On Monday, my daily life, my career path, and my work-related goals will change substantially. You see, Friday was my last day working at an exceptional start-up here in San Diego. (I love you guys. I will miss you all!) (Parenthetical, part 2: anyone software engineers out there want to work at a fabulous, fast-moving financial data and analytics start-up? They’re hiring!) I have spent a great year and a half there, but I have decided I must now turn my eyes to other pursuits.

To be more specific, for the better part of this last year, I have been learning more and more about diabetes. After fifteen years of doing my best to ignore it, I have come to recognize that, unlike obnoxious children, it doesn’t just go away if you don’t pay attention to it, and it certainly doesn’t leave you alone. So I have been reading, learning, trying to understand this disease that affects my daily experience so much.

And here’s what I have learned, in a nutshell: I need to understand this body. This black box, this mysterious series of operations with glucose-level outputs– it is not enough for me anymore just to let it be, or even just to keep going forever, titrating insulin, measuring intake and researching new devices and hormones. Worrying about ups and downs. Throwing inputs at my body and waiting to see what it spits out on the other side.

And I get it– they’re working on a cure. For fifteen years, it’s been just around the corner. And every ten years or so we seem to hit another boom in the cure cycle– we’re almost there! I did it in a mouse! I swear.

But my suspension of disbelief can only span so many years, and I’m over it. No one will cure this for me.

So, I’ve decided to do it myself.

OK, not really, not literally– but what I mean is: I spend a large proportion of my time thinking about treating this disease– How many carbs is that? How much insulin have I taken already, and am I going up or down? What is the likelihood that we’ll find parking close versus having to walk from several blocks away? Is my sensor coming out?– maybe I should start putting some thought toward actually understanding it, how it functions in my body, and how we can cure it.

Not just idle thought; not just arbitrary, when-I-have-spare-time thought. I am a software engineer, and I’m reasonably intelligent, if I may say so myself. And I see a renaissance in drug discovery and development coming, made possible by the molecular insight and predictive power of computational biology– so that’s where I want to be: pushing the edge of science toward a cure for type 1 diabetes.

Because I know enough to know that very, very few scientific discoveries come from single, aha moments of novel inspiration, I do not view this as a binary goal (“Cure diabetes or bust!”), but rather a progression. I am an able and willing worker, and so I can only complain so long about other people not solving my problems before I have to turn the question inward. I believe the cure will come– humans have done more impressive things than cure diabetes!– and I have read about some wonderful research all over the world that continues to move us closer to this end. I want to be there, and to contribute in the most meaningful way I can to the process.

So what does this all look like in practice?

Step 1: Learn. Understand. Trace the input into my body on its route from its origin to its end, including all the molecular pathways and the folding proteins and the microbial influences along the way. And find the points of inflection, the points vulnerable to change and manipulation.

Hence my first move: on Monday, I will start as a computational biologist at a lab at UCSD. I met some great people doing interesting work around innate immunology and metabolomics, and they said they had room for another bioinformaticist to help analyze all the high-throughput sequencing data that the lab was producing. Hey, I can do that. Or rather, I can learn how to do that– I know the computational part; I may need a bit of a crash course on the biological part. So on Monday I hit the ground running (God help me), and at the end of September I will begin taking classes at UCSD simultaneously. I missed the enrollment deadline for this fall, but I will apply for next fall with transferring credits for the Bioinformatics and Systems Biology PhD program.

Come again? PhD program? Eh? Yes– I am going back to school. That’s unexpected, to some degree. It’s been a while since I’ve had to go to classes, take notes… be a student. But, what’s more: six years. Minimum. Woah. That puts the end date into my thirties. I’ve never had an end date in my thirties before.

This is a big change for me, personally, both in terms of goals and lifestyle. This means I am working with graduate student pay (eek!), and I’m working for the first time in about five years separately from my husband. This means I work in a lab– with test tubes and centrifuges and everything!– and I work in academia, where the rules are different than in industry (or so I’m told). And this means biological pathways and therapies are now the top idea in my head.

Needless to say, I’m a little bit nervous, and a lot excited.

And step 2? Well, I’ll let you know when I figure it out. In the meantime, wish me luck!

When I first formulated my plan for trying out Amylin Pharmaceutical‘s amylin agonist, Symlin, I figured the hardest supply to acquire would be a pH meter. Now, granted, I haven’t tried for the pH meter yet, so it still may prove difficult– but getting my hands on Symlin itself has certainly been an unexpected hassle.

I assumed it would be easy. Symlin! Aaron Kowalski and the Artificial Pancreas project have their sights set on it; I’ve met a host of type 1 diabetics now who use it; and, heck, I’m in Amylin’s hometown! San Diego! Certainly a large, publicly-traded company started here has a rep about town, right?

Well, my endocrinologist didn’t like the idea. The general theory in endocrinology seems to be, If it ain’t broke– don’t fix it. You can live for fifty years with middling care, so why should you try to optimize? If there’s any potential downside to a change, just leave it out! Keep on keepin’ on. Don’t rock the boat.

In more specific terms, my post-prandial excursions were not extreme enough to warrant prescribing Symlin. Without seeing numbers above 190, 200 after meals, why risk the potential for hypoglycemia from the improper dosing of a Symlin/insulin combo?

