Adaptation to Malnutrition and Starvation

Adaptation to Malnutrition and Starvation Ashraf Soliman

*Nada Soliman Department of Pediatrics, HMC, Doha, Qatar *PHC, MOH, Alexandria, Egypt

Theories of Adaptation to Malnutrition

Nutritional Edema

Adaptation During Starvation and Malnutrition

The metabolic response to chronic undernutrition covers a wide spectrum • From decreased growth velocity in mild cases to profound distortion of body silhouette and composition and functional derangements in advanced stages of the proteinenergy malnutrition-infection complex. • A wide scale of molecular, enzymatic, and hormonal processes assure a temporary availability of endogenous nutrients and the maintenance of vital functions

S Frenk Journal of the American College of Nutrition,1986, 5:4, 371-381

Adaptation to Starvation Tissues /metabolites

Starvation

THE AMERICAN JOLRNAL OF Clinical Nutrition, 21, No. 12, 1968, 1470

Metabolic Key Concepts • Circulating glucose concentrations do not drop below 3.5 mmol /L even in prolonged starvation. • During starvation, the brain must be supplied with fuel in the form of glucose or ketone bodies. • Carbohydrate reserves are depleted after 24 h of starvation. • In prolonged starvation, gluconeogenesis provides the glucose oxidized by the brain. • The major substrates for gluconeogenesis are amino acids derived from skeletal muscle protein breakdown. • Circulating ketone body concentrations rise during prolonged starvation. • During starvation, most tissues utilize fatty acids and/or ketone bodies to spare glucose for the brain. • Glucose utilization by the brain is decreased during prolonged starvation as the brain utilizes ketone bodies as the major fuel. • High concentrations of ketone bodies result in significant excretion of ketones. • Urinary ketones are excreted as ammonium salts derived from the renal metabolism of glutamine with the carbon skeleton being recovered through renal gluconeogenesis.

Watford, Malcolm(Apr 2015) Starvation: Metabolic Changes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000642.pub2]

Origin of blood glucose during prolonged starvation


Five Metabolic Stages from the post-absorptive state to nearsteady state of prolonged starvation

Ruderman NB, Aoki TT, Cahill GF. 1976. Gluconeogenesis and its disorders in man. In Gluconeogenesis: Its Regulation in Mammalian Species, ed. RW Hanson, MA

Fuel Concentrations During Prolonged Starvation


Fuel Metabolism during prolonged starvation


Daily Urinary Nitrogen excretion during prolonged fasting


Ketone bodies levels during fasting at different ages

Brain Fuel During Fed and Starved States

Annu. Rev. Nutr. 2006. 26:1–22

Fatty acids and ketones concentrations during fasting 4-6 weeks

Annu. Rev. Nutr. 2006. 26:1–22

• Scheme of Fuel Metabolism during Starvation 1. Liver derives its major energy from oxidation of FFA to BOHButyrate and acetoacetate 2. Brain utilizes BOH Butyrate and glucose 3. Muscle and kidney utilize energy by complete oxidation of FFA to Co2 and H2O.

Annu. Rev. Nutr. 2006. 26:1–22

Fuel Homeostasis in Human

https://oncohemakey.com/hormone-fuel-interrelationships-fed-state-starvation-and-diabetes-mellitus/

Fuel Reservoir in Humans


Metabolism: Fed versus fasting Fed State Metabolism

Early starvation (Fasting State)


The myocardium and skeletal muscle use exclusively free fatty acid and ketones

Adaptation to short period of fasting

The glycogen reserves in humans never get completely depleted.

There is at all times a hepatic reserve, waiting to mobilize and rescue the organism from some sort of horrible situation.

Gluconeogenic Substrates in Humans Starved for 24 Hours (short fasting)


The Cori Cycle

Short Fasting The amino acids released during fasting in greatest amount are glutamine and alanine.

Prolonged Starvation

Fuel Use during prolonged fasting


Mitochondrial fatty acid transport.


Figure 2

SHORT

Fasting

LONG

European e-Journal of Clinical Nutrition and Metabolism 2008 3, e267-e271DOI: (10.1016/j.eclnm.2008.06.006)

Summary Hormonemetabolites interaction during fasting

Andrade Jr, J Nutr Diet 2017, 1:1

Hormones and Metabolites During PEM

Hormonal changes in PEM lead to a conservation of substrates and Stunting IGF-I

Decreases growth and anabolism

Increased GH

Increases lipolysis

Decreased

Increased Cortisol Decreased insulin

Decreased T4

Saves calories Provides calories from FA and ketones

Increases muscle protein breakdown Gluconeogenesis Allows gluconeoge nesis

Allows lipolysis

Decreases Metabolic rate and activity

Decreases anabolism

Saves calories

Saves calories

Soliman AT, Soliman N, 2018

High GH – Low IGF-I

High GH, Low IGF-I and Low Insulin

Fasting Increases GH secretion

High Cortisol in PEM

Low Total T4, Low Total T3

Low Total T4, Low Total T3

Low Leptin in PEM

Low Leptin in PEM

Soliman AT, Indian J Endocr Metab 2012;16, Suppl S3:577-87

Soliman AT, Indian J Endocr Metab 2012;16, Suppl S3:577-87

Proposed mechanism of a glucose-fatty acid cycle permitting the maintenance of adequate plasma glucose concentrations in the short-term and prolonged fasted states. WAT, white adipose tissue; HPA, hypothalamicpituitary-adrenal axis. Liver, adrenal, and muscle https://doi.org/10.1080/23723556.2018.1435185

Hypo-leptinemia During PEM 1.

