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Transcript
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
The final exam will be before Thanksgiving. Unfortunately, the audio was less than quality once again. Any
place where (…) appears, there was an abrupt skip in the audio.
I.
Introducing the problem [S2]
a. We’ve had the lecture on the pancreas and how it works to regulate blood sugar. Today we’re going to
talk about two different diseases. Type II may comprise 4 other diseases. They contribute mightily to
both dental and optometric problems. There is a large increase in the number of people who have these
diseases.
b. Today, statistics show that if you are Caucasian the chances are 1 in 3 that you would have a child with
diabetes and if you are African American or Hispanic the chances are 1 in 2. It amazing that in this day in
age that a disease has increased in prevalence as much as diabetes has.
c. Most of it is due to our lifestyle. Too much sitting and not enough working. We don’t utilize as much
energy as we use to. There is a lot of societal impact that we really can’t change.
d. Who gets type I and who gets type II?
i. Type I is more common among children.
ii. Type II is more common among adults.
1. When he went to school it was called maturity onset diabetes and it was defined as
someone over the age of 40 that developed high blood sugar.
2. That definition is obviously wrong now because ½ of the children that come into
children’s with diabetes have type II.
3. In 1990, the number of teenagers with type II diabetes was zero and now ½ of the teens
with diabetes have type II.
4. It’s like HIV; it’s a disease that didn’t exist the way we know it just over a decade ago.
5. We’ve redefined what we call diabetes, and as we do the number of people who have
diabetes keeps getting larger and larger.
e. Type I is a defect of the pancreas.
i. Pancreatic beta cells don’t secrete insulin as they should.
f. We don’t know a specific organ were the defect is in Type II.
i. It is a transitional disease. Initially, insulin resistance occurs due to the over utilization and over
secretion of insulin as a result of excessive amounts of dietary food intake. We respond to food
intake by secreting more insulin and as we do so our body because less and less insulin sensitive
because the number of insulin receptors on our target cells decreases. When we hammer a cell
with a lot of hormone, it binds to the receptors and the receptors become internalized, the cell
becomes less responsive. It is a normal feedback mechanism that is protective. But if we feed
ourselves over and over, don’t utilize glucose, then we bombard the pancreas with glucose all the
time, it secretes insulin all the time, and our muscles and fat become less insulin sensitive.
ii. If you took two people and you injected them both with insulin, one thin and one chubby/obese,
the thinner one may have a blood glucose that goes down from 150 to 100 whereas the same 1
unit of insulin in the obese person who had type II diabetes their blood glucose may go down from
200 to 195. You can sense that the same amount of insulin in the obese person will have less
effect because of their insulin resistance. So when the chubby person eats a meal their blood
glucose goes up, they produce more insulin. The insulin in the chubby person’s blood after a
meal might be 5 times greater than a normal individual after a meal. That high level of insulin is a
bad thing. It makes the organs less insulin sensitive and it wears out the pancreas. If the person
continues like this, it’s like a window air conditioning unit; it is going to wear out sooner. The
person who is overweight and has a predisposition to diabetes either genetic or due to weight
problem is more likely to have their pancreas fade over time.
iii. The type II diabetic patient goes through a period early on in the disease where they are making
lots of insulin. Later they go into a stage where they can’t make as much insulin and then at the
end they aren’t making much at all. At the very end of type II diabetes they become essentially
type I diabetic, that is they are both insulin resistance and they don’t make insulin (or hardly any)
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
and thus they are insulin dependent. The other names of these diseases used to be insulin
dependent diabetes for type I and insulin independent for type II. Those names don’t work
anymore because some type II people require insulin to get their blood sugar down so you can’t
really classify them as insulin independent.
g. There are some names out there such as brittle diabetes, touch diabetes, or pre-diabetes, you should be
familiar with what these terms mean.
