Anabolic resistance: a road map to malnutrition

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Anabolic resistance: a road map to malnutrition

The Danish Society of Clinical Nutrition

Annual Clinical Nutrition Meeting 2012

Copenhagen, Denmark – 8 June 2012

Anabolic resistance:

a road map to malnutrition

Gianni Biolo

Department of Medical Science - University of Trieste

Department of Internal Medicine - AOUTS

Trieste - Italy


g

30

25

20

15

10

J Coll Gen Pract. 1963

5

0

Daily nitrogen intake

Daily nitrogen excretion

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. 1930)


EFFECTS OF AMINO ACID INFUSION ON SKELETAL MUSCLE

PROTEIN BALANCE IN SEVERELY BURNED PATIENTS

MUSCLE PROTEIN BALANCE

phenylalanine nmol/min/100 ml

80

0

-80

Biolo & Wolfe, Clinical Nutrition (abstract) 2001

Healthy

volunteers

*

Burned

patients

Postabsorptive state Amino acid infusion

*, P


F V,A

MODEL OF LEG MUSCLE

AMINO ACID KINETICS

THE ROLE OF TRANSMEMBRANE AMINO ACID

TRANSPORT KINETICS IN ANABOLIC RESISTANCE

A

V

F IN

F OUT

F M,A

F V,M

M

F 0,M

F M,0

JPEN 1992

AJPENDO 1995


F M,A / F IN

F V,A

MODEL OF LEG MUSCLE

AMINO ACID KINETICS

A

V

F IN

F OUT

impaired ability of transport systems

and

increased shunting of leg blood flow from artery to vein

through non-nutritive routes

F M,A

F V,M

M

F 0,M

F M,0

JPEN 1992

AJPENDO 1995


F V,A

MODEL OF LEG MUSCLE

AMINO ACID KINETICS

A

V

F IN

F OUT

F M,A

F V,M

M

F 0,M

F M,0

JPEN 1992

AJPENDO 1995

“Strategies to decrease anabolic resistance should include

attempts to increase microvascular, nutritive muscle blood

flow.”


J. Clin. Invest. 95:811-819, 1995

MUSCLE PROTEIN SYNTHESIS

*

*

nmol /min x 100 ml leg vol.

800

700

600

500

400

300

200

100

0

ml/min/100ml leg vol.

INWARD AMINO ACID TRANSPORT

*

*

(F (FM,A) M,A)

PHE LEU LYS ALA

BASAL INSULIN

LEG BLOOD FLOW

5

4

3

2

1

0

*

BAS INS

*

*


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 protein synthesis

(nmol/min/100ml leg vol)

500

400

300

200

100

0

R 2 = 0.9318

-20

-100

0 20 40 60

Mean changes in leg blood flow

(ml/min/100ml leg vol)

80

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


MUSCLE PROTEIN SYNTHESIS

ml/min/100ml leg vol.

LEG BLOOD FLOW

8

6

4

2

0

*

BAS INS


µµmol · kg-1 · min-1 µµmol · kg-1 · min-1 EFFECT OF INSULIN-MEDIATED GLUCOSE CONTROL ON

1.2

0.8

0.4

0

Whole body

*

Phe Ra from

proteolysis

PROTEIN KINETICS

-1 -1

nmol · 100cc-1 · min- nmol · 100cc-1 · min- 60

40

20

0

Skeletal muscle

*

Phe Rd to

Protein

synthesis

Phe Ra from

proteolysis

24-h HYPERGLYCEMIA (~180 mg/dl) 24-h EUGLYCEMIA (~110 mg/dl)

CANCER PATIENTS AFTER MAJOR ABDOMINAL SURGERY ON TPN


Am J Physiol. 1995 Mar;268(3 Pt 1):E514-20.

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

FSR (% per hour)

0,20

0,16

0,12

0,08

0,04

R 2 = 0.52

1 2 3 4 5 6 7 8

BF (ml/min x 100ml leg vol.)

Exercise increases microvascular, nutritive muscle blood flow


AJPENDO 1997

BASAL

nmol /min x 100 ml leg vol.

