Metabolic interrelationship MBBS II.pptx

FOR MBBS/BDS STUDENTS

1. METABOLIC INTERRELATIONSHIP IN DIFFERENT CONDITIONS Dr. Apeksha Niraula Assistant Professor Clinical Biochemistry Institute of Medicine

2. Objectives Metabolic Interrelationship in starvation and obesity, type 1 and type 2 diabetes mellitus, pregnancy and lactation, cancer cachexia Well fed state, early fasting state, early re-fed state, caloric homeostasis, energy requirements and reserves Five phases of glucose homeostasis and complete starvation cycle Mechanism involved in switching the metabolism of the liver between the well-fed state and the starved state

3. Fasting may result from : Inability to obtain food Desire to lose weight rapidly Clinical situations in which an individual cannot eat (trauma, surgery , etc..) Ramadan fasting for Muslims Plasma levels of glucose, amino acids & triacylglycerol (main nutrients) fall with a resulting decline in insulin secretion & increase in glucagon release The decreased insulin/glucagon ratio & decreased availability of circulating substrates favors a catabolic period in which the degradation of triacylglycerol, glycogen & protein is characteristic Fasting

4. Exchange of substrates between liver, adipose tissue, muscle & brain is guided by two priorities : Need to maintain adequate plasma levels of glucose to secure energy metabolism to the brain, RBCs & other tissues utilizing glucose as the sole fuel Need to mobilize fatty acids from adipose tissue , synthesis & release of ketone bodies to supply energy to other tissues

5. For a normal 70 kg man at the beginning of a fast: Only 1/3 of body`s protein can be used for energy production without fatally compromising vital function Fuel stores at the beginning of fasting

6. Liver in fasting Carbohydrate metabolism : Glycogen degradation (10-18 hrs of fasting) followed by gluconeogenesis (after 18 hrs to secure glucose to brain & other tissues utilizing glucose as a sole fuel) Increased glycogen degradation (glycogenolysis) to produce glucose to blood : exhausted after 10 – 18 hours of fasting (early fasting) Increased gluconeogenesis:  Activation of fructose 1,6-bisphosphatase (due to a drop in its inhibitor, fructose 2,6-bisphosphate) and Induction of phosphoenolpyruvate (PEP) carboxykinase by glucagon begins 4–6 hours after the last meal and becomes fully active as stores of liver glycogen are depleted

7. Fat metabolism : Increased fatty acid oxidation Increased synthesis of ketone bodies: Ketone bodies (unlike FA) are water-soluble & appears in blood & urine by the second day of a fast

8. Adipose tissue in fasting Fat metabolism : Increased degradation of triacylglycerols : Activation of hormone-sensitive lipase(+Glucagon, Epinephrine) with subsequent hydrolysis of stored triacylglycerol are enhanced by elevated catecholamines Increased release of fatty acids from adipose tissue: F at is a source of glucose (carbohydrate) in fasting state

9. Resting skeletal muscle in fasting Resting muscle uses fatty acids as its major fuel source; by contrast, exercising muscle initially uses its glycogen stores as a source of energy Carbohydrate metabolism : Because of low levels of insulin, glucose transport & glucose metabolism are depressed Lipid metabolism : During the first 2 weeks of fasting , muscle uses fatty acids from adipose tissues & ketone bodies from the liver as sources of energy Protein metabolism: R apid breakdown of muscle proteins, providing amino acids that are used by the liver for gluconeogenesis (First few days)

10. Resting skeletal muscle in fasting

11. Brain in fasting During the first few days of fasting, the brain continues to use glucose only as a source of energy In prolonged fasting (more than 2 -3 weeks), plasma ketone bodies reach elevated levels & are used in addition to glucose in as a source of energy the brain This reduces the need for protein degradation for gluconeogenesis

