Control of metabolism, Fox, Chapter 19 (also some other chapter figures,
11 and 3)
Control of energy metabolism is so important that there are two major hormones
(insulin and glucagon, proteins from the pancreas), as well as many others
(thyroxine, epinephrine, and cortisol) to regulate it on short- and long-term
In a lab...
...(BL A347, Fall, 2004), we injected insulin into mice, decreasing glucose,
then injected glucagon, bringing it back up. Data: before: 157 mg/dl. after
insulin 49, after glucagon 197.
More on insulin and glucagon
In pancreas, which is largely a digestive exocrine gland, there are also
islets of Langerhans (as shown in this picture
from our histology course) which are the endocrine glands where the beta
cells make insulin and the alpha cells make glucagon
Fig. (like 11.31a)
Pancreas Insulin- sugar uptake into cells (blood sugar down), make glycogen
2 peptides clipped from one chain held by disulfide bonds
(this sort of processing is common for signalling molecules)
Type 1 autoimmune disease beta cells are destroyed, young people, insulin
inject insulin. protein, must inject
(vs steroid like "the pill" which can be taken orally)
Type 2, older people, genetic, correlated with overweight, non-insulin dependent
sugar in urine- can't pump back, in our physiology
labs, we use these urinalysis
strips which include a test for glucose in the urine. In the aforementioned
endocrine lab, we introduced the students to this
type of strip and meter for testing blood glucose.
Eye problems (too many new blood vessels - angiogenesis) and cardiovascular
Brain is not insulin-dependent - coma from too much insulin because no glucose
Glucagon mobilize sugar to blood like adrenalin
sugar regulates insulin and glucagon
Glucose (and other calories)
Fat, carbohydrate and protein feed into metabolism
What you may not have seen before this figure is ketone bodies, produced
from fatty acids in liver.
Low carbohydrate diet and diabetes can lead to ketosis, even ketoacidosis.
Note also that this figure shows that urea is the nitrogenous waste from
using amino acids for calories.
Blood glucose up, insulin up, glucagon down, cells use glucose
Blood glucose down, insulin down, glucagon up, glycogenolysis & gluconeogenesis
(making of glucose from molecules like amino acids.
The above is given in more detail relative to after meal vs fasting
What the liver does
Here's what the liver does to release:
glucose (from glycogen and amino acids)
ketone bodies (from fat and amino acids)
When you fast, fat and muscle are broken down
Opposite when insulin (and glucose) are plentiful:
Fat deployed (and not released) from adipose tissue
Glycogen deployed (and glucose not released) from liver
How glucose is monitored
How glucose is monitored by a beta cell
glucose is transported in by GLUT2
metabolism makes ATP
ATP is ligand that closes K+ channel
voltage gated Ca2+ channel lets in Ca2+
exocytosis from vesicles with insulin
Insulin receptor is tyrosine kinase
binds insulin extracellularly
puts phosphates on tyrosine residues
Like for epinephrine, receptor for glucagon is G protein coupled receptor
For the umpteenth time, I show you signal transduction cascade
One fact on this figure not shown before:
cAMP acts by binding inhibitory subunits and pulling them off catalytic
subunits of PKA
The kinase phosphorylates enzymes, activating some and inhibiting some
end result, of course, is glycogenolysis in liver and lipolysis in adipose
Glucocorticoids are also involved in stress (mobilizing molecules for catabolism)
Glucose, fatty acids, ketone bodies and amino acids in blood increase.
This is slower than for epinephrine
Test questions from 2004 - 2011 that relate to this outline
What does a cell in adipose tissue do with all the glucose it takes up under
the influence of insulin dependent glucose transport?
turn it to fat
Why is glucose in the urine high in untreated diabetes? Address the question
of whether diabetics have kidneys that are totally unable to transport glucose.
they transport glucose like a non-diabetic, but glucose transport reaches
Blood samples are taken from a mouse before and after insulin is injected
and measured with a blood glucose meter. What happens to the blood glucose
it goes way down
Insulin is made from a precursor (a prohormone). Say something about what
the molecular structure of insulin is and/or how it relates to the prohormone.
two peptide chains are linked by disulfide bonds after a peptide is cleaved
Why would the vitreous of the eye become less transparent after long-term
leakage from blood vessels created by angiogenesis
Metabolism of glucose transported into a beta cell in the islets of Langerhans
increases ATP. How does this ATP mediate the secretion of insulin?
it closes a potassium channel that depolarizes the cell causing calcium
influx for vesicle release
For cAMP, answer either (1) How, molecularly, does it activate protein kinase?
