of energy balance and fat mass Medications and nutraceuticals (?)

48 Department of Internal Medicine Clinica Medica Ospedale di Cattinara University of Trieste Trieste, Italy

Sieroproteine: effetti e vantaggi metabolici

Convegno Nazionale SIAN - WORKSHOP Pre-Convegno VICENZA, 20 settembre 2012 - Sala Convegni presso Centrale del Latte NUTRIZIONE CLINICA IN EVOLUZIONE Sieroproteine: effetti e vantaggi metabolici Gianni