Chapter 22

1. Chapter 22 Metabolism and Energy Balance

2. About this Chapter • How energy is distributed and used in humans • How nutrients are converted to the energy and building blocks for synthesis • How hormones control metabolic processes • How the body maintains a constant temperature

3. Body Energy: Eating Controls • Cortex – "hunger" • CNS Feeding center • CNS satiety center • CNS & GI peptides • Ghrelin • Leptin • CCK • CRH • Neuropeptide Y

5. Body Energy: Input = Output (+ storage) • Energy for temperature regulation – heat • Energy for metabolic processes – work • Transport work – move molecules • Mechanical work – muscle contraction • Chemical work – synthesis & storage • Energy use is measured by oxygen consumption • Calories in food (kilocalorie = 1L H2O 1˚C)

6. Respiratory Quotient • RQ= The ratio of Pure CO2 produced to O2 consumed • For Pure Carbohydrate Catabolism: RQ= 1.0 • For Pure Protein Catabolism: RQ= 0.8 • For Pure Fat Catabolism: RQ= 0.7

7. Changes in Metabolic Rate • Basal metabolic rate (BMR) • Modifying factors • Age & gender • Lean muscle mass • Physical activity level • Diet • Hormones

10. Summary of Metabolic Conversions of Nutrients • Nutrients are used, or stored • In general glucose, fats & AAs can be interconverted

11. Summary of Metabolic Conversions of Nutrients Figure 22-2: Summary of metabolism

12. Metabolic Proscesses: Reversible Conversions • Glycogenesis (glucose to glycogen) • Glycogenolysis (glycogen to glucose) • Gluconeogenesis (amino acids to glucose) • Lipogenesis (glucose or FFAs to fats) • Lipolysis (fats to FFAs & glycerol)

13. Metabolic Energy Production: Review & Overview • Reactants: glucose • Glycogen, FFAs • Amino acids • Phosphoylation • Glycolysis–cytoplasm • 2 ATPs, anaerobic • Citric Acid Cycle-2 ATPs, mitochondria, aerobic • Electron Transport system • High energy e-,  32 ATPs

14. Metabolic Energy Production: Review & Overview Figure 22-3: Summary of biochemical pathways for energy production

15. “Fed State” or Absorptive Metabolism: Anabolic Processes • Reversible pathways shift to anabolic processes • Carbohydrates energize synthesis & storage • Amino Acids built into proteins, surplus stored

16. “Fed State” or Absorptive Metabolism: Anabolic Processes Figure 22-4: 4 Dual (push-pull) control of metabolism

17. Fat Metabolism: Long Term Nutrient Storage • In adipose cells • In blood: HDL, LDL • FFAs, cholesterol • (plaque build up) • Conversion in liver • Excreted in bile • Used for energy & synthesis

18. Fat Metabolism: Long Term Nutrient Storage Figure 22-5: Transport and fate of dietary fats

19. “Fasted State” or Post-Absorptive Metabolism: Catabolic • Pathways shift to maintain energy for metabolism • Storage  glucose in blood  organs in need

20. “Fasted State” or Post-Absorptive Metabolism: Catabolic Figure 22-6: Fasted-state metabolism

21. Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism • Beta cells produce insulin – cellular uptake of blood glucose • Alpha cells produce glucagon –  blood glucose (from cells) • D cells produce somatostatin –  gastric secretion

22. Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism Figure 22-7 b: The endocrine pancreas

23. Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism Figure 22-8: Metabolism is controlled by insulin and glucagon

24. Lipohypertrophy in a Patient • A 55-year-old man with a 31-year history of type 1 diabetes mellitus presented for a routine clinical evaluation, his first in two decades. His insulin regimen consisted of a combination of neutral protamine Hagedorn (NPH) and rapid-acting insulin. In the many years since his diabetes diagnosis, he had habitually injected insulin into two locations in the periumbilical region. Two discrete subcutaneous masses were palpated. Both masses were firm and pendulous. A clinical diagnosis of insulin-induced lipohypertrophy was made. This condition has been documented with many insulin preparations. Careful attention should be paid to the teaching of correct methods of insulin injection, site rotation, and routine inspection of injection sites. Lipohypertrophy can be associated with glycemic flux and can be disfiguring. The patient was counseled regarding injection-site rotation and encouraged to use a 6-mm rather than an 8-mm needle. NPH was replaced with insulin glargine. The patient was subsequently lost to follow-up.

