1. MPBP 301 “Homeostasis” Bob Low Given D-207 656-4338 (W) 434-3132 (H) Bob.low@uvm.edu

2. HOMEOSTASIS "It is the fixity of the milieu interieur which is the condition of free and independent life" Claude Bernard 1813-1878 Unicellular vs Multicellular organisms

3. HOMEOSTASIS "The highly developed living being is an open system having many Relations to its surroundings... changes in the surroundings excite Reactions in this system, or affect it directly, so that internal disturbances are produced... the coordinated physiological reactions which maintain most of the steady states in the body are so complex, and so peculiar to the living organism, that it is suggested that a specific designation for these states be employed --- homeostasis" -W.B. Cannon, 1929 Walter Cannon (1871-1945)

4. EQUILIBRIA: THINK SWIMMING POOLS

5. http://physioweb.med.uvm.edu/homeostasis/ A USEFUL SELF-LEARNING MODULE Design Patterns of Life Pools Balance Equilibria Simple Feedback Complex Feedback

6. –Homeostasis: Maintenance of a constant internal milieu in the face of environmental provocations and fluctuations –Steady State Output rate (amount per time) = Input rate (amount per time) Excretion Rate (mg/min) = Production Rate (mg/min) Examples: Most everything DEFINITIONS

7. STEADY STATE Excretion Rate = Production Rate

8. CONTROL OF BLOOD SUGAR The Glucose Tolerance Test GLUCOSE

9. CONTROL OF BLOOD SUGAR The Glucose Tolerance Test: Insulin Response GLUCOSE INSULIN

10. Insulin Controls Plasma [Glucose] Pathophysiology of Diabetes mellitus NORMAL –Eat sugar   Plasma [glucose]   Insulin secretion by pancreatic  cells   glucose uptake into cells   Plasma [glucose]   Insulin secretion DIABETES –Lose  cells  Insulin deficiency  Type 1 Diabetes Mellitus –  Sensitivity to insulin  Type 2 Diabetes Mellitus

11. EQUILIBRIUM BALANCING INPUT AND OUTPUT On average, skin renews itself every 28 days Muscle Half-life is about a week Bone calcium is exchanged in days Regulatory enzymes have half-lives of hours

12. EQUILIBRIUM IS NOT ALWAYS HOMEOSTASIS STEADY STATE IS AN EQUILIBRIUM BUT http://physioweb.med.uvm.edu/homeostasis/

13. WRONG LEVEL EQUILIBRIUM IS NOT ALWAYS WHAT WE WANT http://physioweb.med.uvm.edu/homeostasis/

14. Steady State pCO 2 is Regulated By the Lungs CO 2 Excretion Rate = CO 2 Production Rate  pCO 2 = 40 mmHg ( Normal Steady State ) Exercise   CO 2 Production  pCO 2 > 40 mmHg   Ventilation   CO 2 Excretion  pCO 2  40 mmHg ( Normal Steady State ) Smoking  Lung Disease   Functional ventilation   Excretion rate   pCO 2 > 40 mmHg  Abnormal Steady State pCO 2 = 50 mmHg ( Abnormal Steady State )

15. NEGATIVE FEEDBACK: Mechanism that RESTORES abnormal values to normal Reverses a change POSITIVE FEEDBACK: Mechanism that MAKES abnormal values MORE ABNORMAL Strengthens or reinforces a change KEY CONCEPTS

16. NEGATIVE FEEDBACK: Mechanism that RESTORES abnormal values to normal Reverses a change THINK THERMOSTATS

17. Negative Feedback Control System Sensor element (e.g., thermostat) measures and monitors the actual value of some aspect of the internal environment. For example, the physiological thermostat measures the temperature of the blood as it flows through the hypothalamus. Integration center or comparator is hard-wired with the ‘set point’ or the target value for an environmental condition and can compare input from the sensor to the set point value. When the input deviates from set point (error detector) then the integration center initiates a response. Heater/Cooler Heat if  > 0 Cool if  < 0 Temperature of Room Desired Temperature Actual Temperature Thermostat Actual Temperature

18. POSITIVE FEEDBACK: Mechanism that MAKES abnormal values MORE ABNORMAL Strengthens or reinforces a change KEY CONCEPTS Angiotensin and salt / water balance Ovulation Digestion of food (Blood Clotting)

19. Positive Feedback in Physiology Rare because it is intrinsically unstable –Must be either carefully controlled, short- lived, and/or have a braking system –Most common examples: Yawning, Laughing, Sneezing Vomiting, Bowel Movement Pariturition Ends abruptly –Physiological Example: Sneeze –Pathological Example: Anaphylaxis Female Menstrual Cycle –Positive feedback of estrogen on itself –LH surge

20. Some times the “RIGHT” level should change “NORMAL” STEADY STATE IS NOT ALWAYS WHAT WE WANT Thyroid Hormone / Fasting; Cortisol / Stress

21. KEY CONCEPT: SETPOINTS IF FEEDBACK SYSTMS ARE WORKING WELL, THE HORMONE / FUNCTION BEING REGULATED “CAN’T” CHANGE. BUT WHAT IF IT SHOULD HAVE TO CHANGE TO MAINTAIN HOMEOSTASIS? SETPOINT

22. FEEDBACK: MAKING MAPLE SYRUP

23. CONTROL SYSTEMS Bang-Bang Control Bang-Bang Control in a Public Bathroom Sink: Try to get Warm water by rapidly alternating your hands between Freezing Cold faucet and Scalding Hot faucet

24. CONTROL SYSTEMS Bang-Bang Control Goal: Keep a bowling ball in the middle of the alley Bang-Bang Control –Smack ball back and forth from gutter to gutter –The average position of the ball is in the middle, but… –The ball spends almost no time actually in the middle Negative feedback using a control system that detects and corrects for a small error is better

25. The rate at which the level of a substance Changes is determined by its rate of degradation Good signal mechanisms must be Turned on AND OFF rapidly. KEY CONCEPT FEEDBACK SYSTEMS MUST BE RAPID RESPONSE

26. A SOLUTION FEEDBACK LOOPS EMBEDDED WITHIN FEEDBACK LOOPS Concept: as soon as a response is set In motion, steps are taken to immediately start turning it off

27. HOMOLOGOUS RECEPTOR REGULATION RECEPTOR MODIFICATION PHOSPHORYLATION CAUSES UNCOUPLING / DESENSITIZATION RAPID: SECONDS / MINUTES More to follow later

28. Why? GOOD SIGNAL MECHANISMS MUST BE TURNED ON AND OFF RAPIDLY REDUCING THE ERROR SIGNAL WITHOUT “INTERNAL” FEEDBACK WITH “INTERNAL” FEEDBACK

29. HOMOLOGOUS RECEPTOR REGULATION: A KEY STRATEGY Examples:  Desensitization in neurotransmission  Chronically elevated levels of insulin Lead to loss of insulin receptors More to follow

30. H + R HR THE PHYSIOLOGY OF SURFACE RECEPTOR REGULATION

31. RECEPTOR NUMBER RECEPTOR NUMBER H + R HR

32. http://physioweb.med.uvm.edu/homeostasis/ A USEFUL SELF-LEARNING MODULE