A twofer

In the past two days, there were two separate (and completely independent) items/events that occurred where I thought to myself: "Hmmm, I should write something about this..." Rather than trying to choose which one to write about in my limited writing time, I've decided to just include both of these unrelated items here in this one post. As such, they are likely to each be given a half-assed treatment, but when put together... well, you get the picture.

So without further ado:

No Delivery

Say these two words to any non-diabetic, and I have no idea what the first thing that might come to mind

Thought experiment

It's actually an interesting mental exercise to try to pull off -- to abstract away from yourself and imagine what someone else might think about a certain situation, event, stream of words, etc. I almost never do things like this instinctively, and my failure to do so often gets me in trouble.

My initial guess would be that the first thing that comes to minds for non-diabetics would be something to do with pizza delivery.

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for them would be. In fact, I'd imagine that these two words are relatively meaningless even for diabetics who are not on an insulin pump. But for those of us with insulin pumps, a quick beep-beep-beep-beep and a NO DELIVERY

I'm curious

I use a Minimed pump, so this is (obviously) the message that the Minimed pumps display. Are there similarly curt onomatopoetic noises and dread-inducing messages flashed on other pumps? I'm guessing, yes, but I don't know what they are, or whether they're any less fearful or more helpful or what.

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message is a hassle and can even cause a good bit of anxiety depending on the situation.

I biked into work on Thursday. I wear my beloved rucksack while biking. This thing weighs a TON. I've got normal everyday diabetes supplies in there, plus clothes for the work day, a packed lunch, a book and/or a magazine, and for some reason, I've been carrying around a bottle of water that I just took out of my bag today. The pack has a waist band and a chest strap. I buckle these both down as tight as I can to help keep the weight off my lower back while biking. On the ride in, I could feel the waist band digging in pretty good on my infusion site.

I got into work, tested my blood sugar (155 mg/dl -- which had actually gone up from the 127 mg/dl I left the house at -- but I've noticed that that happens semi-regularly), and bolused for my breakfast of yogurt and a half cup of Fiber One cereal, per my usual routine.

But before the bolus was fully delivered, I got the dreaded "beep-beep-beep-beep" and I knew before even looking at the pump screen what it was going to say.

And so, sure enough, a quick wave of panic hit me.

Luckily, I keep a little dopp kit of extra supplies in one of my drawers. I pulled it out and opened it and wasn't sure I had the supplies I needed. I saw a few of these big bulky packages of Sof-set

It's ridiculous

I really don't understand why marketing firms need to bastardize the English language so. It's not as if it isn't a difficult enough language to learn without all these "cute" misspellings. Pisses me off.

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QR® Infusion Set and a big blue Sof-serter® in there, but I hadn't used these in quite a while and couldn't remember whether I could connect my reservoir to it or not. Sure enough, I had thought about this situation before when I was packing this little back-up kit, and they fit just fine.

I know that there are times when we complain about how bad diabetes technology can be, or how much better it should be designed, but sometimes we forget to appreciate just how far things have come. And you don't realize how much an improvement something new is really until you are forced to go back to an old method. First off, the Sof-serter® is barbaric. It hammered the infusion set in with such force, I nearly cried. It's the infusion set equivalent to the external, swinging-hammer, blood-letting device that came with the first generation of glucometers.

I love my Quick-set® Infusion Sets and the little blue Quick-serter®. I don't think I've cried once since using them.

Head Slappingly Obvious

I received a copy of JDRF's Research Frontline ("The JDRF Research E-Newsletter No. 63") on Wednesday. There is an article (not sure if it's technically an article... a research summary?) titled "Glucagon May Add Another Dimension To Artificial Pancreas."

The hypothesis is brilliantly simple: to practically implement a closed-loop solution to the "artificial pancreas" quest, it might be a good idea to add glucagon to the mix.

I was struck by how logical this was and shocked that I hadn't heard it mentioned before or even thought of it myself.

Most plans for a closed-loop solution that I've read about includes an insulin pump, a continuous glucose monitor, and some mind-bogglingly crazy difficult to imagine software algorithms to safely administer insulin in exact enough increments to constantly maintain a near-normal blood sugar. I'm certain that there are numerous feed-back loops to hopefully prevent sever malfunction of this device, but the addition of glucogon as a counter-regulatory hormone added to the mix just makes perfect sense to me.

I've always been of the opinion that I would much rather prefer a molecular solution to this "diabetes problem" over a mechanical one. Mechanical things break, go hay-wire, wreak havoc. But, I guess, so too do molecular things. After all, that's how we got in this mess to start with. Perhaps I'll have to re-think my position on this issue.

42

The other day at work I was feeling a little funny before lunch.
Symptoms weren't too strong, and not really my normal visual pin-wheel thing either.

I opened up my meter that I keep out on my desk next to my keyboard and went through the few steps that are so second nature to me that I can literally do them in my sleep.

42 mg/dL

I actually started laughing

Even though...

...we all know that's nothing to laugh about.

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when I saw that.

