C2006/F2402 '11 OUTLINE OF LECTURE #16
(c) 2011 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 03/24/2011 02:14 PM .
Lining of the GI Tract & Typical Circuit
15B -- Homeostasis -- Seesaw view for Glucose and Temperature Regulation;
16 -- Absorptive vs Postabsorptive state
I. Homeostasis, cont. See handouts 15A & B & notes of last time, topic VI.
A. Regulation of Blood Glucose Levels -- Seesaw View #1 (Handout 15B)
B. Regulation of Human Body Temperature -- Seesaw #2 (Handout 15B)
C. The Circuit View (Handout 15A)
II. Matching circuits and signaling -- an example: How the glucose circuit works at molecular/signaling level
Re-consider the circuit or seesaw diagram for homeostatic control of blood glucose levels -- what happens in the boxes on 15A? It may help to refer to the table below.
A. How do Effectors Take Up Glucose?
1. Major Effectors: Liver, skeletal muscle, adipose tissue
2. Overall: In response to insulin, effectors increase both uptake & utilization of glucose. Insulin triggers one or more of the following in the effectors:
a. Causes direct increase of glucose uptake by membrane transporters
b. Increases breakdown of glucose to provide energy
c. Increases conversion of glucose to 'stores'
(1). Glucose is converted to storage forms (fat, glycogen), AND
(2). Breakdown of storage fuel molecules (stores) is inhibited.
d. Causes indirect increase of glucose uptake by increasing phosphorylation of glucose to G-P, trapping it inside cells
3. How does Insulin Work?
(1). Insulin works through a special type of cell surface receptor, a tyrosine kinase linked receptor; See Sadava fig. 7.7 (15.6). Insulin has many affects on cells and the mechanism of signal transduction is complex (activating multiple pathways).
(2). In many ways, insulin acts more like a typical growth factor than like a typical endocrine. (Insulin has GF-like effects on other cells; is in same family as ILGFs = insulin like growth factors). More on GFs and TK receptors later.
b. How Does Insulin Increase Glucose Uptake in different effectors?
(1). In resting skeletal muscle & adipose tissue -- mobilizes GLUT 4: In these tissues insulin mobilizes transporter for facilitated diffusion (of glucose) -- GLUT 4 protein -- promotes fusion of vesicles containing the transporters with plasma membrane. No other hormone can cause this effect.
(2). In liver: Liver (& brain) can take up glucose without insulin -- they do not use GLUT 4. They use different transporters (GLUT 1, 2 &/or 3) located permanently in the plasma membrane.
(a). In liver: Insulin promotes glucose uptake in liver, but not directly. Insulin promotes uptake by increasing phosphorylation (trapping) and utilization of glucose.
(b). Note: Insulin has no affect on glucose uptake in brain.
(3). Working skeletal muscle: Insulin is not required for uptake of glucose in working skeletal muscle because exercise mobilizes GLUT4 in skeletal muscle. (Another good reason to exercise.)
c. Other Effects: In many tissues, insulin promotes utilization of glucose:
(1). Activates appropriate enzymes for synthesis of storage forms of metabolites -- synthesis of glycogen, fat, and/or protein.
(2). Inhibits enzymes for breakdown of stores.
(3). Can promote utilization (breakdown) of glucose for energy.
d. Significance: Some effects of insulin are mimicked by other hormones, but mobilization of GLUT4 cannot be triggered by any other hormone. Therefore loss of insulin, or lack of response to insulin, is very serious, and causes diabetes type I or II, respectively. (See absorptive state, below.)
B. How do Effectors Release Glucose?
1. Primary Effector for Release = Liver
a. Liver is only organ that can release significant amounts of glucose into blood -- why? Liver has phosphatase for G-6-P. Muscle and adipose tissue don't.
b. Other tissues release other things. Other tissues can breakdown stores (fat, glycogen) to release fatty acids or lactate into blood, but cannot release glucose.
2. Overall: Stores are broken down to generate small molecules; liver releases glucose into blood.
3. Role of Glucagon
a. Receptor: Glucagon works through a G protein linked receptor that triggers the cAMP pathway. Therefore it activates PKA. See text or handout on glycogen metabolism for details.
b. Effects: Primary physiological effect is on liver; generally promotes production/release of glucose, not uptake or utilization. (Glucose is produced both by breakdown of glycogen, and build up from lactate = gluconeogenesis. See texts if you are interested in details of gluconeogenesis.)
c. Epinephrine & Glucagon.