12. Kidneys in Long-term Fasting Renal cortex: expresses the enzymes of gluconeogenesis, including glucose 6-phosphatase , and, in late fasting, ~50% of gluconeogenesis occurs here Kidneys: provides compensation for the acidosis that accompanies the increased production of ketone bodies (organic acids) Glutamine released from the muscle’s metabolism of BCAA is taken up by the kidney and acted upon by renal glutaminase and glutamate dehydrogenase, producing α- ketoglutarate, which can be used as a substrate for gluconeogenesis, plus ammonia (NH3)

13. The NH 3 picks up protons from ketone body dissociation and is excreted in the urine as ammonium (NH 4 + ), thereby decreasing the acid load in the body Therefore, in long-term fasting, there is a switch from nitrogen disposal in the form of urea to disposal in the form of NH 4 +

14. A bsor p tive state : 2 – 4 hours period after ingestion of a normal meal T ransient increase in plasma glucose, amino acids & triacylglycerols ( main nutrients ) occur I nsulin secretion is increased fro m the pancreas & glucagon secretion is decreased Elevated insulin/glucagon ratio : I ncreased synthesis of triacylglycerol & glycogen to be stored (anabolic period) During the absorptive period : all tissues use glucose as a fuel M etabolic responses of the body are dominated by alterations of the metabolism of 4 organs : Liver, Adipose Tissue, Muscle & Brain Absorptive (fed) state

15. Enzyme changes in the fed state Flow of intermediates through metabolic pathways is controlled by : Availability of substrates (within minutes) Allosteric regulation of enzymes (within minutes) Covalent modification of enzymes (within minutes to hours) Induction-repression of enzyme synthesis (within hours to days) Each mechanism operates on a different time-scale (i.e. response occurs within minutes, minutes to hours or hours to days) In fed state, these regulatory mechanisms ensure that available nutrients of food (in abundance) are directed to be stored as glycogen, triacylglycerol & protein

16. High Insulin/ Glucagon ratio

17. Phases of Glucose Homeostasis Five Phases Well-Fed State (Phase I) In Fasting: Phase II (Glycogenolysis) Phase III (Gluconeogenesis) Phase IV ( Glucose, Ketone Bodies Oxidation) Phase V (Fatty acid, Ketone Body Oxidation)

18. Liver : Nutrient distribution center Carbohydrate metabolism : Liver metabolism of glucose is increased by: 1. Increased phosphorylation of glucose (i.e. glucose 6-phosphate by glucokinase) 2. Increased glycolysis of glucose (with production of acetyl CoA) 3. Increased glycogen synthesis 4. Increased activity of pentose phosphate pathway of glucose (to provide NADPH) 5. Decreased gluconeogenesis (synthesis of glucose from non-carbohydrate sources)

19. Fat metabolism: Increased fatty acid synthesis : Activation of Acetyl CoA carboxylase (enzyme of the rate-limiting step in fatty acid synthesis) Availability of substrates (acetyl CoA & NADPH from glucose metabolism) 2. Increased triacylglycerol (TAG) synthesis : Fatty acid is provided from de novo synthesis from acetyl CoA & chylomicron remnants taken by the liver Glycerol 3-phosphate is provided by glucose metabolism (glycolysis). Liver packages TAG into very-low- density lipoproteins (VLDL) that are secreted into the blood for use by extrahepatic tissues (particularly adipose & muscle)

20. Amino acid metabolism: 1. Increased protein synthesis : Increase in the synthesis of liver proteins to replace any degraded proteins during fast period 2. Increased amino acid degradation : In the absorptive state, more amino acids are present than the liver can use for the synthesis of proteins (i.e. more than the liver capacity to synthesize proteins) Excess amino acids are not stored in any form BUT , they are released to blood to other tissues for protein synthesis or, deaminated in liver into carbon skeleton & ammonia Carbon skeleton can be catabolized for energy production or used for fatty acid synthesis

21. Adipose tissue : Energy storage depot Carbohydrate metabolism: Increased glucose transport : GLUT-4 of adipocytes are insulin-sensitive In the absorptive state, insulin conc. is elevated resulting in an increased influx of glucose into adipocytes 2. Increased glycolysis : Due to increased intracellular levels of glucose Glycolysis provides glycerol 3-phosphate for triacylglycerol synthesis 3. Increased activity of pentose phosphate pathway (PPP) Increased PPP results in increased formation of NADPH essential for fatty acid synthesis