Or, as I rephrased it, if my control were worse, I could get this new tool. Keep doing well, and I get to.. well.. keep on keepin’ on. Never mind that my control is good because I eat practically the same thing every day, and I would appreciate the added flexibility that Symlin might allow. Never mind that from a biomimicry perspective, there might be a long-term benefit to having the amylin hormone in my body.

My deepest sympathies to Yossarian.

Now, I understand my doctor’s hesitation, and I don’t hold it against him. It’s not his job to optimize my care, certainly not given the risks. It’s his job to keep me within a region of good care, and taking risks to move above that would be unnecessarily dangerous and costly, especially given that he can’t be there all the time, and he can’t just assume that I know what I’m doing. So I get it.

But I am me, and I do have an interest in optimizing my care for the long term. If someone alive today is making it to one-thousand years old, I’m going for at least 125.

My doctor said he wouldn’t stop me from getting Symlin, but he couldn’t in good conscious prescribe it. So a second opinion was in order.

I set up an appointment with a second doctor– recommended by Dr. Steven Edelman, who is a documented fan of Symlin, as one who Dr. Edelman trained. I explain my desire for Symlin; I drop fancy terms like “post-prandial excursions” and “gastric emptying” to prove that I’ve done my homework and I’m not just going to hurt myself trying something I’m not familiar with. And this doctor? Not a fan of Symlin. It complicates things. Why fix what isn’t broken?

Really? I’m in San Diego! You were trained by Dr. Edelman! Amylin’s marketing people haven’t won you over yet? What are they doing all day? Why am I sitting in this office doing product marketing for Amylin?

But this doctor isn’t personally liable for my care. Any potential risks seem smaller from a distance. I ensure him I won’t do anything foolish; that I just want to try it, and if it proves too difficult or unpredictable, I will stop. So, he writes the script. I thank him, and ask him to assure my normal endocrinologist that I still love him, and hope he’s not offended.

And so the prescription is finally acquired. It only took… several weeks, two doctors, and one bout of frustrated crying to my husband.

But the story isn’t over yet: I call the Kaiser pharmacy, asking to have the Symlin mailed to me. Symlin can’t be mail-ordered; I have to pick it up at a local pharmacy.

“Oh? Why?”

“I’m not sure– is it one of those little vials? That can’t be mailed usually.”

“But I mail-order insulin all the time.”

“I’m not sure.”

Ok, fair enough. I order it at the pharmacy. It’s a special order, so it will take at least three days. Really? Have I mentioned Amylin is in San Diego? Closer to me than the pharmacy is? Do they have to manufacture each bottle when it is ordered and walk it over?

But I’m in the final stretch now, at the pharmacy, in line. And the woman behind the counter finds finds the box in the refrigerator after some searching. She walks it back to the cash register. “Oh, my!”" She says, eyebrows hitting her hairline. “Do you know how much this costs?” She actually drops the box on the floor she’s so surprised and flustered.

“Um, no.”

“Wow, this is… this is a lot! Wow.”

And now don’t I feel awkward. Why is this stranger commenting on the price of my medication? Well intentioned, no doubt, but… can we just be a little bit more estranged, please? I think you’re breaking some established social rules here.

But: $273. Ouch. For a tiny, 5 mL bottle, with only 3 milligrams of pramlintide. And that’s just my portion, a fraction of what the insurer theoretically pays. At that price, why not just buy some cocaine and call it a day? That would certainly reduce the perceived effect of post-prandial excursions.

But now I’ve got my little vial of Symlin, so I’m one step closer to figuring out what I can do with it, and whether it’s worth using. Given that I have to go in to the pharmacy to pick it up, and given that it’s apparently worth its weight in gold, it better make a noticeable difference in control, and I better find a way to administer it without additional shots.

The take home message here, though, is this: Amylin marketing needs to get its act together. Really. I have such a hard time getting Symlin, and I am a patient asking for it by name, cash in hand, in San Diego, where the drug should have a hometown advantage! And, I didn’t even know about Symlin before seeing people use it, all the way across the country in Florida. I mean, I’ve known people who work for Amylin for years now, and still until a few months ago, I thought they only did type 2 drugs!

Mr. Icahn? Carl? Give me a call. We should talk.

Please note: I am not a doctor, or a medical professional, or even a chemist. Anything I write about Symlin is based on my own research; it has not been independently verified, and is not medical advice.

If I left align my body
throw its edges
against a wall I
built inside
a membrane locking out
the memory of
excursion an up
and a down

 

Sea I am jealous
your tide mediocre
at least you
have the moon to blame

 

If I left align my body
hold it
still forehead to cement
against a cold thymus
he doesn’t recognize
me I’m pretty sure

 

Do you remember
when you remembered me
we were friends then you
grew too big maybe
too many too busy now
my teeth cut funny
angles in the sun
your eyebrows raised

 

If I left align my body
reset the roads
the routes that we
traced red and inflamed
forgetting who and why
dyeing coriander and
selling saffron
forgetting who and why
and me in the mix

 

You gave away my
lichen moss
my mold you said
nomad you nomad
don’t keep pets

 

If I left align my body
and I am straight
I am flat against
this column its white
border arm in arm
still waiting
for you
will you
come back to me
my own body
will you remember
my teeth the sun
the shape of dancing
the taste the tissue
me?