2.

3.

Hypoleptinemia promotes HPA-axis-driven WAT lipolysis to maintain euglycemia Increased hepatic acetylCoA content maintains euglycemia during starvation Substrate limitation reduces mitochondrial VCS and VPC flux during a prolonged fast

Cell, Volume 172, Issues 1–2, 11 January 2018, Pages 234-248.e17

Metabolic changes in Short Starvation lead to a conservation of substrates and Stunting

Short Fasting Response

https://derangedphysiology.com/main/requiredreading/endocrinology-metabolism-andnutrition/Chapter%203.1.8/physiologicaladaptation-prolonged-starvation

Metabolic changes in Prolonged Starvation lead to a conservation of substrates and Stunting

Hormones and receptors in Severe Acute Malnutrition (SAM) and Moderate Malnutrition (MAM) PEM

Journal of Tropical Pediatrics, 2018, 64, 364–372 Journal of Tropical Pediatrics, 2018, 64, 364–372

Nutrients 2015, 7, 517-551; doi:10.3390/nu7010517

Delayed Bone age in Malnourished children

Archives of Disease in Childhood, 1986, 61, 257-262

Bones in PEM • 1. Bone age • 2. Bone Growth (growth plate) • 3. Bone accretion

Bones in PEM • 110 children (0.5 -6 yr) with PEM • Osteoporosis of the bones in 75.4 percent cases. • Cystic spaces in the shafts of metacarpal bones (12.7 per cent) • Transverse lines of arrested growth—TL (54 per cent), • Frank rachitic changes (5.4 per cent), • Ground glass appearance (3.6 per cent) and • Ringed epiphyses (7.2 per cent). All these changes were inversely proportionate to the severity of PEM except for the TL.

Journal of Tropical Pediatrics, Volume 30, Issue 3, 1 June 1984, Pages 150–153,

Soliman AT, Journa l o f Tropica l Pediatric s Vol.4 2 February 1996

Epiphyseal Growth Plate

Nutrients 2015, 7, 517-551; doi:10.3390/nu7010517

Nutritional status Metabolic control over chondrocyte growth is mediated by Systemic and Local Factors

GH -IGF-1 ,IGFBP-1 and 7 and FGF-21 thyroid hormone, cortisol, Leptin

Nutrients 2015, 7, 517-551;

• Can lead to growth attenuation. • The change in specific miRNAs and HDACs in response to the metabolic state, both in vivo and in vitro, suggests that they play an important role in the nutrition-growth link.

Local (intrinsic) factors

Nutrients 2015, 7, 517-551;

Local Intrinsic Factors Nutrients 2015, 7, 517-551;

Adaptation versus Failure of adaptation

CMAJ. 2001;165(10):1345-9.

CMAJ. 2001;165(10):1345-9.

Paediatr Int Child Health. 2015;35(2):83-9.

Paediatr Int Child Health. 2015;35(2):83-9.

Changes During Refeeding

Figure 1

Recovery – Catch up period)

European e-Journal of Clinical Nutrition and Metabolism 2008 3, e267-e271DOI: (10.1016/j.eclnm.2008.06.006)

Hormonal changes during nutritional rehabilitation

Journal of Tropical Pediatrics, 2018, 64, 364–372

Insulin and C-peptide were the variables most strongly associated with WAZ gain. C-peptide was the only variable for which baseline values predicted the response to nutritional rehabilitation

Metabolic Changes during Refeeding

European Journal of Endocrinology (2007) 157 157–166

Biochemical parameters during Refeeding

European Journal of Endocrinology (2007) 157 157–166

Hormonal changes during refeeding

Summary of the physiological responses • The metabolic response to starvation is characterized by a switch from carbohydrate metabolism to fat metabolism, in the context of a hypo metabolic state, with minimized catabolism. • Initially, stores of carbohydrate precursors (eg. glycogen) are depleted. • Then, in the first 24-48 hours there is increased gluconeogenesis from amino acids and glycerol. • Subsequently, ketogenesis takes over, and much of the body metabolic needs are met by ketone bodies and free fatty acids. • This is the consequence of decreasing insulin levels, and relatively increased influence from catecholamines and cortisol. • Over prolonged starvation, protein catabolism begins, resulting in degradation of structurally important proteins, and organ system dysfunction.

Summary • Humans adapt well to short- or a longer-term starvation, using their reserve stores of carbohydrates, fat and protein. • Reduction of energy expenditure and conservation of body protein are further reaction to starvation. • Energy stores are replenished during feeding period. Longterm partial or total cessation of energy intake leads to marasmic wasting.

e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism (2008) 3, e267ee271

During Refeeding • Hormonal changes revert to normal:

1. 2. 3. 4.

IGF-I, IGFBP3 increase Insulin increases Cortisol deceases GH decreases

• Hypophosphatemia and Vitamin deficiencies • Avoid Refeeding Syndrome

Thank You