22. Fat metabolism: Increased synthesis of fatty acids ( NOT A MAJOR PATHWAY): Fatty acid synthesis in adipose tissue is not a major pathway Instead, most fatty acids added to adipose tissues are provided by diet Fat (in chylomicrons) with a lesser amount supplied by VLDL of liver Increased triacylglycerol synthesis : Exogenous fatty acids (from diet fat : chylomicrons & liver fat : VLDL) & glycerol 3 phosphate (from glycolysis of glucose ) are used for synthesis of triacylglycerol in adipose tissue

23. Effect of Insulin on various metabolic enzymes

24. Effect of different hormones in intermediary metabolic pathways

25. Metabolic Changes in Type 1 and Type 2 DM

26. Type 1 DM

27. Hyperglycemia in Type 2 DM

28. Metabolic changes in Pregnancy In response to the increased demands of the rapidly growing fetus and placenta- pregnant woman undergoes metabolic changes No other physiological event in postnatal life induces such profound metabolic alterations E.g., the additional total pregnancy energy demands have been estimated to be as high as 80,000 kcal or about 300 kcal/day BMR is increased to the extent of 30% higher than that of average for the nonpregnant women Pregnancy is an anabolic state

29. Weight Gain: Most of the increase in weight- uterus and its contents, the breasts, and increases in blood volume and extravascular/ extracellular fluid Average weight gain during pregnancy is approximately 12.5 kg Water Metabolism M inimum amount of extra water that the average women accrues during normal pregnancy is about 6.5 L Retention is mediated by a fall in plasma osmolality of approximately 10 mOsm/kg - induced by a resetting of osmotic thresholds for thirst and vasopressin secretion

30. Protein Metabolism Products of conception, the uterus, and maternal blood - relatively rich in protein Nitrogen balance increases with pregnancy- more efficient use of dietary protein ( positive nitrogen balance throughout pregnancy Breakdown of AA to urea is suppressed- Blood urea level falls to 15-20 mg%

31. Total protein Increases from the normal of 180 gm (non pregnant) to 230 gm at term However, due to hemodilution plasma protein concentration falls from 7 gm% to 6 gm% Results in diminished viscosity of the blood and reduced colloid osmotic tension Because of the marked fall in albumin level from 4.3 gm% to 3 gm% (30% fall) - normal A: G ratio of 1.7:1 is diminished to 1:1 There is only a slight rise in globulin concentration

32. Carbohydrate Metabolism Transfer of increase amount of glucose from mother to the fetus is needed throughout pregnancy Insulin secretion is increased in response to glucose and AA Hypertrophy and hyperplasia of β cells of the pancreas Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia The fasting plasma glucose concentration falls somewhat- result of the increased plasma levels of insulin

33. Pregnancy-induced state of peripheral resistance to insulin , the purpose of which is likely to ensure a sustained postprandial supply of glucose to the fetus Insulin resistance- more pronounced as the pregnancy progresses The mechanism of resistance is not clearly understood- progesterone and estrogen may have role Plasma levels of placental lactogen increase with gestation , and this protein hormone is characterized by growth hormone–like action that may result in increased Lipolysis with liberation of free fatty acids which may facilitate increased tissue resistance to insulin.