On Monday, August 9th, the Archives of Internal Medicine published a ten-year study of over ten-thousand individuals that showed that waist circumference, even independent of body mass index (BMI), is directly correlated with higher rates of death. Now, this is hardly new news, but the study, covered as it was by the Washington Post, the Associated Press, and many others, reinvigorated a question that is becoming more and more prevalent in America: what’s the deal with fat?

Why would waist circumference matter independent of BMI? Why isn’t fat in one place as good or bad as fat anywhere else?

Well, the current theory goes like this: there are many different kinds of adipose tissue (fat). The one you’re most likely to picture in your head is subcutaneous fat (I would call it “subcute” fat if I were a hipster in the metabolic world)– the fat that sits below the skin, and the fat you feel when you pinch your belly. As far as researchers can tell, subcutaneous fat isn’t the “bad” fat– the fat that causes major health problems like type 2 diabetes and cardiovascular complications. The human body, it seems, can mostly handle subcutaneous fat.

The problem occurs when subcutaneous fat is just the tip of the iceberg– and underneath the skin and the first layer of fat and the organs is visceral fat. (Now that just sounds villainous, doesn’t it?) Visceral fat, also known as abdominal fat, sits deep inside the body, packed in between organs in the body. And visceral fat screws the balance of the internal ecosystem up. How, why, and in what manner isn’t exactly clear yet– but the current picture involves the fact that adipose cells recruit macrophages– important players in the innate immune system– to the adipose tissue. These macrophages cause an inflammatory response within the body, and the delicate balance of hormones, proteins, and other cellular mechanisms within the body is thrown off-kilter. Levels of important proteins like adiponectin, leptin, and of course insulin get thrown off; the secretion patterns of cytokines, proteins that help control immune processes, changes; and when these molecular changes are followed to their ends, serious health conditions like type 2 diabetes and, implied by the recent study, death can result.

But, like I said, that’s old news. The role of visceral fat and abdominal adipose tissue has been a popular topic for researchers for years now. The reemergence of this news, though, reminded me, though, that one form of visceral fat that doesn’t make the headlines: epididymal white adipose tissue.

Now, visceral fat is the parent category of several different specific kinds of fat, including perirenal fat, which acts as a little blanket for your kidneys.

But my favorite visceral fat by far is epididymal fat. I first heard about it in a study published in Nature looking at phosphorylation in adipose tissue cells caused by agents like rosiglitazone (Avandia, for example); looking up the term, I found that epididymal adipose tissue is a very popular object of study, since the mouse and rat versions are particularly sensitive to changes in insulin and glucose levels, and are relatively easy to extract from the animals.

But, as soon as I found out what epididymal fat actually was, I couldn’t help but giggle. You see, epididymal fat is the fat that lives around the epididymis. And the epididymis? The epididymis is the tangled-up tube that lives at the end of the vas deferens and helps to transport sperm out of the testes.

In other words, many researchers are very closely analyzing mouse balls. Or, better still, mouse ball fat.

The existentialist in me laughs at the absurdity of the mental image: a whole nation, up in arms over obesity, staring intently at rat testicles to find an answer.

And the twelve-year-old girl in me? Giggles. Giggles and giggles because I read about balls in Nature, and because I just got you to listen to me talk about it!

she wrote her
poem on his wrists
love transcribed in code
a double-backed
polynucleotide beast
sealing the air
between his lungs
and his wrists
on his wrists she wrote
her love son
son I a Silverstein
tree give you all
all that I have
that I know that
I am son son
but son not that
not that son I didn’t intend
my change is my
own she said
the link in my lifeline
crushed to powder
infertile and unexpressed
you son you are not
immune to my failing
take that link elsewhere
find your father
my solitary battle I
unbequeath this love
I give this war
I keep son
it is sadness take
that apple from
you father
please she wrote
please she said
on his wrists through
his veins sealed
in code between the
folds of infant skin.

The diabetic information superhighway has been trafficked lately by news of GlaxoSmithKline’s Avandia, and the recent FDA declaration that the once-promising drug may be more dangerous than previously thought, and may substantially increase the risk of heart problems for patients.

Concern about new drugs is hardly novel, but amidst all this recent news, I can’t help but consider the potentially unforeseen side effects of avant-garde therapeutic agents as I read about them.

Take 11β-HSD1 inhibitors, for example. These guys are pretty cool; a number of pharmaceutical companies, including Merck, Pfizer, Amgen, and Incyte, have formulations of these 11β-hydroxysteroid dehydrogenase type 1 inhibitors in phase I and II clinical trials, with the hope of adding a new, salable tool to the type 2 diabetic’s toolbox.

Here’s how it works: throughout the course of the day, the adrenal gland releases the hormone cortisol, either due to normal circadian (daily) and ultradian (hourly) rhythms, or in reaction to stress. Cortisol is an important stress hormone, but many of its effects, while good in a fight-or-flight scenario, are bad over time in terms of diabetes and obesity: cortisol increases glucose production and release in the liver; increases appetite in anticipation of any necessary reaction to the stress-causing situation; and alters metabolic processing such that fat is preferentially stored in the central abdominal region. So, for diabetics, this means stored glucose directly increases blood sugar, new calories are ingested and increase both blood sugar and weight, and, to top it all off, the new weight tends to be the “bad,” visceral, disease-causing weight.

There are a couple of therapeutically important pit-stops for cortisol throughout this process, though; the active hormone cortisol can be converted in the kidney, colon, and some other tissues into the inactive molecule cortisone. The enzyme 11β-HSD2 aids this conversion, and allows cortisol to be stored out of the bloodstream.