i. Touch of diabetes- someone whose blood sugar is high some of the time, but not others. So if
you are not being treated by a good physician and you test your blood sugar one day it is 130 and
the next it is 270, you may say that you have a touch of diabetes. That is wrong. They have
diabetes. Touch diabetes doesn’t exist. This is really mild diabetes that is not under good
control. If someone tells you this then it is a red flag
ii. Brittle diabetes- someone that has diabetes and it goes up and down like a rollercoaster. One
day they may be 400 then 30 then 350 then 120, 400, 60. This usually a type I that is taking an
insulin therapy regimen that is not very effective. Another red flag.
iii. Pre-diabetes- a real condition. Many of us are pre-diabetic and many of our parents probably are
if they are not already diabetic. One way to distinguish someone who is pre-diabetic is that their
pancreas is still functioning under suboptimal conditions so that it is able to keep blood sugar
under control unless it is presented with a real challenge. If they get prednisone added to their
regimen, they don’t get pre-diabetic over night, they are pre- diabetic over night, pre-diabetic
means their blood sugar control is marginal and if something else happens then it gets out of
control. Pre-diabetic means that their pancreas is secreting a suboptimal amount of insulin and
the tissues are responding to it sub optimally. When they are presented with challenges then
their blood sugars gets too high.
iv. If you have two people one of whom is pre-diabetic and one who is not pre-diabetic, you give both
a thanksgiving dinner and then you check their blood sugar two hours later, the non-diabetic will
have gone up but then down to below 140. The pre-diabetic’s blood sugar will be 140-199 and if
the diabetic was here then their blood sugar would be above 200. It’s a matter of degrees. It’s
difficult to draw a line, but we have numbers to put people in categories. We use the blood sugars
values right after a meal or when you first wake up in the morning to categorize people as
diabetic, pre-diabetic or normal. You should know these numbers. You may be in a position
where you tell a patient to check their blood sugar level first thing in the morning before they have
breakfast to see what their blood sugar is. There are caveats to this though.
h. When does it occur?
i. It can occur anytime throughout life. You can have a viral infection of your pancreas anytime.
Type I diabetes is diagnosed more often in younger people because they are more likely to get an
infection of pancreatic destruction. If they are going to get it any time in their life it is more likely
that they get it as a teenager than when they are 40,50 or 60 years old, but it can happen.
i. Where is the diagnosis made?
i. One of two ways:
1. Go to a doctor: a physician, dentist, or optometrist without major symptoms, but mention
that you have minor symptoms and they can help diagnosis you with it. Many cases of
diabetes are diagnosed by the optometrist. Some by the dentist. To make the diagnosis
you have to know what to look for. The average person with type I, when they come out
with the disease, they get very suddenly and very hard and they are in the emergency
room with a blood sugar of 700-800. They get very sick, they throw up, they urinate, they
get dehydrated, and it is very serious
2. This is not the case with type II. Type II is insidious. You get to an old age and you have
symptoms that you associate with old age and not disease but that’s the way diabetes
presents itself. The average person has diabetes for seven years before diagnosis.
Think about your eyes, teeth, kidneys, heart and legs being untreated for seven years
before the diagnosis is made.
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
a. SQ: Before the diagnosis is made, if you were to test your blood glucose levels it
would present as an elevated number? Yes, and at health fairs where they
typically screen for high blood pressure and such they are now screening for
diabetes by testing HbA1C. Diabetes is silent. It has been controversial and
only in the past year has the American diabetes association acknowledged that a
high HbA1C…
ii. How is it treated
1. Type I diabetes is treated with daily insulin replacement. It is a lifelong disease. If they
are stranded in the desert or in a panic room they will die. It is a very serious situation
and they have to make arrangements to have insulin therapy with them at all times.
Insurance covering for medications and supplies is a must.
2. Type II is treated with diet, exercise, oral drugs, and insulin. The drugs that we use for
diabetes, the oral hypoglycemic, are not always the best course of action to take. A lot of
clinicians believe actually in treating type II diabetes with insulin at the beginning. Most
type II diabetics don’t like the idea of going on lifelong insulin therapy which requires
blood sugar testing and pricking your finger.
