Control of metabolism, Fox, Chapter 19 (also some other chapter figures, 11 and 3)

General considerations

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 bases.

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

Fig. 11.29
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 in liver

Fig. 3.23
2 peptides clipped from one chain held by disulfide bonds
(this sort of processing is common for signalling molecules)

Diabetes mellitus

Type 1 autoimmune disease beta cells are destroyed, young people, insulin dependent
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 problems
Brain is not insulin-dependent - coma from too much insulin because no glucose for brain
Glucagon mobilize sugar to blood like adrenalin
sugar regulates insulin and glucagon

Glucose (and other calories)

Review


Fig. 19.2
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.

Fig. 11.31
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.

Fig. 19.10
The above is given in more detail relative to after meal vs fasting

What the liver does

Fig. 19.9
Here's what the liver does to release:
glucose (from glycogen and amino acids)
and
ketone bodies (from fat and amino acids)
When you fast, fat and muscle are broken down

Fig. 19.7
Opposite when insulin (and glucose) are plentiful:
Fat deployed (and not released) from adipose tissue
and
Glycogen deployed (and glucose not released) from liver

How glucose is monitored

Fig. 19.8
How glucose is monitored by a beta cell
glucose is transported in by GLUT2
metabolism makes ATP
ATP is ligand that closes K+ channel
cell depolarizes
voltage gated Ca2+ channel lets in Ca2+
exocytosis from vesicles with insulin

Signal transduction

Fig. 11.11
Insulin receptor is tyrosine kinase
a dimer
crosses membrane
binds insulin extracellularly
puts phosphates on tyrosine residues

Fig. 19.14
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 tissue

Glucocorticoids

Fig. 19.15
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 saturation

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 level?

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 and discarded

Why would the vitreous of the eye become less transparent after long-term diabetes.

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 caffeine
 
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?

ATP

What is the activity of the insulin receptor enzyme?

tyrosine kinase

What is the polymer of glucose that is so important in muscle and liver metabolism?

glycogen

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?

muscle

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?

glucagon


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 its energy?

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?

disulfide bonds

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?

fasting

What would insulin cause an adipose cell to do?

take up glucose

What donates the phosphate when the insulin receptor gets phosphorylated?

ATP

"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 [1] what is the precursor? or [2] 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 and gut

What would an injection of glucagon do to the blood glucose level?

raise it

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?

brain

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?

fatty acids

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 hormone?

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?

decrease

Under what circumstances would muscle be broken down for energy?

fasting

With respect to your eating habits, when would ketogenesis occur?

fasting

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 glucose?

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?

increase

What hormone promotes the storage of triglyceride into an adipose cell?

insulin

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 metabolic mill?

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?

glucagon

"ATP is the ligand that closes the K+ channel in the islet's beta cell." What does this do to the electrical potential?

depolarize

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) required?

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 tissue?

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 glucagon?

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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