The other side of the equation is controlled by 11β-HSD1, which converts the stored cortisone back into cortisol in the liver, fat tissue, the brain, and other tissues. This conversion and release happens in time with the adrenal gland and natural rhythms, and therefore contributes to the disadvantageous effects of circulating cortisol.

11β-HSD1 inhibitors, then, aim to disrupt this pathway; restrict the ability of 11β-HSD1 to convert cortisone into cortisol and you decrease the amount of circulating cortisol, thereby reducing the amount of glucose released in the liver and slowing the increase of appetite and unfortunate storage of visceral fat.

Or so the theory goes. In light of the recent Avandia news, I give not one but two ears to those who are inclined to raise concerns, as Erika Harno and Anne White do in their paper in Trends in Endocrinology and Metabolism, “Will treating diabetes with 11β-HSD1 inhibitors affect the HPA-axis?” Their particular concern: if you artificially reduce the level of circulating cortisol by means of the 11β-HSD1 gateway, will the adrenal gland just overcompensate, activating the hypothalamic-pituitary-adrenal (HPA) axis, and producing extra cortisol for release, thereby defeating the whole point of the inhibitors? Plus, if the HPA-axis all starts working overtime to compensate for the lower detected levels of cortisol, cortisol wouldn’t be the only hormone overproduced. THe adrenal gland might also simultaneously produce excess adrenal androgens, which, at high levels, have been known to cause osteoporosis, hypertension, poly cystic ovarian syndrome, hirsutism (think female beards!), and a number of other nasty-sounding complications.

In their review, Harno and White analyze a number of studies that have been done in mice and humans, hoping to determine the likelihood that 11β-HSD1 inhibitors would cause such adverse complications. They first thing they found was that measuring and adequately evaluating cortisol levels is extremely difficult, given the natural hourly fluctuation, the fact that the stress on subjects during observation often changes the patterning of cortisol release, and the deficiency in rodents of the adrenal androgens that are also of interest.

Despite these difficulties, Harno and White were able to gain some insight from studies of mice which were engineered to lack the enzyme 11β-HSD1 entirely. THe complete deletion of 11β-HSD1 in mice had, overall, inconclusively minimal effects on adrenal action. Mice of a certain genetic background saw a 70% increase in the weight of the adrenal gland, implying increased adrenal activity, but mice of another genetic background saw only a 20% increase, which, given the 46% change in adrenal weight throughout the course of a normal mouse day, is not too jarring.

Looking at the amount of cortisol secreted in the 11β-HSD1 knockout mice, researchers found again inconclusiveness; mice from the first genetic type had a higher base level of cortisol, but peak levels remained mostly unchanged. These knockout mice also took longer to return to base levels of cortisol after stress. However, the 11β-HSD1 knockout mice from the other genetic typing remained largely unchanged, retaining normal levels and rates of cortisol secretion.

Points are added in to the “Pro” column of 11β-HSD1 inhibitors by studies of the inhibitor compounds themselves. In a Merck study of the new drug’s effects on mice and rats, circulating levels of the precursor and co-marker of cortisol were not increased, implying the hypothalamus was not inducing overaction of the adrenal gland. Similarly, the human trials done thus far by drug companies indicate that the hormonal precursors to adrenal cortisol production are not upregulated, and the HPA axis remains unperturbed.

In the end, then, Harno and White conclude that there is a pretty good chance that 11β-HSD1 inhibitors will not increase the release of cortisol from thim adrenal gland. In other words, 11β-HSD1 inhibitors are probably good additions to the diabetic toolbox.

But, as we saw with Avandia and as we see with all the “likely”s and “maybe”s that come with the manipulation of molecular pathways in the body, this is a risky endeavor. Harno and White propose some potential ways to reduce the risk of upregulating the adrenal gland– using tissue-specific 11β-HSD1 inhibitors, for example, to focus on tissues that are shown to have less of an effect on the feedback loop up to the adrenal gland; or reducing cortisol levels only during certain times of the day, at advantageous places within the natural circadian rhythm– but they also point out that more study of the cortisol pathway is needed, especially in long-term clinical trials on human patients. It seems clear to me, too, that variation in patient responses should be analyzed in terms of genetic profiles, given the differing responses in genetically disparate mouse models.

And all this is possible. And all this is quite potentially very good. But we should not forget that we are pioneers in a New World, full of both promise (think John Winthrop’s City on a Hill) and danger (think Roanoke).

So this was weird:

I wake up from a dream at about 12:30 AM. My continuous glucose monitor (CGM), which I had inserted and calibrated once before going to bed, showed a blood sugar measurement of 99 mg/dL. Perfect, I think to myself as I stumble out of bed toward the bathroom. I measure my blood sugar on the OneTouch UltraLink I keep on the bathroom counter so that I can enter the second calibration point into the CGM and not have to wake up again later in the night.

56. Eh? I don’t feel 56. I would feel it if I were that low, right? I should feel it if I were that low, at least.

I measure again on the UltraLink, to double-check, knowing that glucose meters can be inaccurate and sometimes way off for whatever reason (Something on my hands? Temperature? Contaminated strip?). Again, 56. Exactly the same.

So, despite not feeling low, I eat eight grams of corrective carbohydrates. As I’m doing so, I have woken up enough to realize, wait, I really don’t feel low. I don’t even feel like I feel after I’m low and don’t really feel low. I just feel normal.