II. The story has changed [S3]
a. So the story has changed, in the 1920s, this was the typical type I diabetic. This young lady was treated
with state of the art care in the 1920’s which was at the time to limit her diet to bread and water. She
would die pretty much as a prisoner of war.
b. 1922, they isolated insulin from dogs and it was a summer research project for a medical student. He
took out the pancreas from a dog, ground it up, extracted it with alcohol, and injected it back into the dog.
It rescued the dog from dying from diabetes. About six months later they started putting it into humans.
c. Just after starting treatment this young lady looked absolutely normal.
d. You can see the side effects of diabetes: your body starts to break down muscle and fat. You body
produces glucose because the cells in your body can’t get glucose into them. Glucose remains high in
the blood stream and when it gets above 200, it goes across the glomerular filter; you can’t resorb it, and
comes out in your urine. You become glycosuric. When glucose goes out in your urine it takes water
with it. As that happens you get dehydrated and when that happens, the concentration in your blood
falls…and when it gets below a pH of 7, insulin won’t bind to it’s receptor anymore. The reason the pH
goes down is because some of the glucose gets converted to ketoacids like acetoacetetic acid and
ketone bodies and they are acidic and they make the blood pH get lower and lower. Ketoacidosis is what
the term is called.
III. Part 1: Treating and Curing Type 1 Diabetes [S4-5]
a. It happened not only in the 1920s, but it happens today. If a kid or a young adult with type I diabetes don’t
get their insulin then they can go into ketoacidosis and their blood sugar is typically above 500
b. …they fall down out in the street, they have a bracelet, how do you know if their blood sugar is too high or
too low? Because they could go unconscious either because their blood sugar is too high or too low.
Why would they go unconscious with a low blood sugar? They might not have eaten, they might have
taken too much insulin, or they might have exercised. If they took too much insulin or if they skipped a
meal, it could cause them to pass out and even die from too low of a blood sugar. If one of us comes
across someone like this passed out, how do you know if they have too high or too low blood glucose? It
would be nice if you had a glucose meter where you could prick their finger, put it on a strip, and have the
answer in a few seconds (HI or LO). High is above 500; low is below 40. Probably they would be one of
those extremes. Some meters will give you the exact number. Be aware of what glucose meters are out
there and be familiar with how to read them.
c. But if you didn’t have one in your office, you have two courses of action, given that they may have a blood
glucose of 700 or 30, if you were to give them a little bit of sugar you would save their life if they were at
30 and not that big of an impact if they were at 700. Usually the first thing you want to do is give them
something that will raise their blood glucose up. What hormone raises blood glucose?... (I believe the
answer was glucagon) Most of us produce both of them all the time and we “goose” up one or the other
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
depending on it we are in a post absorptive phase after a meal or a non post absorptive period between
meals.
d. Between meals we make more glucagon and after meals we make more insulin. All of the time we make
both. As a diabetic you stop making insulin because your cells have been destroyed. If you’re not sure
then you’re going to give glucagon.
e. The problem with giving glucagon to someone that is unconscious is glucagon comes as a dry powder
and a dilutent. You have to draw up the dilutent with a syringe shot it into the vial with powder, so it is not
very user friendly. If you’ve never done it, he advises to get a kit of glucagon emergency, practice it one
time with an orange because it could save someone’s life.
f. Everyone with type I diabetes is advised to buy a glucagon emergency kit once a year and then throw it
out because it goes out of date. Before you throw it out though, practice with it.
g. For a really small person, you would want to give them ½ of the normal amount. A vial contains 1 mL
when you draw it up, and if you have a small person ½ mL is good.
h. After you inject, their blood glucose will go up, they will wake up. If their blood sugar was 700 and you
gave them glucagon, then their blood sugar may go up to 800. They wouldn’t change, they wouldn’t
wake up, they wouldn’t get better. But if their blood sugar was 30 and you gave them glucagon they
would come up to 50 or 80. Then you would give them…
i. Glucagon causes cramping and vomiting. All of that food that you just put in their mouth is going to come
up which is not good because you can’t just give them another shot of glucagon. You only get one
chance.
j. In the mean time, call 911. They will hang an IV line and get glucose running in that way. It’s not easy to
get glucose into someone that is in hypoglycemic coma or shock because they have clenched down. If
someone is in a hyperglycemic crisis you do want to get the paramedics there very quickly
k. What does this guy have? Type II diabetes.
l. Type I: pancreatic beta cells are destroyed, insulin secretion decrease, glucose levels go up, ketoacidosis
can occur, fat is broken down, ketones are released, pH falls, insulin binds but not its receptor, severe
dehydration.