26. Insulin Action on Cells: Dominates in Fed State Metabolism •  glucose uptake in most cells • (not active muscle) •  glucose use & storage •  protein synthesis •  fat synthesis

27. Insulin Action on Cells: Dominates in Fed State Metabolism Figure 22-10: Insulin’s cellular mechanism of action

28. Insulin: Summary and Control Reflex Loop Figure 22-13: Fed-state metabolism

30. Relationship between HbA1c and average finger blood glucose HbA1c of 9% = 260 mg/dl (14.4 mmol/l) HbA1c of 8% = 220 “ (12.2 “ ) HbA1c of 7% = 180“ (10.0 “ ) HbA1c of 6% = 140“ (7.7 “ ) HbA1c of 5% = 100“ (5.5 “ )

31. Glucagon Action on Cells: Dominates in Fasting State Metabolism • Glucagon prevents hypoglycemia by  cell production of glucose • Liver is primary target to maintain blood glucose levels

32. Glucagon Action on Cells: Dominates in Fasting State Metabolism Figure 21-14: Endocrine response to hypoglycemia

33. Diabetes Mellitus: Abnormally Elevated Blood Glucose (Hyperglycemia) • Type 1: beta cells destroyed- no insulin producedchronic fasted state, "melting flesh", ketosis, acidosis, glucosurea, diuresis & coma

34. Diabetes Mellitus: Abnormally Elevated Blood Glucose (Hyperglycemia) Figure 22-15: Acute pathophysiology of type 1 diabetes mellitus

35. Diabetes Mellitus: Type II a Group of Diseases • Over 15 million diabetics in USA- 10% type I, 90% type II • Insulin resistance keeps blood glucose too high • Problem with receptors, glucagons levels • Chronic complications: atherosclerosis, renal failure& blindness

37. Diabetes Mellitus: Type II a Group of Diseases Figure 22-16: Normal and abnormal glucose tolerance tests

38. Energy Balance: About 50% used for Body Heat Figure 22-17: Energy balance

39. Body Temperature Balance: Homeothermic • Metabolic heat production usually required to maintain balance • Balance is very narrow range, usually higher than environment

40. Body Temperature Balance: Homeothermic Figure 22-18: Heat balance

41. Thermoregulation: Homeostatic Balancing of Body Temperature • Peripheral and body core receptors – senses change • Hypothalamic thermoregulatory center – integrates & initiates: • Shivering, non-shivering thermogenesis, vasoconstriction

42. Thermoregulation: Homeostatic Balancing of Body Temperature Figure 22-19: Thermoregulatory reflexes

43. Thermoregulation: Prevention of Overheating • Sweat: evaporates from skin – cooling • Vasodilation of cutaneous vessels transports heat from core • Behavior:  activity, exposure to heat

44. Thermoregulation: Prevention of Overheating Figure 22-20: Homeostatic responses to environmental extremes

45. Thermoregulation: Pathologies • Hyperthermia: body temperature too high • Fever: pyrogens fight pathogens • Heat exhaustion (1020F) • Heat stroke (1060F)  death • Malignant hyperthermia – defective Ca++ release • Hypothermia: body temperature too low • Metabolism slows  loss of consciousness, death • Surgical applications: heart surgery

46. Malignant Hyperthermia • Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.

47. Malignant Hyperthermia: Molecular Genetic Testing • To date, only two genes in which mutation causes MHS have been identified: • RYR1 (MHS1 locus) encodes the type 1 ryanodine receptor of skeletal muscle. Molecular genetic testing indicates that mutations in RYR1 are identified in up to 70%-80% of individuals with confirmed MHS [Sambuughin et al 2005, Galli et al 2006, Robinson et al 2006, Kraeva et al 2011]. • CACNA1S (MHS5 locus) encodes the α1-subunit of the skeletal muscle dihydropyridine receptor L-type calcium channel. Mutations in CACNA1S account for 1% of all MHS [Stewart et al 2001].

48. Summary • Eating provides carbohydrates, proteins, & fats for metabolism • Reversible reactions allow interconversion of nutrients • Energy is used for body heat and work: transport, synthesis, storage • Metabolic rate changes with age, sex, body fat, activity & diet • Insulin regulates anabolic cell activities & glucose uptake in cells

49. Summary • Glucagon regulates catabolic reactions & prevents hypoglycemia • Diabetes is a major disease associated with insulin lack or tolerance • Maintaining homeothermy takes 50% of our energy • Hypothalamic thermoregulatory center controls heat homeostasis