% per hour

1200

1000

800

600

400

200

0

0,18

0,15

0,12

0,09

0,06

0,03

0,00

HYPERAMINOACIDEMIA

AT REST

HYPERAMINOACIDEMIA

AFTER EXERCISE

INWARD AMINO ACID TRANSPORT

(FM,A) (FM,A) (FM,A)

PHE LEU LYS ALA

FRACTIONAL SYNTHESIS RATE

OF MUSCLE PROTEIN

Fractional Synthesis rate

(% per hour)

0.20

0.16

0.12

0.08

0.04

0.00

F V,A V,A V,A

A

V

F IN

F OUT

F M,A

F V,M

M

F 0,M

F M,0

R 2 R = 0.61

2 = 0.61

0 200 400 600 800 1000 1200

Inward Transport (nmol/min x 100 ml)


nmol PHE/min x 100 ml leg vol.

Regulation of muscle protein balace in the fasting

and postprandial states at rest and after exercise

50

40

30

20

10

0

-10

-20

-30

REST

POST-EXERCISE RECOVERY

FASTING

*: P


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 2001; Am J Kidney Dis 2004

Patients with chronic kidney

disease, not on dialysis therapy

n = 26

Randomized, Controlled Trial

CRP

(mg/L) changes

p


EXERCISE

INACTIVITY

?

INCREASED

ANABOLIC

EFFICIENCY

ANABOLIC

RESISTANCE


anabolic resistance

CONTROLS

CIRRHOTIC PATIENTS

CHANGES VERSUS BASELINE

AFTER INSULIN, GLUCOSE AND AMINO ACID INFUSION


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 1984

501 ± 39 kcal

0.8 g protein/kg ideal BW

559 ± 79 kcal

1.5 g protein/kg ideal BW

WEIGHT

NITROGEN

BALANCE

LOSS p = NS p < 0.01


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)


MUSCLE MASS

NORMAL

NUTRITIONAL

STATUS

MUSCLE WASTING

IN CHRONIC DISEASES AND AGING

TIME

ACUTE

STRESS

COMPLICATIONS

MORTALITY


PREOPERATIVE INSULIN RESISTANCE AND THE IMPACT OF FEEDING ON POSTOPERATIVE

Delta in phenylalanine protein balance

(micromo/kg/min) expressed expressed as

differences fed values minus fast

7

6

5

4

3

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 2011

2

1

0

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=0.04, surgery effect of; p=0.002, group effect; p


AGING

HORMONE

DEFICIENCY

OR EXCESS

Sarcopenia of aging

Cancer cachexia

Chronic renal failure

Rheumatoid arthritis

Osteoarthritis

HIV/AIDS

COPD

Anorexia

Male hypogonadism

Obesity (weight loss)

LOW PROTEIN – ENERGY

INTAKE

MECHANISMS OF ANABOLIC RESISTANCE

IN CHRONIC CONDITIONS

CHRONIC CONDITIONS WITH ANABOLIC RESISTANCE

HYPOPERFUSION

HYPOXIA

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)

OXIDATIVE STRESS

AND

CHRONIC

INFLAMMATION

CANCER

CACHECTIC

FACTORS

LOW PHYSICAL

ACTIVITY


Inactivity Amplifies the Catabolic Response of

Skeletal Muscle to Cortisol

Ferrando et al., J Clin Endocrinol & Metab, 1999

Ambulatory

5-days

nmol phenylalanine/

/min/100 ml leg vol.

12-h hydrocortisone infusion

(120 microg/kg/h)

0

-25

-50

-75

Bed rest

14-days

MUSCLE PROTEIN BALANCE

P


percent

50

25

0

Meal-induced

stimulation of protein synthesis

* *

AMB BR AMB BR

Eucaloric diet Hypocaloric diet

micromol leucine/kh/min

kg

0.30

0.25

0.20

0.15

0.2

-0.2

-0.6

-1

-1.4

CHANGES IN

LEAN MASS (DEXA)

Eucaloric

Ambulatory

Hypocaloric

Ambulatory

Eucaloric

Hypocaloric

Bed Rest

Bed Rest

Protein catabolism

in the fasting state

AMB BR AMB BR

Eucaloric diet Hypocaloric diet

*

*


MALNUTRITION IN PATIENTS WITH

CANCER OR CHRONIC DISEASES

Anabolic resistance → muscle atrophy

CACHEXIA

ANOREXIA

SARCOPENIC OBESITY

ADEQUATE OR INCREASED

NUTRIENT INTAKE


percent

40

30

20

10

0

PREVALENCE OF OBESITY IN COPD PATIENTS

Body Mass Index (kg/m 2 ) (BMI)

Low (30)

628 elderly patients with moderate to severe COPD (61% male)

Breyer et al., Clin Nutr 2009


(kJ/d)

6000

5750

5500

5250

5000

time effect

P = 0.02.

