Development of Type 1 Diabetes Mellitus by Doctor Michael Agus.
Hi, and welcome. I'll be speaking today about diabetic ketoacidosis, or DKA. My name is
Michael Agus. I am a pediatric intensive care doctor, and a pediatric endocrinologist at
Boston Children's Hospital. I'm the Director of the Medicine Critical Care Program here
at Children's, and an Assistant Professor at Harvard Medical School.
I'll start by explaining how one gets diabetes to begin with, because it's a surprise to
many that diabetes really occurs, develops over a period of many, many months. When endocrinologists
in Boston set up the Diabetes Prevention Trial, or DPT1, several years ago, although we weren't
able to stop the onset of diabetes, we were able to track people getting diabetes. And
the way we chose the most likely people to get diabetes were to look at first degree
relatives of patients with diabetes.
We know that patients who are about to get diabetes have a genetic predisposition, and
then they have some environmental component that occurs at some point in their life. We
don't understand what that environmental component is, but we understand that if you have that
genetic predisposition, you are at risk to be affected by the environmental exposure.
When trying to identify patients at increased risk, those first degree relatives-- so siblings,
parents, children-- instead of having the usual background rate in the North American
population, for example, of 0.5%, roughly, of Type 1 diabetes, people who have a first
degree relative with diabetes are at a tenfold increased risk, and now have a 5% incidence
of Type 1 diabetes. So you went from 1 in 200 to 1 in 20. By following these people
who are at increased risk of getting diabetes, we can understand that they begin to lose
beta cell function, months and months and months prior to the onset of clinical symptoms
of diabetes.
So if we were going to take an example of a child who is developing diabetes, we could
look at this particular graph. And you see that even though she didn't know she was on
her way to get diabetes, she's been losing beta cell function, beta cell mass, from autoimmune
destruction over a period of many months. When she's at the point that you see here,
there's no symptoms whatsoever. She has enough insulin to cover the meals, cover her basal
production.
When she moves to the next step, she has intermittent hyperglycemia. That refers to the fact that
when she has a large carbohydrate load, an ice cream sundae, for example, blood sugar
may go up into the 200s, 300s. She may get a little flush. She may have increased urine
output, because her glucose has exceeded the renal threshold of 180 milligrams per deciliter.
But she'll have an extra cup of water, may be be a little bit thirsty, and come right
back down into the mid to low 100s after that.
Almost nobody gets diagnosed in that particular period, with the rare exception of a child
of a mother with diabetes. That's not a medical rule, but it's a sociological reality that
a family member who has diabetes, in particular a mother, will be much more vigilant at checking
the child from the time they're born, doing a finger stick here and there when they have
a tantrum, when something doesn't look quite right. And so those patients are likely to
get diagnosed a little bit earlier.
Most patients will continue to lose beta cell function, and move into this yellow zone of
frequent hyperglycemia. And with hyperglycemia again over the renal threshold of 180, you
get polyuria, and when you lose that water, you'll get thirsty. And so you get polydipsia.
And diagnosis at this point may have more to do with the family's sleep set up than
anything else.
If, for example, a child is going to share the bathroom with the adults, then they're
going to notice in the middle of the night that they're getting up four times at night.
They live in a massive house, or the child uses a different bathroom, it may be a longer
period until the parents notice that the child's getting up at night. Same thing at school,
depending on how vigilant or how much the teacher notices.
But despite the difference in what the adults see, what happens to the child is pretty identical.
And over a period of at very least a couple of weeks, the child will become more and more
symptomatic. In retrospect, one can often find symptoms well beyond just the two weeks
of polydipsia and polyuria-- see a little bit of weight loss, maybe some growth stunting,
maybe some increased hunger, because of that weight loss they're not able to sustain a
normal weight.
If this period goes unnoticed, the patient can progress to diabetic ketoacidosis. And
we'll talk about that in a minute. The interesting thing, however, is that not all patients really
have a clear history of two or three weeks of polydipsia and polyuria until they present
with ketoacidosis. Rather, they're basically fine on Monday, and then on Tuesday they're
in extremis, quite ill.
And so if we go back and look at a patient who, say is in the green zone on a Monday,
what changes between Monday and Tuesday? Is it that they lose beta cell mass, a massive
amount of beta cell function over a day? That can't be true, because we know that it takes
months and months and months, up to 10 to 12 months, to develop clinical diabetes.
So much more likely what happens is that they encounter a stress. And if you look at the
patient in the green zone, when they go from Monday to Tuesday, what changes is not their
beta cell mass. What changes is their insulin requirement. And what was enough insulin on
Monday to keep them under control is suddenly on Tuesday not nearly enough, and it throws
them right into ketoacidosis.
And so what could have happened between Monday and Tuesday, to create that kind of differential
in insulin requirement? Well, stress is a very straightforward answer, and basically
in childhood it can be virtually any kind of stress. It can be a viral illness, can
be dehydration. It can be an injury, a fever.
Now if we take one of those, say a viral illness, and look how it progresses through, we see
that any viral illness can lead to decreased water intake, dehydration. And in any of us,
when we get a little bit of hypovolemic, when we get a little bit of hypovolemia, we will
begin to counter-regulate with stress hormones. Primarily those are cortisol and epinephrine,
but there's a whole host of hormones, catecholemines, that begin to get increased in a setting of
stress.
And those give anybody a little bit of insulin resistance. And so in somebody without diabetes,
that might bump their blood sugar from a baseline of, you know, 80, to a baseline of 95. Still
within the normal range, but a slight increase.
Why is a body triggering a response to increased blood sugar slightly? No one really understands
that. No one understands if there's any survival benefit to 95, for example, over 80. But in
patients with evolving diabetes, or with frank diabetes, a little bit of insulin resistance
goes a long way, from a blood glucose point of view. And instead of bumping from 80 to
95, they go from 80 to 180, and then to 280, and to 380.
And as they hit that renal threshold of about 180 milligrams per deciliter, they'll begin
to spill a lot of urine. And with that polyuria, they will lose even more fluid, they'll get
even more dehydrated. They'll counter-regulate even more. And as a result, they'll begin
to develop even more significant insulin resistance.
That insulin resistance will become significant enough that instead of just increasing the
glucose concentration, they'll begin to have significant ketone production. Ketones are
a weak acid, but in significant concentrations they'll give you a significant acidosis, that
will trigger even more counter-regulation.
Once you get into this cycle, there is no way out without insulin. This is a spiral
that, untreated with insulin, will result in death. This is the death spiral, to demonstrate
that there are no case reports of somebody getting diabetic ketoacidosis and spontaneously
surviving. Unless you get insulin therapy, there is no way out. The problem with DKA
is insulin deficiency, and the cure for DKA is insulin.
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