About two minutes after my original glucose meter check now, not even close to enough time for the corrective carbohydrates to have taken effect, I measure my blood sugar on my other meter, a OneTouch Mini I keep in my purse. 95 mg/dL.

Oh. Really? No, but, really? I try again on the Mini. 93. OK; that, plus the CGM, plus how I feel, indicates that the 56 was probably wrong.

But wrong twice? And wrong to exactly the same degree twice? I’ve seen one really far off measurement at a time, or two really far off measurements that were also very different from each other. But consistent inaccuracy? That’s new. And frustrating– I accept that the meter will be inaccurate sometimes, but I would prefer the inaccuracies to be obvious, or to at the very least not give me two misleading measurements in a row so as to imply a statistically significant likelihood that the measurements are indeed correct!

I measured myself again on the UltraLink just for good measure. 83 mg/dL.

So what were those two 56 data points? I don’t know. The meter’s fault? The strip’s? Mine? Random chance? Sadly, I don’t know.

Working in software, I find that sometimes a mysterious problem arises that, after much debugging, proves to not be a software issue, but a hardware one– the hard-drive is making clicking noises, and is failing; or the server’s random-number generator broke, and so there is insufficient randomness available for applications on the system. In those times, I often have a sense that, well, the theory and the application code was perfect; it’s reality that keeps getting in the way. Literal, physical, atoms-in-space-and-time reality!

As a diabetic, meter inaccuracy, insulin pump clogs, and CGM sensor failures give me a very similar sense– in theory, everything works in perfect concert. Reality, though, is much rougher around the edges, and it is at this interface between concept and reality that I can get frustrated and hurt if I don’t keep a firm hold on the fact that, yeah, it happens, and therefore it is in my best interest to keep vigilant, reasonable, and flexible as new data comes in.

Luckily, in this particular collision with reality, all I lost was about five minutes of sleep.

Where I Left Off
In the last installment of my symlin saga, I had found that Symlin, Amlyn Pharmaceutical‘s synthetic amylin, helped slow gastric emptying and reduce post-prandial spikes. I also found that Symlin had to be injected subcutaneously, either with the Symlin Pen or from a second pump, and that allegedly, Symlin and insulin cannot be mixed. This segregationist statute comes from the fact that Symlin is manufactured at a pH of 4.0, and insulin runs at a pH of about 7.0 – 7.5. And, insulin being as finicky as it is, lowering the pH of of insulin too close to the isoelectric point drastically increases the risk that the insulin will precipitate and be insoluble, clogging up pumps and failing to absorb into the bloodstream.

Where I’m Going
But: Novolog, Novo Nordisk’s rapid-acting insulin, maintains a high degree of solubility even with a pH in the mid sixes. So the question that’s up next is, can the pH of Symlin be raised sufficiently such that the two solutions can remain soluble and effective while mixed in a single pump chamber?

The pH of Symlin
The first part of determining whether it is safe to alter the pH of Symlin is to determine why it is manufactured with such a low pH to begin with. Most insulins are made with a pH in the 7 range to ensure maximal solubility; is the same true for Symlin in the 4 range?

According to Amylin and research reported in “Kinetics of Pramlintide Degradation in Aqueous Solution as a Function of Temperature and pH,” the standard pH of Symlin has less to do with solubility of the peptide, and more to do with degradation over time. The isoelectric point of Symlin, as I mentioned in the last installment, is above 10.5, so Symlin has a lot of upward mobility before the molecules lose their charge and therefore motility.

However, the Symlin solution naturally degrades and becomes less potent over time, and this degradation happens at a rate that depends heavily on both storage temperature and pH. This particular study found that at a pH of 4.0, Symlin maintains potency for about two years at 5ºC (i.e., in a refrigerator) and for about one month at 25ºC (i.e., at room temperature). In contrast, at a pH of 5.0, the Symlin solution was found to degrade about three times faster. Similar results were published in a patent held by Amylin, in which the pH of 4.0 is selected as the most stable formulation of the solution, as, as the graph to the right shows, the rate of reaction increases rapidly with increasing pH.

But What About Me?
Clearly, for sale and commercialization of Symlin, long shelf life and solution stability is important. But I only need to the Symlin to maintain potency for as long as it lives in my pump plus the small amount of time it takes upon entering my body to be absorbed. So, thirty days at room temperature is probably more than I need. I could do with a week at room temperature, and that would still give me some wiggle room.

So let’s say– let’s say I mixed my Novolog and Symlin in a ratio that would be appropriate for my bolusing needs generally (that, of course, I would have to determine…), and added a weak base to raise the final pH of the solution to somewhere in the 6.5 – 7.0 range. Let’s say. Would I be able to get at least a week of solubility out of the insulin? And a week of potency out of the Symlin?

It certainly seems possible. And the reward if it works– the ability to use Symlin without separate injections or a second pump– is indeed tempting, enough that I will have to run at least a few tests to determine the feasibility of this.

Tests? Like, Human Tests?
Eventually, if everything goes as planned, I will have to try out any resulting mixture on myself, since I’m pretty sure it’s not legal to run ad hoc lab tests on pet store mice. That said, I’m certainly not going to just mix insulin and Symlin, load up my pump, and see what happens; a few test-tube trials are in order first.