See, luckily I knew that the number one rule of intergalactic travel is:
"DON'T PANIC"

So I didn't. And everything turned out OK.
After eating a box of raisins, 7 glucose tabs, and a granola bar, that is.
(Though I guess there was a little bit of panic in that eating binge).

Lunch was officially spoiled.

Very Depressing

Today in the comments section of my previous post, the Inflexively Flixable Flux Guy pointed out some research by Robert J. McCarter et al.. Below are some of the more salient sentences from their paper:

Blood glucose levels are clearly a major determinant of HbA1c levels. Population studies in patients with diabetes have shown that HbA1c is highly correlated with preceding MBG [Mean Blood Glucose]. However, evaluation of the relationship between HbA1c and MBG among individuals within a population shows that there is considerable variation in HbA1c [for] any given MBG value. This variation is often treated as random, but there is considerable evidence that much of it is due to nonrandom, patterned variation of biological origin. Thus, some individuals at the same MBG value have consistently higher HbA1c levels [like me!] and others consistently lower HbA1c levels [not like me!] than that expected under the hypothesis that HbA1c is solely determined by MBG.

In a previous study, we developed a hemoglobin glycation index (HGI) based on the relationship between observed and predicted HbA1c levels. ...HGI quantifies the magnitude and direction of individual differences in observed HbA1c from that predicted by the population regression equation while accounting for the influence of MBG. The accumulated evidence... strongly suggests that an individual’s HbA1c levels are determined by two major components: 1) MBG and 2) other individual factors responsible for biological variation in HbA1c.

Data were available to evaluate the relationship between HGI and risk of retinopathy and nephropathy for up to 7 years. Risk for development or progression of retinopathy with MBG held constant was significantly different (P < 0.0001) among patients in the low-, moderate-, and high-HGI groups (Fig. 2A). After 7 years, patients in the high-HGI group had three times greater risk of retinopathy (30%) compared with those in the low-HGI group (9%). Risk for development or progression of nephropathy was also significantly different (P < 0.0001) in the low-, moderate-, and high-HGI groups (Fig. 2B). After 7 years, patients in the high-HGI group had six times greater risk of nephropathy (6%) compared with those in the low-HGI group (1%).

The important novel finding of this study is that biological variation in HbA1c is an important predictor for the development and progression of diabetes complications. This suggests that there are two important components of risk for the microvascular complications of diabetes. The first is the well-recognized effect of chronically elevated blood glucose. The second component is the less-recognized and poorly understood effect of factors other than glucose that are responsible for biological variation in HbA1c.


Robert J. McCarter, SCD, James M. Hempe, PHD, Ricardo Gomez, MD, and Stuart A. Chalew, MD. 2004. "Biological Variation in HbA1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes" Diabetes Care 27:1259:1265.

This shit scares me (a lot). Even so, and in all seriousness, thanks for passing this on, Dr. Fluxtable.

Sincerely

I hope you don't take any offense to my having fun with your nom de internets. If so, I apologize in advance.

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While it scares me sometimes, knowledge is power. And if I have to work harder, than so be it. That's what I'll have to do (though this analysis implies that even that might not be sufficient).

On top of this/that "well, what'd ya know, I learned something new" feeling today, I had a hell of a roller-coaster day blood-sugar-wise.

Hold on to your hats folks! You might lose your cookies on this one!
(Note also, that this graph doesn't show the string of readings in the low 50s at around 3am the previous evening).


"Oh shit, that was fun!"
"Yeah! Wanna go again?"
(Um, no thanks (and besides, I don't even know who those sick characters having that conversation were). I hate roller-coasters (both literally and figuratively).).

Number Crunchin'

Okay.

So last weekend I ate the better part of a half gallon of Breyer's Vanilla ice cream, had a slice of birthday cake, and a few Girl Scout cookies.

I think I've got that out of my system now (at least I hope so).

But the non-movement of my A1c still haunts me.
So when faced with a situation like this I decided to do what any self-respecting geek would do: turn to the data.

WARNING

This is going to get a little technical.
You might want to turn back now.

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So after explaining my dilemma here and to a few other friends or family, several have asked whether there's an issue with when I'm measuring my blood sugar: Could I be missing peaks? Could I be biasing my results with more frequent tests when I'm low? And I think these are valid questions.

Going into all of this, I have as my baseline a report in Diabetes Care titled "Defining the Relationship between Plasma Glucose and HbA1c." The result of the article is to estimate a reltionship between average meter readings and HbA1c readings (duh). And basically, the table below is what was found.

A1c (%)	Mean Plasma Glucose
	mg/dl	mmol/l
6	135	7.5
7	170	9.5
8	205	11.5
9	240	13.5
10	275	15.5
11	310	17.5
12	345	19.5
From Diabetes Care - 26 (Supplement 1): Table 1

This relationship was based on a sample of 1,439 type 1 diabetics producing 26,056 quarterly HbA1c readings (mean duration of participation in the study was 6.5 years), and blood glucose readings taken 7 times/day (before and after each of 3 meals and at bed time). The relationship was estimated using least-squares linear regression.

