MPBP 301MPBP 301

“Homeostasis”

Bob LowGiven D-207656-4338 (W)434-3132 (H)Bob.low@uvm.edu

HOMEOSTASIS

"It is the fixity of the milieu interieurwhich is the condition of free and independent life"

Claude Bernard1813-1878

Unicellular vs Multicellular organisms

HOMEOSTASIS

"The highly developed living being is an open system having manyRelations to its surroundings. . . changes in the surroundings exciteReactions in this system, or affect it directly, so that internal disturbancesare produced. . . the coordinated physiological reactions which maintainmost of the steady states in the body are so complex, and so peculiarto the living organism, that it is suggested that a specific designationfor these states be employed --- homeostasis"

-W.B. Cannon, 1929

Walter Cannon(1871-1945)

EQUILIBRIA: THINK SWIMMING POOLS

http://physioweb.med.uvm.edu/homeostasis/

A USEFUL SELF-LEARNING MODULE

Design Patterns of LifePoolsBalanceEquilibriaSimple FeedbackComplex Feedback

– 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

STEADY STATE

Excretion Rate = Production Rate

CONTROL OF BLOOD SUGAR

The Glucose Tolerance Test

GLUCOSE

CONTROL OF BLOOD SUGARThe Glucose Tolerance Test: Insulin Response

GLUCOSE

INSULIN

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

EQUILIBRIUMBALANCING 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

EQUILIBRIUM IS NOT ALWAYSHOMEOSTASIS

STEADY STATE IS ANEQUILIBRIUM

BUT

http://physioweb.med.uvm.edu/homeostasis/

WRONG LEVEL

EQUILIBRIUM IS NOT ALWAYSWHAT WE WANT

http://physioweb.med.uvm.edu/homeostasis/

Steady State pCO2 is Regulated By the Lungs

• CO2 Excretion Rate = CO2 Production Rate pCO2 = 40 mmHg (Normal Steady State)

• ExerciseCO2 Production pCO2 > 40 mmHg Ventilation CO2 Excretion pCO2 40 mmHg (Normal Steady State)

• Smoking Lung Disease Functional ventilation Excretion rate pCO2 > 40 mmHg Abnormal Steady State pCO2 = 50 mmHg (Abnormal Steady State)

NEGATIVE FEEDBACK:Mechanism that RESTORESabnormal values to normal

Reverses a change

POSITIVE FEEDBACK:Mechanism that MAKES abnormal values MORE ABNORMAL

Strengthens or reinforces a change

KEY CONCEPTS

NEGATIVE FEEDBACK:Mechanism that RESTORES abnormalvalues to normal

Reverses a change

THINK THERMOSTATS

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/CoolerHeat if > 0Cool if < 0

Temperatureof Room

DesiredTemperature

ActualTemperature

Thermostat

Thermostat

ActualTemperature

POSITIVE FEEDBACK:Mechanism that MAKES abnormal valuesMORE ABNORMAL

Strengthens or reinforces a change

KEY CONCEPTS

Angiotensin and salt / water balanceOvulationDigestion of food(Blood Clotting)

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

Some times the “RIGHT” level should change

“NORMAL” STEADY STATE IS NOT ALWAYSWHAT WE WANT

Thyroid Hormone / Fasting; Cortisol / Stress

KEY CONCEPT: SETPOINTSIF FEEDBACK SYSTMS ARE WORKING WELL,THE HORMONE / FUNCTION BEING REGULATED“CAN’T” CHANGE.

BUT WHAT IF IT SHOULD HAVE TO CHANGETO MAINTAIN HOMEOSTASIS?

SETPOINT

FEEDBACK: MAKING MAPLE SYRUP

CONTROL SYSTEMSBang-Bang Control

Bang-Bang Control in a Public Bathroom SinkBang-Bang Control in a Public Bathroom Sink::Try to get Warm water by rapidly alternating your Try to get Warm water by rapidly alternating your

hands between Freezing Cold faucet and hands between Freezing Cold faucet and Scalding Hot faucetScalding Hot faucet

CONTROL SYSTEMSBang-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

The rate at which the level of a substanceChanges is determined by its rate ofdegradation

Good signal mechanisms must beTurned on AND OFF rapidly.

KEY CONCEPTFEEDBACK SYSTEMS

MUST BERAPID RESPONSE

A SOLUTION

FEEDBACK LOOPS EMBEDDEDWITHIN FEEDBACK LOOPS

Concept: as soon as a response is setIn motion, steps are taken to immediatelystart turning it off

HOMOLOGOUS RECEPTOR REGULATIONRECEPTOR MODIFICATION

PHOSPHORYLATION CAUSESUNCOUPLING / DESENSITIZATION

RAPID: SECONDS / MINUTES

More to followlater

Why?GOOD SIGNAL MECHANISMS MUSTBE TURNED ON AND OFF RAPIDLY

REDUCING THE ERROR SIGNALWITHOUT“INTERNAL”FEEDBACK

WITH“INTERNAL”FEEDBACK

HOMOLOGOUS RECEPTORREGULATION: A KEY STRATEGY

Examples:

Desensitization in neurotransmission Chronically elevated levels of insulin Lead to loss of insulin receptors

More to follow

H + R HR

THE PHYSIOLOGY OF SURFACE RECEPTOR REGULATION

RECEPTORNUMBER

RECEPTORNUMBER

H + R HR

http://physioweb.med.uvm.edu/homeostasis/

A USEFUL SELF-LEARNING MODULE