IV. Long term complications of diabetes: [S6]
a. Long term complications shared by both type I and type II
b. there are a couple of studies that show that they are related to the degree of hyperglycemia so we think
that the underlying theme is that glucose reacts with protein amino groups to form what we call
glycosylated proteins and all of the proteins in our body.
c. The higher the glucose in our body the more the reaction it is a 1:1 reaction. So if my blood sugar is 100
and hers is 200, then she is going to have twice as many glucose molecules attached to her proteins as I
do. And if her blood sugar is 300 then she is going to have 3 times as much as I do.
d. What you do about diabetes and the fact that we have long term complications, what do you think about
the fact that we have glycosylated proteins? Do you think it is a good thing or a bad thing? Probably a bad
thing. It’s probably what causes nephropathy, neuropathy, retinopathy, glaucoma, cataracts, depression,
gangrene, erectile dysfunction, cardiovascular disease, and cerebral vascular disease. All of these things
are probably related to our proteins getting glycosylated more than they should be.
e. So if you can find the drug that deglycosylated proteins that would be a good thing and a way to treat
diabetes.
V. Normal response to a meal: Insulin is released [S7]
a. Here is the normal way the… the vagus nerve to release insulin. It also gets stimulation from the gut to
release insulin and from the substrate to release insulin.
b. Those are the three things that release insulin.
c. The substrate is glucose.
d. When we eat a meal there is a time factor. If I eat a meal at 10:30, my blood glucose starts to go up and
get to my pancreas in 15- 20 min later. This is the time it takes for the food to get to my stomach, get
absorb, travel through the portal vein, go to the liver and get to the pancreas.
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
e. Turns out that the vagus nerve doesn’t have to wait for the glucose to get there. When you sit down to
eat it sends a signal to your pancreas to start making insulin. Why is that important? In type II diabetics
that nervous input is the first thing that goes. Early type II diabetics can respond to glucose in the blood
but they can’t respond to the sight of food.
f. So we may use insulin a little later than someone who doesn’t have diabetes. Insulin has a head start in
someone who doesn’t have diabetes because they make insulin ahead of time and it is already at your fat
and muscle cells. When we get to what insulin does, in one case the insulin has already done it and in
the case of someone with type II diabetes, insulin doesn’t start to do it until 15-20 minutes after a meal.
That 15 minutes turns out to be critical in how much glucose we absorb…
g. Up here in vagal stimulation and then later on after you’ve had the disease for 10-15 years, then the
pancreas can’t even respond to a high glucose anymore because it gets worn out. It’s kind of like a dual
high and one comes before the other. The insulin goes to the liver, the liver changes the amount of
glucose it puts out.
h. When the glucose is low is the liver putting out glucose or not putting out glucose? What is the other
enzyme from the liver that we talked about? …(Again, I think the answer is glucagon) It is always on
board, it is always there. So if you don’t have insulin, it’s like you don’t have your foot on the brake. You
still have your foot on the accelerator. You’re car is still going to move forward and your liver is still going
to put out glucose that’s why someone who has type I diabetes, if they don’t get their insulin, their liver is
slamming out lots of glucose . Even if their blood sugar is 500, they are still putting out more glucose.
That’s why they have to have insulin. The liver is always putting out glucose until insulin tells it not to.
Insulin is the brake that slows down glucose output from the liver. Think of the liver as the organ that
pumps out glucose unless insulin slows it down.
i. What about fat and muscle? Do they put out or take up glucose? They take it up as fuel. To take it up
they have to have insulin react with its receptor and increase the number of glucose transporters called
GLUT 4 transporters and those two organs specifically respond to insulin with increased glucose uptake.
