In the interest of getting a better understanding of the endocrinology behind diabetes, I decided this afternoon to have a poke around the web at information on hormonal glucose regulation.

Type 1 diabetes is fundamentally a disorder of glucose regulation related to the body’s inability to produce insulin. The cells of the body that produce insulin are located in the pancreas in the regions known as the “islets of Langerhans” [2]. In type-1 diabetes, these insulin-producing cells (beta-cells) are destroyed due to an autoimmune response resulting in a dramatic reduction or elimination of the body’s production of insulin.

Since there are a number of glucoregulatory hormones which increase blood glucose levels (including one produced in alpha-cells of the pancreas called glucagon), the absence of insulin leads to a state of hyperglycaemia if untreated. Chronically high levels of glucose in the bloodstream can lead to a number of complications. A lack of insulin in the bloodstream can also lead to diabetic ketoacidosis. Ketoacidosis means the pH level of the blood falls below its normal range due to the acidic effect of ketone bodies in the bloodstream. The reason for the presence of ketone bodies in the bloodstream is related to the body’s mechanisms for handling starvation.A human body requires an energy source for body metabolism. In particular, the brain requires glucose as its energy source and is unable to perform direct uptake of free fatty acids (FFAs) for use in metabolism. It also always requires glucose as an energy source. In a human undergoing starvation, insulin levels in the blood fall to low levels. The effect of this is to stimulate lipolysis in adipose tissue as part of a wider mechanism of conserving glucose. Lipolysis is the breakdown of body fat into FFAs in the bloodstream and adipose tissue is fat-storage tissue located around the body. The liver processes these FFAs into “ketone bodies” (actually carboxy acids – acetoacetate and beta-hydroxy butyrate) [5]. Ketone bodies can be used in a 50-50 ratio with glucose by the brain as an energy source. The body must carefully regulate ketone body production during starvation via the insulin:glucagon ratio during starvation as overproduction will overwhelm the blood’s pH buffer capacity resulting in ketoacidosis.

The reason for ketoacidosis in type-1 diabetes is probably becoming a little clearer. In the absence of insulin, lipolysis proceeds at a rapid rate and the liver processes FFAs into ketone bodies. Lipolysis is increased because an insulin-inhibited enzyme called lipase in adipose tissue is active in the absence of insulin. Since there is no mechanism for the body to control the insulin:glucagon ratio and thus regulate lipolysis, ketone body generation soon overcomes the blood’s pH buffer and the pH begins to fall. Ketoacidosis can lead to coma and death through disruption to metabolism.

What are the hormonal causes of hyperglycaemia experienced in untreated type-1 diabetes? I mentioned early on that there are a number of glucoregulatory hormones which cause an increase in blood glucose levels. Hormones don’t just act as activating agents though, they also act as inhibitory agents. We saw this in the example of the increased rate of lipolysis without insulin. Insulin also acts as an inhibitory agent for hepatic gluconeogenesis – the production of glucose from a substrate in the liver. Even though blood glucose concentrations are already high, the lack of insulin in the blood causes the body to break down muscle protein, convert it to alanine and send it to the liver for gluconeogenesis, further increasing blood glucose concentration [7]. Generally most other complications from diabetes are related to the flow-on effects of hyperglycaemia.

I think that’s about all the scientific jargon I can take for today. For more reading about glucoregulatory hormones, check out my first reference. It’s quite dense on the biochemical jargon. Feel free to post a comment if you want anything translated – I did study two years of biochemistry after all – might as well use it!

[1] http://spectrum.diabetesjournals.org/cgi/content/full/17/3/183 (Very useful)
[2] http://web.indstate.edu/thcme/mwking/diabetes.html
[3] http://en.wikipedia.org/wiki/Diabetes_mellitus_type_1
[4] http://en.wikipedia.org/wiki/Diabetic_ketoacidosis
[5] http://www.medbio.info/Horn/Time%203-4/homeostasis_2.htm (Very useful)
[6] http://en.wikipedia.org/wiki/Acidosis
[7] http://web.indstate.edu/thcme/mwking/gluconeogenesis.html

During my hours of productive work today, I noticed an article on smh.com.au about the death of a 33 year-old woman to paracetamol poisoning. I briefly considered how tragic this was but in typical fashion soon began wondering about the medical mechanism of paracetamol poisoning. I’d heard that it’s a particularly gruesome kind of death involving liver failure but wasn’t sure of the details. Off to the net I went!

A tiny bit of background (though you’re probably already quite familiar with paracetamol). Also known as acetaminophen, paracetamol is a condensed name derived from para-acetyl-amino-phenol. It’s an analgesic (painkiller) and antipyretic (used for fever relief). Unlike aspirin or ibuprofen, paracetamol is not an anti-inflammatory drug and is therefore more gentle on the stomach. In therapeutic doses, it is among the safest analgesics in use however the therapeutic dose is quite close to the toxic dose. A typical dose consists of 1 gram, taken no closer than 4 hours apart. Packaging usually recommends against consumption of more than 8 tablets in a 24 hour period.

While toxic doses are variable, a toxic dose after a single ingestion is 150mg/kg or approximately 7g for an adult [5]. Toxicity can occur when several smaller doses combine to this level within a 24 hour period and can occur more easily with chronic use [2]. When paracetamol is processed by the liver, a substance called NAPQI (N-acetyl-p-benzoquinone imine) is produced. This potentially harmful substance is quickly neutralised in the liver using glutathione, a liver protein with a variety of functions. However, the liver has a limited amount of glutathione and once it is depleted the result is the onset of liver failure [4]. Hepatic necrosis (death of liver cells) can also be caused by sufficiently large concentrations of NAPQI which overwhelm the liver’s ability to conjugate it with glutathione and eliminate it via the kidneys.