My plan is to acquire some Symlin, some sodium acetate trihydrate (the weak base used to buffer and modify the pH of Symlin, according to Amylin’s documentation; fortunately, this is a standard sodium acetate, and even available from Amazon.com), and a pH meter. The pH meter may be a bit tricky, since meters with a decent level of accuracy are at least $100 (perhaps someone I know locally will have one to spare?). After I collect these materials, I will be able to mix and monitor the pH of various combinations and ratios.

I’ll keep my mixtures around for a while, and see if I get any obvious precipitation, clouding, or other corruption. Exact solubility and potency of each solution will be much harder to measure given my lack of lab equipment (anyone have a chromatograph I can borrow?), but… well… I’ll figure that one out when I get there.

Assuming any formulation of my mixture appears to maintain clarity for at least a week, and assuming I don’t get cold feet, I can consider moving on to stage two, where I become my own lab rat.

(Let me pause for a moment here and say: if you are a medical professional, Amylin employee, Novo Nordisk employee, or other knowledgeable party, and have reason to believe I might do some serious harm to myself, please, please, let me know.)

Why Hasn’t Anyone Else Done This Yet?
Now, that plan sounds pretty fun to me, but I must ask: if it’s so easy, why hasn’t someone done this? Why isn’t Amylin or Novo Nordisk all over this, marketing a mixable formulation? I have far too much faith in the power of the free market, human innovation, scientific inquiry, etc. etc. etc. to believe that no one’s thought of selling a mixable formulation!

And indeed, after some research, I found that as I suspected, Amylin and others are indeed all over this problem. On top of the studies mentioned earlier on mixing pramlintide and insulin, and on formulations of Symlin at different pHs, I came across a few patents that reassured me that my home-brew method will likely be made obsolete soon enough. Amylin Pharmaceuticals has a number of patents covering different formulations of pramlintide, one of which speaks specifically about solid formulations for pills, polymerized formulations for nasal or pulmonary delivery, and, most interesting for my purposes, formulations that were mixed with insulin and tested for solubility and potency. According to the tests cited in the patent, pramlintide was mixed with Regular insulin and alsp 70/30 Regular/NPH combinations. The resultant solutions had pHs in the upper-six to seven range, and, according to the cited tests, maintained insulin solubility for up to 33 days at 30[0][C]. Not bad! And, very promising for my upcoming home trials.

The obvious question is, why isn’t this on the market yet? And that I must admit I do not know; I don’t know enough about the pharmaceutical pipeline and FDA regulations to know what it takes for an idea, tests, and a patent to come to the shelves. (Any Amylin employees out there want to weigh in?)

More promising still, Amylin is not the only player in this game. In addition to patent applications for dual-chamber pumps, I came across a very interesting series of applications from Novo Nordisk for their own proprietary amylin agonist, and formulations based upon it. According to the application, their version of the peptide is more stable than Amylin’s version, with a longer action time in the body, and also reduced chance of degradation and fibrillation at higher pH levels. This allows for more easy mising with Novo Nordisk’s own insulins, and thus is a very promising prospect for us diabetics. The applications are from early 2009; so I’ll keep my eye out, but I certainly won’t hold my breath, given that the Patent Office and the FDA are two notoriously slow regulatory agencies standing in the way of any new drug.

To Be Continued
So, clearly, the free market is out there, working to create the next drug I will happily purchase, but until then, it looks like I’m on my own. I admit, part of me isn’t really disappointed; I’m pretty excited about my home-chemistry project. It’s been a while since I’ve gotten to play with pH buffering!

And One Last, Really Interesting but Only Tangentially Related Addendum
In the course of my patent search, I came across one other Amylin patent for Symlin uses that I found particularly notable: “Amylin agonist for treating depression, anxiety disorder and schizophrenia.” Apparently, Amylin Pharmaceuticals has found that

amylin is shown to share properties of anxiolytic, antidepressant, and antipsychotic agents in behavioral testing. Thus, it has now been discovered that amylin and amylin agonists may have the surprising ability to treat psychiatric disorders. Psychiatric disorders that can be treated include mood disorders, anxiety disorders, schizophrenia and other psychotic disorders, substance-related disorders, sleep disorders, somatoform disorders, and eating disorders. These compounds may be particularly effective in treating psychiatric disorders that have elements of metabolic disturbances, e.g., eating disorders, or in treating patients with a psychiatric disorder or those with a psychiatric disorder and who also suffer from a metabolic disturbance.

Allegedly, according to a number of animal tests that Amylin has done, amylin and amylin agonists like Symlin have been shown to reduce anxiety and stress, perhaps by modulating the corticotropin-releasing factor and glucocorticoid pathways. The pathways proposed in the patent are known to play a role in the intricate and delicate interactions of the hormones of the brain and endocrine system, stopping along the way at the hypothalamus and metabolic processing. Plus, unlike other psychiatric drugs out there, pramlintide tends to cause weight loss rather than weight gain, so that would be one less side effect to worry about.

Clearly, this has not been proven effective or commercialized yet, but it’s an interesting idea and an interesting read, especially if you, like me, are fascinated by the interdependencies of metabolism, endocrine hormones, inflammation, and various incarnations of depression and anxiety.

Please note: I am not a doctor, or a medical professional, or even a chemist. The above is intended to be purely informational, and is based on my own research; it has not been independently verified, and is not medical advice.

I know what you’re thinking.

Please, for the love of God, stop coughing.