But first, in order to estimate the relationship, they needed to come up with a measure of "mean plasma glucose" that is appropriately weighted for time.

This is important.

Below is a simple example I created. Imagine you have 3 blood sugar readings over a period of 4 hours. At 1 PM you have a reading of 200 mg/dl, at 3 PM you have a reading of 150 mg/dl, and at 4 PM you have a reading of 100 mg/dl. If you were to take the simple average of these three readings, you'd have an average of 150 mg/dl over the 4-hour period.

But that's not likely to be what you're "True Average" blood sugar reading was over the 4-hour period. If we assume a straight drop in blood sugar between 1 PM and 3 PM, you could imply (or interpolate) a reading for 2 PM of 175 mg/dl. If you include this reading of 175 mg/dl, your average for the 4-hour period now goes up to 156 mg/dl -- 6 mg/dl higher.

Conversely, if you were to have the timing switched up a little (like Scenario 3), you could arrive at a lower average reading if you were to interpolate between readings (150 mg/dl vs. 144 mg/dl).

Meter Readings
Time	Scenario 1	Scenario 2	Scenario 3	Scenario 4
1:00 PM	200	200	200	200
2:00 PM		175	150	150
3:00 PM	150	150		125
4:00 PM	100	100	100	100
Average	150	156	150	144

To account for this timing effect of blood sugar readings, the authors "linearly interoplate" between the 7-points of actual data they collected. Or in their own words:

"For each profile, the seven time points were connected by straight lines over time for a 24-h period, and then the trapezoidal areas under each curve were determined, added together, and divided by time. A constant BG level between bedtime and the following morning was assumed."

Basically, you need a measure of the "area under the glucose curve." If you had a continuous function, you would simply take the integral of the function to calculate the area under the curve. To arrive at an approximation of this, however, you can chop up the area under the glucose curve into small units of time, create rectangular areas for each unit of time that go as high as the glucose curve, and add up the area of all these interpolated rectangles, and divide by time to come up with a properly weighted average blood sugar reading.

So... based on their table, my 7.1 HbA1c reading indicates that my average blood sugar has been around 170 mg/dl. This is been IMMENSELY puzzling to me as my average meter readings for the past 9 months(!) have been almost entirely below 150 mg/dl and as low as 130 mg/dl.

To (attempt to) get to the bottom of my dilemma, I exported the data from my OneTouch meters to comma separated values (*.csv) file going all the way back to November 2005. I read these data into SAS and wrote a program

Details

SAS is a statistical programming language used heavily in research and particularly in clinical trial research. I don't know exactly what time increment the authors used in the Diabetes Care paper, but I interpolated readings for each-and-every-one of the 1,440 minutes in a day. I also didn't assume that blood sugars remained constant over night like the authors did. I simply interpolated them to the next morning's blood sugar reading. I'm not sure whether these differences would bias my averages one way or the other relative to the methodolgy used in the other analysis.

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to interpolate the value of blood sugar in between all my meter readings and produce 7, 14, 30, 60, and 90 day averages. I also calculated these averages based solely on the meter readings for comparison.

First, below is a graph of the average readings from November 2006:



Clearly, the interpolated averages are higher than my simple averages of meter readings by about 8 mg/dl.

And then here is a similar graph of my average readings from February 2007:



While the interpolated average is still a bit higher than my simple averages that I've been relying on, the most remarkable thing about this graph is how much lower my readings are relative to my November averages (both interpolated and simple).

What I was hoping to get out of this exercise was to find that the interpolated values were indeed higher than my meter readings (which I did learn), but also that there would be little difference between the interpolated average in November and the interpolated average in February.

Unfortunately, that is not the case. My blood sugar averages dropped significantly over the 3-month period, but my A1c stayed rock solid at 7.1.

So.

All that, and I'm still puzzled as ever...

BULLSHIT

I got my A1c result back.

7.1

No change since November.

It makes NO sense.

Doc says it's because the standard deviations of my blood sugars are too high.
"Once you get your standard deviations down around 30, you'll be in the 6s!"

Never mind the fact that I have lowered both my average readings and my standard deviations since November.

My Stats

November Stats
days	mg/dl	# tests	tests/day	S.D.
7	149	89	12.7	62
14	149	182	13.0	62
30	143	402	13.4	60
60	155	799	13.3	67
90	154	1,229	13.7	68

February Stats
days	mg/dl	# tests	tests/day	S.D.
7	136	88	12.6	57
14	132	202	14.4	56
30	130	436	14.5	51
60	139	859	14.3	61
90	137	1,335	14.8	60

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She also likened my A1c to getting pregnant.
"As soon as you stop trying so hard... yadda, yadda, bullshit."

Diligent Effort + No Results = Extremely Demoralized.

I went through the holidays (and then some) completely abstaining from sweets, and for what?

Nothing.
Zero.
Zilch.
Nada.

This sucks.

There's a half gallon of ice cream in my freezer calling my name...