MPBP 301
“Homeostasis”
Bob Low
Given D-207
656-4338 (W)
434-3132 (H)
Bob.low@uvm.edu
HOMEOSTASIS
Claude Bernard
1813-1878
"It is the fixity of the milieu interieur
which is the condition of free and independent life"
Unicellular vs Multicellular organisms
HOMEOSTASIS
Walter Cannon
(1871-1945)
"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
EQUILIBRIA: THINK SWIMMING POOLS
A USEFUL SELF-LEARNING MODULE
http://physioweb.med.uvm.edu/homeostasis/
Design Patterns of Life
Pools
Balance
Equilibria
Simple Feedback
Complex Feedback
DEFINITIONS
– 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
STEADY STATE
Excretion Rate = Production Rate
CONTROL OF BLOOD SUGAR
The Glucose Tolerance Test
GLUCOSE
CONTROL OF BLOOD SUGAR
The 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
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
STEADY STATE IS AN
EQUILIBRIUM
BUT
EQUILIBRIUM IS NOT ALWAYS
HOMEOSTASIS
http://physioweb.med.uvm.edu/homeostasis/
EQUILIBRIUM IS NOT ALWAYS
WHAT WE WANT
WRONG LEVEL
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)
•
ExerciseCO2 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)
KEY CONCEPTS
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
NEGATIVE FEEDBACK:
Mechanism that RESTORES abnormal
values to normal
Reverses a change
THINK THERMOSTATS
Negative Feedback Control System
Thermostat
Desired
Temperature
Actual
Temperature
Heater/Cooler
Heat if  > 0
Cool if  < 0
Temperature
of Room
Actual
Temperature
Thermostat
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.
KEY CONCEPTS
POSITIVE FEEDBACK:
Mechanism that MAKES abnormal values
MORE ABNORMAL
Strengthens or reinforces a change
Angiotensin and salt / water balance
Ovulation
Digestion of food
(Blood Clotting)
Positive Feedback in Physiology
• Rare because it is intrinsically unstable
– Must be either carefully controlled, shortlived, 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
“NORMAL” STEADY STATE IS NOT ALWAYS
WHAT WE WANT
Some times the “RIGHT” level should change
Thyroid Hormone / Fasting; Cortisol / Stress
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
FEEDBACK: MAKING MAPLE SYRUP
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
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
KEY CONCEPT
FEEDBACK SYSTEMS
MUST BE
RAPID RESPONSE
Good signal mechanisms must be
Turned on AND OFF rapidly.
The rate at which the level of a substance
Changes is determined by its rate of
degradation
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
HOMOLOGOUS RECEPTOR REGULATION
RECEPTOR MODIFICATION
PHOSPHORYLATION CAUSES
UNCOUPLING / DESENSITIZATION
RAPID: SECONDS / MINUTES
More to follow
later
Why?
GOOD SIGNAL MECHANISMS MUST
BE TURNED ON AND OFF RAPIDLY
REDUCING THE ERROR SIGNAL
WITHOUT
“INTERNAL”
FEEDBACK
WITH
“INTERNAL”
FEEDBACK
HOMOLOGOUS RECEPTOR
REGULATION: A KEY STRATEGY
Examples:
 Desensitization in neurotransmission
 Chronically elevated levels of insulin
Lead to loss of insulin receptors
More to follow
THE PHYSIOLOGY OF
SURFACE RECEPTOR REGULATION
H + R
HR
RECEPTOR
NUMBER
RECEPTOR
NUMBER
H + R
HR
A USEFUL SELF-LEARNING MODULE
http://physioweb.med.uvm.edu/homeostasis/