PHYSICAL

ACTIVITY

ENERGY

INTAKE

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 2004

PRE CHEMOTHERAPY

2 wk 6 wk

43

kg 42

kg

23

41

40

39

time effect

P < 0.05

LEAN MASS

24

22

21

time effect

P < 0.05

FAT MASS


∆ (kg)

2

Changes in fat mass

(bioimpedence)

3 * §

1

0

Positive Energy Balance

Near-neutral Energy Balance

* , p


kg

STEPS/DAY

12000

10000

8000

6000

4000

2000

0

15

10

5

0

PRE

2 wk

TOTAL FAT

ml

Metabolic Responses to

Reduced Daily Steps in Healthy

Nonexercising Men

750

700

650

600

550

500

*, P


∆ (kg)

Changes in fat mass

(bioimpedence)

3 * §

2

1

0

Positive Energy Balance

Near-neutral Energy Balance

* , p


THE VICIOUS CYCLE OF SARCOPENIC OBESITY

INCREASED

FAT DEPOSITION

ABDOMINAL

PERIPHERAL

HEPATIC

MUSCULAR

POSITIVE

ENERGY

BALANCE

DECREASED

PHYSICAL

ACTIVITY

MUSCLE

ATROPHY

SYSTEMIC

INFLAMMATORY

RESPONSE

INSULIN

RESISTANCE

ANABOLIC

RESISTANCE

TO AMINO ACID

AND PROTEIN


2115

cancer patients

15%

obesity

15%

sarcopenic obesity

SURVIVAL


kg

100

80

60

CROSS-SECTIONAL STUDY

252 healthy subjects with normal body mass index, 35 to 65 years

BODY WEIGHT AND COMPOSITION IN AGING

40

20

0

BODY WEIGHT

LEAN MASS

FAT MASS

30 40 50 60 70

Age (years)

Clinica Medica – University of Trieste


Percent loss of lean body mass

Long-term bed-rest

(60 days) in healthy

female volunteers

WISE 2005 (Women

International Space Simulation

for Exploration)

0

-1

-2

-3

-4

-5

-6

-7

-8

-9

-10

ESA/CNES/NASA/CSA

BR

15 days

*

BR

31 days

Control

High-protein diet

BR

43 days

SKELETAL MUSCLE

ATROPHY (DEXA)

N = 8

N = 6

BR

60 days

Bed rest effect: p = 0.01; bed rest × diet interaction: p = 0.01

(repeated measures ANCOVA)

ADAPTATION

(20 days)

Ambulatory

conditions

Ambulatory

conditions

EXPERIMENTAL PERIOD

(60 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)

0.16 g BCAA / (kg · day)

non-protein calories to nitrogen ratio

86±2 kcal/g

REABILITATION

(20 days)

Ambulatory

conditions

Ambulatory

conditions

High-protein

CARDIAC ATROPHY (MRI)

Dorfman et al., J Appl Physiol 2007


Adjusting for covariates (age at inclusion, BMI at

inclusion, and BMD of the femoral neck at

inclusion) a significant (P < 0.05) difference was

seen in the response to training of bone mineral

density between the two groups.

Strength improvements from 6 to 24 wk, a

significant difference was apparent between

groups: nutrient group, 9±3% vs. control, 1±2% (P

< 0.05).


The majority of sick elderly patients require at

least 1 g protein/kg/day and around 30

kcal/kg/day of energy, depending on their

activity.


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. 2009

• 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

6

4

2

0

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


Whole-body Whole-body Whole-body protein loss

(kg (kg (kg / 2 weeks)

PROTEIN REQUIREMENT IN CRITICAL ILLNESS

AT ADEQUATE ENERGY INTAKE

Wolfe et al., Ann Surg 1983; Ishibashi et al., Crit Care Med 1998

0

-0.5

-1

-1.5

-2

Hoffer Am J Clin Nutr 2003

g protein / kg IBW per day

≈ 0.7 ≈ 1.0 ≈ 1.5 ≈ 2.2


Protein/amino acid

requirement

“1.3–1.5 g/kg ideal body weight

per day in conjunction with an

adequate energy supply”

(Grade B)

2009 ESPEN Guidelines


Medications and

nutraceuticals to

counteract

anabolic resistance


8 weeks supplementation

CLAMP = INSULIN+GLUCOSE+AMINO ACID INFUSION


90-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


ANABOLIC

RESISTANCE

Critical illness

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 (?)


iolo@units.it

Department of Internal Medicine

Clinica Medica

Ospedale di Cattinara

University of Trieste

Trieste, Italy

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