If you don’t have insulin then you don’t have glucose transporters and glucose doesn’t go into skeletal
muscle and fat. Think about your own body. You have glucose going around in your blood and when it
gets to skeletal muscle or fat it goes in. It gets utilized. If it didn’t get in then the level in your blood just
gets higher and higher and that’s what happens in diabetes. So normally muscle and fat cells take up
glucose in response to insulin action….
VI. Diagram [S8]
a. So in the pancreas, glucose binds to a GLUT 2 glucose transporter. Is GLUT 2 the same as GLUT 4?
No. GLUT 2 is there all the time and takes up glucose. GLUT 4 is inside the cell cytoplasm and only
comes out when insulin does it’s thing in the cells of the skeletal muscle or fat. GLUT 2 just sits there all
of the time and allows glucose to go in. So glucose goes in and the more you have the more goes in.
The more ATP, the more you close this potassium channel which depolarizes the cell which allows
calcium to burst and that causes vesicles to go to the surface and secrete their contents. The whole
calcium thing and release of transmitters should look familiar because a lot of cells in the body have a
similar pathway. That’s what happens when you eat a meal and you get glucose in the bloodstream. You
increase the amount of insulin that gets released.
VII. Treating Type 1 Diabetes [S9]
a. Treatment of type I: you can give injection subcutaneously before a meal to balance the amount of food
you consume. It’s not possible to control blood sugar by injecting insulin like the normal pancreas does.
Abnormal levels of glucose levels represent both morbidity and mortality.
VIII. Yesterday [S10]
a. Your pancreas is a wonderful organ. It saves your life every day. In the old days, we gave those with
type II diabetes a shot twice a day that was a mixture of regular and NPH insulin. Regular insulin is
purified from a cow or pig, but in 1993 it was the first protein made by recombinant DNA. Now we make it
in E. coli and we can make big batches of it. In the old days, though, meat packing companies would
take out the pancreas, send it to Eli Whitney and he would grind them up and purify the insulin to give to
people to inject. Regular insulin was the insulin that they got from the pancreas. If it was injected into a
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
human being, usually, it took about 30-45 minutes to be effective which was a problem because you had
to take it 30-45 minutes before you ate and the amount you took you had to base upon how much you
expected to eat. If you expect a bowl of cereal in the morning so you take 5 units of insulin. On a good
day you eat that exact amount at the time you expect. On a bad day, you get more or less than you
thought or something interrupts you before you even get a chance to eat and that insulin in your blood
now is enough to send you to the hospital or kill you. Today we have some analogs of insulin that don’t
require 30-45 minutes to work. The new insulin we can sit down and have our food before us when we
take our insulin. The regular insulin is not what we use much anymore. NPH insulin is type of insulin that
we mix with protamine. Protamine is a type of salmon protein from DNA, like histones, and it formed a
milky cloudy solution with insulin. If you injected it then it is slowly released. It formed a depot where you
injected it. If you injected it at 7 in the morning then it would be released for the next 12 hours. That’s
good because that mean you have insulin on board all day long. They would make people mix NPH and
regular insulin and take a shot in the morning and a shot at night. The problem is most people eat three
times a day. Can you think of a way that you could deliver this insulin and have it match what their eating
and when their eating? It’s hard. With shots twice a day they would make them only eat twice a day and
then throughout the day have snacks so that their blood glucose wouldn’t get too low. They had to take
enough insulin to cover their big meals but not too much that in between meals their blood glucose got
too low. Kids were given snacks at 10, 3, and 10 along with breakfast, lunch, and dinner. They had to
have 6 food intervals every day. What do you think that leads to? They end up pudgy… They have to
eat all of that food because they have insulin on board. It’s a bad situation. These are the kids that most
of the statistics that you see about glaucoma , blindness, cataracts, and amputations are generated from
the folks who got the disease 30-40 years ago and have been treated that way. We don’t do it that way
anymore, and it remains to be seen how the outcome will be for the kids we are treating today in 30-40
years.