I know you’re thinking it because I’m thinking it too. And maybe the fact that I assume you’re thinking that says more about me and my self-centric view of the world or my projection or my fears or something, but maybe I don’t care.

I care about very little of that higher-order stuff right now. I just want to stop coughing. For the love of God.

6 days and counting now. It’s no longer a productive cough, or so I have determined from WebMD. It’s just an awful, painful, grating cough.

When I was younger our neighbors remodeled, restuccoed, and they sandblasted their walls. It’s like that.

Whooping cough. Bronchitis. Tuberculosis.

Please, dear body, just stop coughing. There’s no foreign entity left to remove. I promise. It’s just my immune system overreacting, refusing to let me be. Again. Please, just leave me alone.

Please, stop coughing.

I don’t think I’ve ever used up so many sick days in a row at work. And when I go back, I can’t even really work, because I’m trying so hard to stiffen my throat and not cough, not release this horrid illness on my colleagues.

How do you get rid of a cough like this? Steroids? Botox? Amputation?

I can’t sleep at night, which doesn’t help. After three hours of lying awake, breaking into fits or coughing, I finally drifted off. But then I was up again, every half-hour, punctuating coughs with profanity. Or maybe it was punctuating breaths with coughs.

And so I go to the doctor. Take a deep breath. Blow in this.

It’s not whooping cough. Not bronchitis. Not a sinus infection, or even bacterial.

It’s just viral. A cold. With a lingering witch of a cough.

“How long could it last?” I ask.

“Could be up to two months,” the doctor replies.

Oh no. Please, no.

Isn’t there something I can do? Something I can take? Nope. It’s viral. Wait it out. Put some tussin on it.

And as if that weren’t bad enough: I leave the doctor. I continue in my vain attempts to suppress this cough. I realize the discharge in my eye is getting worse. My eye is all pink and inflamed.

I have pinkeye.

Really? No, but really? Pinkeye?

Pinkeye, which can follow a cold, especially one marked by upper respiratory symptoms.

Oh for crying out loud. Pinkeye. Like in grade school. But without Nickelodeon and no-school-days on the couch, with my mom taking care of me.

Pinkeye, and an evil cough. Incessant, painful, abrasive cough.

I want my mommy.

P.S. DiabeticTussin! Who knew. Now that makes me laugh. Until I take it. And then I cringe and grimace, because that stuff tastes horrid. But it’s allegedly safe for diabetics. But, ew. No wonder they sweeten the normal stuff.

One of the biggest takeaways for me from the ADA Scientific Sessions was that I needed to learn about the magic drug everyone was talking about, Symlin. So, over the past week, I’ve been doing some reading, and this is what I’ve found:

Symlin (also known by the generic name pramlintide acetate) is Amylin Pharmaceutical‘s patented and commercially available synthetic analog of the naturally occurring endocrine hormone amylin.

Amylin is circulated throughout the body and helps to control post-meal glucose levels by impeding the release of glucagon from the liver and simultaneously slowing the rate of gastric emptying and subsequent intestinal uptake of carbohydrates. In short, amylin works in tandem with insulin to mitigate the effects of glucose that is ingested.

This close concert of amylin and insulin, however, does not stop with their joint functionality: amylin is made by the beta cells in the pancreas, and secreted in conjunction with insulin. And to all of us familiar with type 1 diabetes, this is where we say, “Alas and avast,” because, sadly, my body makes neither insulin nor amylin.

So that’s where Symlin comes in. Symlin has been available commercially for a number of years now, and an increasing number of type 1 and type 2 diabetics are augmenting their insulin-replacement-therapy with Symlin. The use of both hormones has been shown to reduce postprandial glucose spikes and reduce HbA1c measurements overall for patients, implying better glucose control.

I like this idea, and I want me some Symlin to replace my amylin.

But there’s a problem. Like insulin, Symlin can’t be taken orally. And it can’t be mixed with insulin in its synthetic formulation. So taking Symlin means either separate injections using something like Amylin Pharmaceutical’s Symlin Pen, or wearing a second pump to inject the hormone subcutaneously.

Some people I’ve spoken to say Symlin pumps work better, as they mimic more closely the natural flow of amylin throughout the body. But that would mean adding another hole to my already assailed body, and, frankly, I’m running out of space to stick things.

On the other hand, I’m not keen about the idea of injections either. Been there, done that, moved on. The thought of carrying around pen needles, and having to take shots before meals again… ugh. And ow.

So I’m back to square one, it seems. So much for Symlin.

Pause. Wait. Why isn’t anyone saying anything? This is where you’re supposed to say, “What, and give up that easily?”

And I respond, “Wait a minute, you’re right. Where’s my inner rebel when I need her?”

Take a look a few paragraphs up. Here’s what I said: “But there’s a problem. Like insulin, Symlin can’t be taken orally. And it can’t be mixed with insulin in its synthetic formulation.”

The skeptic in you should have complained at that point. You should have said, “Well, who says you can’t take it orally? Who says you can’t mix them?”

But that’s OK; I’ll say it for the both of us: Who says Symlin has to be such a pain-in-the-abdomen?

Claim 1: Symlin must be injected, and can’t be taken orally.
This one I can’t really get around; like insulin, Symlin needs to be circulating throughout the bloodstream in order to work properly, and science has not yet found a reliable way with either insulin or amylin to create a synthetic, oral version for type 1 diabetics. The complexities of digesting a drug that must in turn be used to monitor and manage the act of digestion have not yet been surmounted by the major drug players yet. Bummer.