(1) The same signaling pathway can be used for both hormones.
(a). How? Epi.(epinephrine) & glucagon bind to different receptors, but both receptors activate the same G protein and trigger the same series of events → cAMP → etc. so can get same response to both hormones in same tissue (if both receptors are present).
(b). Why? Two hormones control same process (glycogen metabolism) for different purposes -- Epi to respond to stress; glucagon to respond to low blood sugar (maintain homeostasis).
(2). Different tissues can respond differently to these hormones. How? Both hormones trigger production of cAMP and activation of PKA. But there are differences in which receptors and/or which targets of PKA are present
(a). Receptors: Receptors present on cell surface determine which tissues will respond to each hormone.
Muscle has Epi receptors (but no glucagon receptors); therefore responds to Epi but not glucagon
Liver has receptors for both epi and glucagon and responds to both.
(b). Targets: Even if receptors are same, different enzymes and/or processes are available to be affected by same kinase. For example, glycogen metabolism in liver vs. skeletal muscle. Both tissues break down glycogen in response to epi, but result is different.
In muscle, breakdown is to lactate, and lactate is released to blood.
In liver, breakdown is to glucose - P, phosphate is removed, and glucose is released into blood.
d. Significance of glucagon: Actions of glucagon can be mimicked by other hormones (see above); there is no known medical condition caused by lack of glucagon.
C. Overall Function of Effectors -- Summary:
1. Liver -- both releases glucose to blood and stores excess (as glycogen).
a. Carries out both storage and release of glucose so acts as buffer.
b. Only organ that can release significant glucose into blood (kidney may do some).
c. Takes up glucose without insulin -- uses GLUT 2 (always in plasma membrane), not GLUT 4. Insulin stimulates phosphorylation & utilization of glucose, not direct uptake.
2. Muscle -- stores or releases energy.
Takes up glucose; stores excess as glycogen.
When glycogen is broken down, releases lactate, not glucose, into blood.
3. Adipose Tissue -- stores or releases fat/ fatty acids.
Uses up glucose & fatty acids; stores excess as fat.
When fat is broken down, releases fatty acids into the blood.
4. All three organs co-operate -- for example lactate generated in muscle is not broken down further in muscle -- it is shipped to liver and metabolized further in the liver. For many more details than you need see Sadava 50-20 (7th ed only) or advanced texts.
D. Absorptive vs Postabsorptive State -- A more complex view of the circuit
1. What is really being regulated by insulin & glucagon? Really two different things:
a. Maintenance of glucose homeostasis
b. Managing an episodic event (eating) -- this can be considered just another example of homeostasis -- here the 'episodic' nature of eating generates two basic states that must be controlled differently to maintain homeostasis.
2. There are two main states of food (not just glucose) supply. A detailed diagram of fuel traffic in both states (that goes way beyond what you need) is in Sadava fig. 50.20 (7th ed only) and in all physiology books.
a. Absorptive State
(1). Energy Metabolism: mostly anabolic → synthesis & storage of macromolecules.
(2). Energy Source: glucose is primary energy source.
(3). Risk? In this state, right after you eat, the risk is that blood glucose levels will rise too much.
(4). Hormone: Absorptive state is completely dependent on insulin. Insulin affects all three effector organs.
b. Postabsorptive State
(1). Energy Metabolism: mostly catabolic → breakdown of macromolecules to release glucose*;
(2). Energy Source: fatty acids are primary energy source (except in brain).
(3). Risk? In this state, between meals, the risk is that blood glucose levels will fall too much.
(4). Hormones: Postabsorptive state is largely caused by lack of insulin; also utilizes glucagon, but stress hormones (cortisol and epinephrine) can fill in for glucagon. Glucagon mainly affects liver.
*(Gluconeogenesis also occurs in liver = re-synthesis of glucose from smaller molecules; see texts if you are interested.)
For questions on this topic
see problem set 7,
questions 7-23 to 7-26, and 4R-3.