IX. Insulins [S11]
a. The new rapid acting insulins: lispro, aspart, and glulisine. These insulins are injected and have almost
immediate action, say 15 minutes, but literally you can sit down at your meal and take your injection.
That will be a test question. Which are the fast acting insulin analogs and those three you’ll have to be
familiar with. They are currently widely used in the U.S. Third world countries can’t afford them.
b. Most people in the U.S. are on lispro…. Most are premixed insulins where you get a 70/30 mixture of
NPH and regular or 75/25 of the fast acting or the intermediate acting.
c. There is an inhaled insulin that came on the market 3 years ago but has been taken off the market…
X. Picture of Insulin molecule [S12]
a. Originally a single peptide and its has a connecting C peptide that gets cut off. You cut in two places.
b. So C peptide doesn’t have a function except for that fact that if you have someone with a blood sugar of
1000 and you don’t know if they have type I or type II, you can measure their blood sample and see
whether they have c peptide present. If they have c peptide that means type II. If they don’t have c
peptide that means they have type I because they are not making insulin.
c. Sometimes people come into the hospital and you measure their insulin, but you don’t know if its insulin
they injected or insulin they made.
d. Another situation where it comes into play is in court cases where insulin has been used to kill people. If
you measure the amount C peptide and insulin, the insulin is off the chart but the C peptide is low then it
was a case where someone gave them too much insulin to kill them and not where they over produced it.
C peptide should follow normally with insulin.
e. Probably if you come back in ten years we’ll probably find out that C peptide does something. He thinks
that one of the shortfalls of insulin therapy is that we don’t give C peptide because we don’t know what it
does.
XI. Graph [S13]
a. Here is a time chart of the action of different insulins. Hours at the bottom. Notice that lispro, aspart, and
glulisine all have a very rapid onset and rapid removal from the system. If you took a shot of these before
breakfast it would peak in about an hour and then 3-4 hours they would be practically gone.
H & E: 10:00-11:00
Friday, November 13, 2009
Dr. Pillion
Scribe: Teresa Kilborn
Proof: Ashley Holladay
b. If you were treating yourself with these insulins then you would take a shot before breakfast, lunch, and
dinner.
c. What about during the middle of the night? You have no insulin on board at 3 in the morning, even
though you are not eating, what would you expect to happen? You’re blood sugar would be high because
your liver is going to pump out glucose and insulin is not there.
d. If you don’t take the insulin then you are pumping out insulin and 3,4,5 in the morning your blood sugar
may be 300, 400, or 500 even if you don’t have anything to eat.
e. In the old days we would give them NPH before bedtime. Nowadays, we give them glargine or detemir
once a day so that in the middle of the night they have some insulin on board. If you took too much of
this long acting insulin what would happen? Your blood sugar would get low and you would be
hypoglycemic. There is a fine line in taking too much or taking too little and oftentimes its worked on by
trial and error.
f. The circaidian rhythm that goes on to control our blood sugar. Cortisol is high in the morning. At 5 or 6,
in the morning you make cortisol. If you are a non-diabetic, then your body is able to modulate how much
insulin and glucagon your body gives out automatically, but you’re a diabetic then it doesn’t. If you’re a
diabetic and your body puts out cortisol at 5 or 6 in the morning that would increase your blood sugar
level. Typically you’d have a type I diabetic check their blood sugar in the morning and if their blood
sugar was 50 then you’d conclude that you took too much insulin the night before. If your blood sugar
was 100 in the morning then that’s great. But the trouble is that at 7 when you check it you already have
the effects of cortisol. You should really check it at 3 in the morning before cortisol kicks in and when we
do that, many people who we are thinking are getting good treatment, their blood sugar is actually….
g. So it would be good if we had a type of insulin that we could give at bedtime that didn’t kick in until
morning when cortisol does but we don’t have that yet. One thing we do have is continuous glucose
monitors that are like an insulin pump that you wear on your belt. (audio abruptly ended here)
[END 40:23]