Claim 2: Symlin and insulin cannot be mixed.
This claim gives us a bit more wiggle room. I’m not going to try drinking insulin or Symlin, but mixing them seems like it _should_ be an option, right? Figure out a standard ratio that works for me, include both in the pump reservoir, and use as if they were being simultaneously secreted by my stand-in pump pancreas?

So what’s the problem? People say the two shouldn’t be mixed. But who trusts an internet forum, right? Well, the prescribing information for Symlin says the two should not be mixed as well. Hm. But who trusts a drug company, right?

I look deeper, and find an American Journal of Health-System Pharmacy article from April 2005 called “Properties of pramlintide and insulin upon mixing.” Perfect. Written by a number of clinicians and directors at Amylin, this paper makes clear the issue with mixing Symlin and insulin:

“Pramlintide and insulin formulations interact primarily through their buffering systems. Most insulins have an isoelectric point in the range of 5–6 and are formulated at a pH of around 7. Pramlintide has an isoelectric point of >10.5 and is formulated at a pH of 4. The interaction of pramlintide and insulin formulations at different pHs (with different buffering capacities) potentially could result in precipitation of soluble insulin components or solubilization of crystalline insulin components. In vitro studies with pramlintide and short- and long- acting insulin formulations found substantial variability in insulin solubility when various quantities of insulin were mixed with fixed quantities of pramlintide.” (p. 821)

Darn. What does this mean? Synthetic insulin formulations, with the exception the long-lasting insulin glargine, like to live at a pH of about 7.4. This is because the isoelectric point of these synthetic insulins is about 5.4. The isoelectric point is the point at which the molecules of insulin in solution have no electric charge; at and near the isoelectric point, then, the insulin molecules are no longer active and ionic, and they become very stable. This stability, unfortunately, means that the insulin precipitates; the active insulin molecules bind and form a powder-like substance that falls out of the solution. The insulin molecules, no longer dissolved and distributed, cannot be absorbed or used by the body, and so the insulin is at worst useless and at best unpredictable.

By keeping insulin at a pH in the 7.0 – 8.0 range, then, manufacturers can ensure that that the insulin will not acidify and precipitate out of solution. This, clearly, is important to the potency and usefulness of insulin, but it makes mixing insulin with another solution that has a pH of 4.0 very questionable indeed.

In the 2005 study, mixing the two within a syringe that was used immediately seemed OK, and did not seem to decrease the solubility and absorption rates of the insulin, but the authors caution that the study did not test the many insulin types (just Regular and long-acting insulin), and that in vitro studies imply precipitation might occur, and that insulin’s pharmacokinetic properties are so variable according to person and environment that they can’t say for sure that the slightly longer time-to-max-effect of insulin in some of the trials was not caused by the mixing of insulin and Symlin (p. 821).

Plus, the study was conducted using syringe injections, which present a different set of problems than my hope of mixing the two in an insulin pump. The syringe concoction only has to last as long as it takes to inject and be absorbed by the body; mixing the two in a pump requires that the insulin remain soluble and uncorrupted for several days in the reservoir. Additionally, even a small amount of precipitation can have large effects in a pump, since the precipitated insulin can clog up tubing and infusion sites. In fact, though the prescribing information for both Humalog and Novolog says that “Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH,” they also specifically warn that the insulin “should not be diluted or mixed with any other insulin when used in an external insulin pump.”

Vive la resistance!
So, as many of us know from experience, insulin is a finicky little chemical, and does not like to have its pH changed. But, importantly, not all insulins are created equal; the pH sensitivity of different insulin formulations varies, according to the 2005 paper “Precipitation of Insulin Products Used for Continuous Subcutaneous Insulin Infusion.” (Note: this paper is written by chemists at Novo Nordisk; take it with a grain of salt if that’s your style.) The study compared the relative amount of precipitation at varying pHs for insulin aspart (Novolog), insulin lispro (Humalog), and Regular insulin. As you can see in the chart they produced, the solubility curve on each type of insulin is very steep; that is, there is a region in which they are not soluble at all, a region in which they are nearly entirely soluble, and then a very short region of transition between the two where the insulin is variably soluble. And, Novolog, Novo Nordisk’s own rapid-acting insulin, doesn’t start precipitating until a pH as low as about 6.0.

And here I run to the refrigerator, and check which brand of insulin I am issued by Kaiser. Novo Nordisk Novolog. Sweet. That gives me some leeway. I don’t like the idea of messing with the temperamental insulin’s pH, but if I’ve got from the neutral pH of 7.2 – 7.6 all the way down to the minimal allowable pH of 6.0, then perhaps, if I can bring up the pH of Symlin to between 6.0 and 7.0, then I can safely mix them.

So– the next set of questions– why is Symlin kept at such an acidic pH? Can it be safely kicked up a notch or two? What would that require?

I have begun to investigate these questions, and the preliminary answers are promising; but there’s more research to do before I advance to step two: Fun with Home Chemistry! And, if all goes well, step three: Karmel becomes her own lab rat! So, we’ll continue this conversation in the next installment of this Symlin saga.

Please note: I am not a doctor, or a medical professional, or even a chemist. The above is intended to be purely informational, and is based on my own research; it has not been independently verified, and is not medical advice.