Or (2) How could you persuade that cAMP to stick around a little longer?
(1) binds to (and removes) inhibitory subunits (2) block its breakdown with
Suppose there were a new substance, a potential drug or poison, that increased
the cytoplasmic Ca2+ level in the beta cells in your islets of Langerhans.
What do you expect would happen if you tested this substance on an animal?
More insulin vesicles released, possibly leading to coma
Insulin is made from a prohormone. State one of the things that are done
to make insulin from this prohormone.
A peptide fragment is removed from between the 2 that are part of insulin
and these are linked by 2 disulfide bonds
The long term health of a person with type 1 diabetes is best if the right
amount of insulin is given, keeping the person's blood sugar just above
the level that would result in coma. What would happen if less than that
amount of insulin were injected one time?
the blood glucose would not be quite as low, that's all
Answer either (1) for gluconeogenesis, where did the glucose come from?
Or (2) for ketogenesis, where did the ketone bodies come from?
1 from amino acids, 2 from triglycerides
Suppose there were a new substance, a potential drug or poison, that depolarized
all the beta cells in your islets of Langerhans. What do you expect would
happen if you tested this substance on an animal?
more insulin release, lower blood glucose, maybe coma
What is the ligand that closes the K+ channel in the beta cell's mechanism
for monitoring glucose?
What is the activity of the insulin receptor enzyme?
What is the polymer of glucose that is so important in muscle and liver
In the process where epinephrine causes glucose release from liver, what
enzyme does cAMP activate?
protein kinase A
In fasting, gluconeogenesis can provide some glucose from amino acids. Where
do these amino acids come from?
If you had a lot of ketone bodies, what does that tell you about what is
going on in your metabolism?
you are using fats, probably fasting
How is glucose detected by b cells in the islets of Langerhans?
being metabolized to make ATP, ligand for channel
Insulin injected into an anesthetized mouse would decrease blood glucose.
What other hormone, normally produced in the islets of Langerhans, would
raise the glucose levels back?
When I remind you that the insulin receptor is a tyrosine kinase, where
is tyrosine and what happens to it?
on intracellular side of enzyme, tyrosine (amino acid) becomes phosphorylated
Epinephrine, acting on the beta adrenergic receptor, causes what to happen
to glycogen in the liver?
breakdown to glucose and release to bloodstream
In addition to facilitated diffusion, there is a transport mechanism for
glucose requiring energy delivery from ATP. To what molecule does ATP deliver
the sodium pump
The insulin receptor dimerizes when it binds insulin. What do these molecules
do that gives them the description "tyrosine kinase?"
they phosphorylate the amino acid tyrosine
If you need to take insulin, why do you need to inject it?
if you ate it the protein would be broken down
As it applies to diabetic retinopathy, what is angiogenesis?
formation of new, fragile, blood vessels
What holds the two peptide chains of insulin together?
What process is mediated by the entry of Ca2+ into the pancreatic beta cell?
release of vesicles
What allows the return of the inhibitory subunit to the catalytic subunit
of protein kinase in the signal transduction pathway for glucagon?
conversion of cAMP to 5'AMP
Under what circumstances would ketone bodies be released from the liver?
What would insulin cause an adipose cell to do?
take up glucose
What donates the phosphate when the insulin receptor gets phosphorylated?
"Insulin is a receptor tyrosine kinase." Receptor - it is a receptor
molecule." Kinase - it is an enzyme that phosphorylates proteins. What
does the word tyrosine imply?
it is the amino acid that gets phosphorylated
Why can't you just swallow insulin (instead of injecting it)?
would be broken down in digestion
How is cAMP made? (Answer either  what is the precursor? or  what
is the enzyme?)