34. The pregnant woman changes rapidly from a postprandial state characterized by elevated and sustained glucose levels to a fasting state characterized by decreased plasma glucose and AA During fasting, the plasma concentrations of free fatty acids, triglycerides, and cholesterol are higher Pregnancy-induced switch in fuels from glucose to lipids- accelerated starvation When fasting is prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly appears

35. Oral glucose tolerance shows abnormal pattern As maternal utilization of glucose is reduced – there is gluconeogenesis and glycogenolysis Glomerular filtration of glucose is increased as the result of increased GFR to exceed the tubular reabsorption threshold (180 mg%) Glycosuria is detected in 50% of normal pregnant women

36. Fat Metabolism Concentrations of lipids, lipoproteins, and apolipoproteins in plasma [Levels of lipids and apolipoproteins decreases after the delivery] The storage of fat occurs primarily during mid-pregnancy- deposited mostly in central rather than peripheral sites Later in pregnancy, as fetal nutritional demands increase remarkably, maternal fat storage decreases Might protect the mother and fetus during time of prolonged starvation or hard physical exertion Lactation speeds the rate of decrease of many of these compounds

37. Tests of Renal Function The physiological changes in renal hemodynamics induced during normal pregnancy have several implications for the interpretation of tests of renal function. Serum creatinine and urea nitrogen levels decrease from a mean of 0.7 and 1.2 mg/dL to 0.5 and 0.9 mg/dL, respectively Creatinine values > 0.9 and BUN >1.4 mg/dL suggest underlying renal disease and should prompt further Creatinine clearance in pregnancy should be 30 percent higher than the 100 to 115 mL/min normally measured in non-pregnant women

38. Urinalysis Glucosuria during pregnancy is not necessarily abnormal Due to- appreciable increase in glomerular filtration , together with impaired tubular reabsorptive capacity for filtered glucose Even though glucosuria is common during pregnancy, the possibility of diabetes mellitus should not be ignored when it is identified Proteinuria normally is not evident during pregnancy except occasionally in slight amounts during or soon after vigorous labor Albumin excretion is minimal and ranges from 5 to 30 mg/day

39. Metabolic Changes in Cancer Cachexia: Kakos- Bad; Hexus- Condition Complex multifactorial metabolic syndrome associated with underlying illness and characterized by muscle loss with or without fat mass that cannot be fully reversed by conventional nutritional support and lea ds to progressive functional impairment

40. Diagnosis of Cancer Cachexia Weight loss >5% over the past 6 months (in the absence of simple starvation; or BMI <20 kg/m 2 and any degree of weight loss >2%; or Appendicular skeletal muscle index consistent with sarcopenia (Males: <7.26 kg/m 2 ; females <5.45 kg/m 2 ) and any degree of weight loss >2%

41. Causes of Cancer Cachexia Multifactorial Anorexia Nausea, Vomiting, pain, Dysphagia Abnormal metabolic rate Altered cellular metabolism of carbphydrate, lipid and protein Change in cytokine milieu

42. Epidemiology Can occur at any stage of the disease; common at the advanced stage Vary with cancer types, size, site, stage and age, and treatment types but most common in pancreatic and upper GIT cancers Breast and Sarcoma- 40% Lung Ca- 60% Stomach and pancreas- 85%

43. Metabolism Resting energy expenditure ( REE ) increase s in cancer patients but total energy expenditure is reduced beca us e of decreased activities in these patients Increased turnover of proteins and lipids: Feature of cancer-associated cachexia; leading to decreased skeletal muscle mass and deplete d fat stores Metabolic changes in Cachxia are as a result of: Tumour Factors Host factors Interaction between two

44. Proteolysis inducing factor (PIF): Major mediator of protein catabolism in cancer patients Activates nuclear factor kappa beta (NF-𝛋B) which in turn activates the ubiquitin proteasome proteolysis pathway Lipid mobilizing factor (LMF): central to adipocytes lipolysis via regulation of hormone sensitive lipase (HSL) Most weight loss in cancer cachexia: Depletion of fat stores Both proteolysis and lipolysis are not supressed with the administration of exogenous nitrogen and glucose

45. Glycolysis: main energy generation process in cancer cells Energy is insufficient and leads to an increase in hepatic gluconeogenesis and cause the normal tissues to be energy starved

46. Cytokines and Hormones Both tumour cell production and host responses contribute to the deranged cytokine milieu IL-1 IL-6 TNF-𝝰 IFN-𝛾