After an initial period of stomach upset and general malaise, poisoning sufferers experience a roughly 24 hour period of wellness before symptoms of liver failure begin to present themselves. Over a period of 3 days, symptoms progress from pain in the upper-right abdomen to jaundice, hepatic encephalopathy (brain disorder caused by liver failure) and possible death from complete organ failure. Due to its ready availability over the counter, paracetamol is sometimes used in suicide attempts by “those unaware of the prolonged timecourse, and high morbidity (likelihood of a severe or fatal outcome)” [2].

Treatment is by application of the antidote NAC (N-acetylcysteine). NAC works through a variety of mechanisms. It is a chemical precursor of glutathione which is thought to enhance the availability of glutathione to bind to NAPQI. It also acts as an antioxidant and anti-inflammatory agent which can assist in reducing the poisoning effects even when damage to the liver has been established. Treatment with NAC is most effective within 8 hours of the consumption of the toxic dose after which time its effectiveness reduces rapidly. This is due to the cascade of toxic events in the liver already having begun.

Having read all this, I’m quite surprised that (as the woman’s family barrister alleges) “despite showing “classic symptoms of paracetamol poisoning”, and blood tests showing abnormal liver function, she was treated with antacids [at Blacktown hospital] and discharged” [7]. Paracetamol is one of the most common agents involved in overdose in the US and is the number one cause of liver failure requiring transplant in Great Britain [5].

[1] http://www.pharmweb.net/pwmirror/pwy/paracetamol/chart.html
[2] http://en.wikipedia.org/wiki/Paracetamol
[3] http://www.emedicinehealth.com/acetaminophen_tylenol_poisoning/article_em.htm
[4] http://www.sciencedaily.com/releases/2002/10/021014072451.htm
[5] http://www.emedicine.com/emerg/topic819.htm
[6] http://en.wikipedia.org/wiki/Glutathione
[7] http://www.smh.com.au/news/national/headache-pills-killed-mother-court-told/2006/10/31/1162278141489.html

• Blood’s buffering capacity is around 38.5 mEq/L/pH at physiological pH levels, and is more capable of buffering in an acidic than an alkaline direction.
• 1 mEq of formic acid is 46 milligrams.
• Acidosis is clinically defined as a drop in blood pH below 7.35 (Edit: I forgot to mention, blood’s usual pH is 7.4). By those numbers above, I figure it would take about 88 milligrams of formic acid to reduce the pH of a litre of blood by this amount – remember, you’ve got around 5 litres of blood. You’d have to have over 20 times as much formic acid as is produced by the consumption of one can of artificially sweetened soft-drink. That’s a pretty big margin of safety right there. I mean, as that professor in the document I linked below says, toxicity is all about the dose.

“The adage among toxicologists is “the dose makes the poison”–vitamin
A, iron, and selenium, to name a few, are required by the body but are
toxic at too-high levels.”

So – unless someone can show how methanol harms humans in some way unrelated to the production of formic acid, I’m pretty satisfied this particular metabolic byproduct of aspartame is safe. This is consistent with empirical studies. Next, the other two! Well later, anyway. Feel free to tear down my logic or chemistry in the meantime. It’s been a loooong time since I’ve tried to figure out some of this stuff.

I’ve been messing around with the chemistry for an hour or so, but am way too out of practice to write anything sensible about it. So for now, I’m going to go with the following bits and pieces I’ve found out:

• The lowest recorded fatal dose of methanol is 6 grams. That’s 300 times the amount of methanol produced by the metabolism of one can’s worth of aspartame.
• Methanol is metabolised with a half-life of around 1.5 to 2 hours in humans at levels found in artifically sweetened drinks, fruit juices and red wine.
• A glass of tomato juice contains enough pectin to produce approximately 85mg of methanol during metabolism – as compared to apple juice (21mg) and diet coke (20mg).

Draw whatever conclusions you like from that. Perhaps when I’ve got a bit more free time I might have another stab at calculating the ability of blood to buffer the formic acid. If you feel like having a stab, here’s a journal article outlining the buffering capacity of human blood.

Oh and check out this article too, on aspartame metabolism relating directly to methanol production.

I admit, it’s not the best habit to be drinking some kind of synthetic beverage a couple of times a day. It’d probably be more healthy if I drank water instead. However, water doesn’t taste fizzy and delicious so I choose the browner, tastier option. There are several fronts on which people base their concern but certainly the most adamant opposition is due to the use of aspartame as an artificial sweetner. Here’s a quote from the FDA in 1999: “[aspartame is] one of the most thoroughly tested and studied food additives the agency has ever approved.” Just putting that out there, to begin with.

Over the next little while, I’m going to try and bust up some myths using a collection of theoretical biochemistry and citation of empirical studies. I want to debunk the toxicity of each of the first-order metabolic products of aspartame – methanol, phenylalanine and aspartic acid.

I’ve half-written and half-researched methanol thus far. I intend not only to quote the numerous studies and facts everyone else does, but also to show theoretically that the amount of methanol produced from the metabolism of aspartame is far from enough to overcome the blood’s various pH buffering mechanisms. It is metabolic acidosis which leads to the typical symptoms of methanol poisoning.

If I’m not bored after debunking aspartame, I’ll treat you to a couple of other debunkings I’ve come across – like the one about how caffeinated beverages dehydrate you.

Stay tuned! I’m on my little high-horse!

Sadly, spewing bleach all over the place tends to kill neutrophils, sending their proteiny remains out into your tissue to brighten your day. These are the things I think about when I cough up goo.