ATP -> adenylyl cyclase
Facilitated diffusion for glucose transport does not utilize ATP. Under
what circumstances does ATP get used for glucose transport?
Indirectly, Na+K+ATPase, to let Na+ drive co transport in kidney tubule
What would an injection of glucagon do to the blood glucose level?
I repeated the point "Insulin increases glucose transport into cells
in insulin-dependent tissues like liver, muscle and adipose tissue."
What is the most important non-insulin-dependent part of the body?
What is gluconeogenesis?
forming glucose from other molecules such as amino acids
What special job is there for the ATP that is generated by glucose metabolism
in the beta cell of the islets of Langerhans?
ATP is ligand that closes K+ channel to depolarize cell
What is released from adipose tissue under the influence of glucagons?
Give one phrase to describe Type 2 diabetes.
non-insulin dependent, correlated with overweight, affecting receptor, occuring
at a later age
What happens to the translated amino acid sequence to make the final insulin
part gets cleaved off, 2 chains linked by disulfide bridges
Why would the physician deliberately burn holes in the retina (laser photocoagulation)?
to decrease angiogenesis in diabetes
If the insulin/glucagon ratio favored gluconeogenesis, what would be happening
to the insulin dependent cellular uptake of glucose?
Under what circumstances would muscle be broken down for energy?
With respect to your eating habits, when would ketogenesis occur?
What happens to the membrane voltage when glucose signals a beta cell in
the islet, and how is ion flow affected to cause this electrical change?
depolarize, K+ flow decreased
How does cAMP activate PKA?
pull inhibitory subunits off catalytic subunits
What is the circuitous route by which cortisol causes the increase in blood
muscles release amino acids that are converted to glucose in the liver
What is proinsulin, and how is this processed to make the active hormone?
It is a longer polypeptide, a chunk is chopped out of the middle, and the
two parts of insulin are tied together by disulfide bonds
How does destroying part of a diabetic's retina preserve vision?
It decreases the signal for angiogenesis
During fasting, what will happen to the level of ketone bodies in the blood?
What hormone promotes the storage of triglyceride into an adipose cell?
How, specifically, is Ca2+ involved in how beta cells put out insulin?
When the beta cell depolarizes (ATP closes K+ channel) Ca2+ comes in, involved
in insulin vesicle release
he "water turbine" to generate ATP
"Tyrosine kinase" - where did the phosphate come from?
ATP donates the phosphate there (and pretty much everywhere)
Amino acids can be used for catabolic energy. Where do they feed into the
Into pyruvic acid just before acetyl co-A
What would a beta adrenergic receptor on a liver cell mediate?
Via cAMP, increase conversion of glycogen to glucose
What pancreatic hormone is increased during fasting?
"ATP is the ligand that closes the K+ channel in the islet's beta cell."
What does this do to the electrical potential?
What effect does cortisol have on adipose tissue?
Cause release of free fatty acids
For glucose transport across the membrane, answer either (1) How does insulin
cause an increase [in glucose transport] for facilitated diffusion? Or (2)
Why, for a different type of transporter, is energy (in the form of ATP)
more transporters (GLUT-4) are deployed to the membrane, for the sodium
glucose cotransporter, sodium then needs to be pumped
Why would you go into shock if too much insulin were injected?
insulin sensitive tissues like muscle woulddecrease blood glucose leaving
too little for brain function
What effect would glucocorticoids, glucagon and epinephrine have on adipose
release free fatty acids
For insulin, answer either (1)Why would you need to inject it (i.e., why
can't you take it by mouth? (2) How does it look relative to the precursor
molecule from which it is made?
proteins would be digested, larger protein was clipped to 2 fragments bound
with disulfide bonds
Why does laser photocoagulation slow the progress of diabetic retinopathy?
decreases angiogenesis signal
Gluconeogenesis would result from what change in the ratio of insulin and
I/G low, i.e. glucagon mobilizes new glucose formation formation
Beyond its function as the "currency for energy," what important
function does ATP have in the beta cell of the islets of Langerhans?
intracellular ligand, ultimately for insulin release
By what molecular mechanism does cAMP activate protein kinase A (A-kinase)?
2 cAMPs each bind 2 inhibitory subunits to activate 2 catalytic subunits
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