47. Muscle Breakdown Ubiquitin-Proteasome pathway Nitric oxide synthase expression Fat Depletion Lipolysis through the activation of HSL Decreased lipogenesis Anorexia IFN-𝛾 contributes to muscle wasting and fat loss via same processes TNF-𝝰

48. IL-1 AND IL-6 IL-1: Anorexia Increased peripheral breakdown of muscle Promotes the release of IL-6 IL-6 Increase Hepatic gluconeogenesis Increased peripheral proteolysis Result in a more profound wasting than TNF-𝝰

49. Hormones and Tumour Drive proteins Leptin Host tissue Serotonin PIF Tumour LMF

50. Obesity Results from increased intake of energy or decreased expenditure of energy

51. The primary metabolic effects of obesity include Dyslipidemias, glucose intolerance (hyperglycemia below that classified as diabetes and insulin resistance, expressed primarily in the liver, muscle, and adipose tissue These metabolic abnormalities reflect molecular signals originating from the increased mass of adipocytes

52. Malnutrition Cellular imbalance between the supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance and specific functions Develops when the body does not get the right amount of vitamins, minerals and other nutrients it needs to maintain healthy tissues and organ function

53. Protein Energy Malnutrition: Group of body depletion disorders; includes Kwashiorkor, Marasmus and Intermediate stages Marasmus: Form of Starvation/ severe malnutrition Body adapts to a chronic state of insufficient caloric intake Seen before 1 years of age Kwashiorkor: Body’s response to insufficient protein intake but usually sufficient calories for energy Sufficient energy intake but low protein intake Occur r ence increases afetr 18 months

54. Etiology Socioeconomic Factors: Lack of breast feeding, improper complementary feeding, Poverty, Infection, Ignorance Biological Factors Environmental Factors Role of Free Radicals and Aflatoxin: Damage Liver cells by aflatoxins Age of the Host: Infants and young children (rapid growth increases nutritional requirement), pregnant, lactating women and elderly women

55. Kwashiorkor

56. M a rasmus

57. Biochemical and M e tabolic Changes Kwashiorkor: Hypoalbuminemia (1.0-2.5 g/dl) Marasmus: < 2.8 gm/dl Hypoproteinemia: Transferrin, Essential amino acids, Lipoprotein Hypoglycemia Increased plasma Cortisol and Growth Hormone; Decreased Insulin and I n sulin-like growth factors Electrolytes: Decreased Potassium, Magnesium Ketonuria; Decreased excretion of urea due to decreased protein intake K w ashiorkor and M a rasmus: Iron Deficiency Anemia and Metabolic Acidosis

58. R eye’s Syndrome Charac ter ized by acute non-inflammatory encephalopathy and fatty degenerative liver failure; a rare but serious condition Peak at about 6 years; 4-12 years of age Seasonal relation with influenza and varicella outbreaks Most often affect children and teenagers recovering from a viral infection (commonly influenza, flu, chicken pox) Multi-stage illness (0-6) Case fatality rate: 25%-50%

59. Post-infectious triad: Encephalopathy Fatty Liver Degeneration Transaminase Elevati ons Exact cause: Unknown Triggered by using Aspirin to treat viral illness/infection Fatty acid oxidation disorders (MCAD deficiency) Exposure to insecticides, herbicides, paint thinner, etc.

60. Acute Encephalopathy: G e neralized brain dysfunction Fatty tissue infiltration: Most prominent Liver; other organs might be affected Organ changes: Hepatic Cerebral Renal

61. Diagnosis Diagnosis is probable if: Elevated serum ammonia (> 125-150 pg/dl) 2-100 times increases serum transaminase Prolonged Prothrombin time [unrepsonsive to Vitamin K] CSF: N ormal Diagnosis confirmed by Liver biopsy

62. Carbohydrates: Hypoglycemia (80% of cases in patients < 4years) Raised precursors of gluconeogenesis (Pyruvate, Lactate and Alanine) Lipids: Raised non-esterified fatty acids Reduced cholesterol, HDL, LDL, and VLDL

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