To review and to be sure you have this topic straight, fill in the following tables:
|Responds to Insulin?||Responds to Glucagon?||Can Release Glucose to Blood?||Uses GLUT 4||Can take up Glucose w/o Insulin?|
|Skeletal Muscle||+||-||-||+||only when working; not at rest|
* Adipose tissue has glucagon receptors, but there is no known response to physiological levels of glucagon.
|Type of Receptor/signaling pathway|
|Effect on blood glucose -- release or uptake?|
|Effect on glycogen -- synthesis or breakdown?|
|Result of intracellular glucose metabolism -- use it up or generate it?|
|Effect on pathways of intracellular glucose production -- inhibit or stimulate?|
III. Introduction to Hormones (Endocrines) & Growth Factors
A. How to describe or classify hormones?
1. Many Possible Classification Schemes -- Hormones can be classified by effect, chemical nature, source (which gland?), target cells, etc. etc. See Topic IV (for reference) for a extensive list.
2. Issues to keep in mind as course proceeds
a. Processes controlled by hormones -- for examples, see above.
b. The major hormone producing glands -- we'll go over this later.
c. Details for specific hormones -- for examples, see above; more will be discussed as they come up.
B. Summary of typical hormone roles and examples. See Becker Table 14-3 or Sadava fig. 41.6 (41.5) for a tabulation of hormones by type of function (Becker) or by source (Sadava).
1. Stress response -- cortisol, epinephrine. Regulate heart rate, blood pressure, inflammation, etc.
2. Maintenance of Homeostasis -- insulin, glucagon, cortisol. Regulate blood glucose/energy supplies and concentrations of substances in general. Maintain more or less constant conditions = homeostasis.
3. Regulation of episodic or cyclic events -- estrogen, insulin, oxytocin -- regulate lactation, pregnancy, effects of eating, etc.
4. Growth/overall regulation -- growth factors, tropic hormones -- regulate production of other hormones. (Note: not all GF's are endocrines.)
5. Hormones may have more than one function. Note that some hormones are listed twice above, as many have multiple functions. For example, cortisol is constantly made to maintain homeostasis, but it is secreted in larger amounts in response to stress.
IV. How to Keep Track of Hormones -- How to Classify Hormones & Growth Factors (or Signal Molecules in General). The following is meant as a check list to help you keep track of the various signal molecules as they come up. It is for reference & study purposes; it will not be discussed in class.
Some of these questions/categories overlap, and you can't answer all the questions for all the hormones, growth factors, etc., but the list helps to organize the information you do have.
1. Type of Action -- Is it paracrine, endocrine (hormone), growth factor, neurotransmitter, etc.? (See handout 7B)
2. Chemical nature -- Is it a peptide, amino acid or derivative, fatty acid or derivative, or steroid? See Becker table 14-4.
3. Where is it made? In what gland or tissue? (HT? pancreas?) See Sadava fig. 41.6 (41.5).
4. Target Cells -- where does it act? (Muscle and liver? Just liver?)
5. Mechanism of signal transduction
A. Location/type of receptor on target cells -- Is receptor on surface or intracellular? TK* or G protein linked?
B. Type of signal transduction -- Is there a second messenger? Which one?** If none, what links receptor to intracellular events?
C. Intracellular mode of action -- what mechanism is used to get the end result? Is there a change in enzyme activity? change in transcription? both? change in state of ion channel?
6. What actually gets done? What happens?
A. Biochemically speaking: Which target enzymes, proteins or genes are affected (glycogen phosphorylase activated? Gene for enzyme X transcribed?)
B. Physiological End Result: Another hormone secreted? Glycogen broken down, & Glucose in blood up? Note the "result" may have several steps, and more than one can sometimes be considered "the end."
C. What's the (teleological) point? What overall function is served by the signal molecule's action?
1. One list of possibilities: Homeostasis, response to stress, growth*, maintenance of some cycle;
2. An alternative version of the list: Regulation of rates of processes, growth & specialization, Conc. of substances, and response to stress.
3. The 2 lists are really the same = homeostasis (control of rates & concentrations), response to stress, & regulation of growth (unidirectional and cyclic).
* Details of TK linked receptors have not been discussed (yet)
in 2011. The point so far is that they are not GPCRs, and work differently.
** Signal transduction involving 2nd messengers other than cAMP will be discussed after nerves.
Next Time: Dr. Firestein will discuss Electrical Communication. If you want to look ahead, see lectures 15 & 16 of 2010.