Sunday, March 15, 2015

Insulin detemir (3)

I think it is quite clear how I view insulin detemir. Kindke was unable to resist finding the link to the abstract with the diametrically opposing view. I'll just stick both links in here to keep them together, so people can look at both research findings and draw their own conclusions.

Insulin detemir is not transported across the blood-brain barrier.


Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin.

I think it is reasonable to assume that at least one of these two papers is factually incorrect.

If you search on Begg and Woods as co-authors you will find papers redolent with words like "reward", "hedonic" and "dopamine".  That's Begg and Woods, if anyone can stomach it.

I was, in my normal confirmation biased way, much more interested in the sort of work produced by Banks, Morley and/or Mooradian. These folks appear to be scientists rather than psychiatrists and they have some great publications. They include major work on the blood brain barrier, leptin transport, insulin transport, leptin resistance, gerontology, diabetes, antioxidants, the list goes on and on.

Here are a few little gems I particularly enjoyed in abstract form which might be worth a mention.

I dislike antioxidants. This is quite interesting from Banks and Morley:

Effect of alpha-lipoic acid on memory, oxidation, and lifespan in SAMP8 mice.

Alpha lipoic acid is a mitochondrial component present in normal cells and is available in mega doses as a supplement. It's a serious and deeply mitochondrial penetrative antioxidant. It helps a lot with diabetic neuropathic pain. SAMP8 mice are oddities which have been bred for early onset senility and memory loss. They are used (probably totally inappropriately) for Alzheimers Disease research. Treating them with antioxidants improves their memory performance. You might think this is a good idea. The cost is measured by a shortening of their life as elderly SAMP8 mice from 34 weeks to 20 weeks after start of treatment (started at 11 months of age). This may or may not be a good thing if you are an SAMP8 mouse (death might be a release). How it applies to a person managing their diabetic neuropathy or trying to delay the progression of their Alzheimers Disease is fascinating and slightly worrisome. I'll stick to a life based around beta oxidation, normglycaemia and a little superoxide signalling, stuff the antioxidants. Last sentence of the abstract "These findings are similar to studies using other types of antioxidants". Sweet, provided you avoid sugar. And antioxidants.

The next snippet includes Morley and Mooradian as authors and relates to making your blood sweet,  literally this time, using intravenous glucose:

Mechanism of pain in diabetic peripheral neuropathy. Effect of glucose on pain perception in humans.

Simple hyperglycaemia in a normal person reduces the threshold for feeling pain. It reduces the severity of pain you can tolerate. This applies to a normal human being on a glucose infusion or a diabetic person on a diet designed by a diabetologist, no glucose infusion needed. If hyperglycaemia makes a tolerable stimulus in to a painful experience and makes just bearable pain become unbearable, how many chronic pain syndromes would go in to remission with sustained normoglycaemia? Fat phobia makes this question currently un-answerable. The paper was published in 1984. Does anyone fancy having a gangrenous foot amputated for diabetic complications and waking up on a dextrose saline infusion in recovery? And then being offered the "diabetes diet" on the post op ward?

Banks and Morley were also instrumental in the generation of data for the concept that trigycerides in plasma induce leptin resistance at the blood brain barrier, a few years old now but still quite a useful concept:

Triglycerides induce leptin resistance at the blood-brain barrier.

I find the cream bashing in this last paper a little distasteful and I have to admit that Banks appears to be unaware that high saturated fat low carbohydrate diets are THE way to reduce fasting trigycerides in real people. Can't have everything I suppose. But even if the cream effect applies to people, who cares if I am leptin resistant with a full stomach provided leptin will work perfectly well in the post absorptive (low triglyceride) period? I am a human, not a mouse. I ate a high fat meal without sugar last night, ergo I'm not hungry today. Low trigs equal leptin sensitivity...

I'll call a halt there. Life is full of interesting snippets which make sense. They usually come from the sort of people who say insulin detemir does not cross the blood brain barrier.



Ilaine Upton said...

The term "antioxidant" bemuses me. I think of things you use to keep your car and other metal objects in your life from rusting out. Wax, paint and varnish to inhibit rust. Solvents to dissolve rust and other oxidation. Brass cleaner. Silver tarnish remover. And then there's lemon juice to keep apples and artichokes from turning brown. "Take this, it's an antioxidant." Err, why?

I take R-ALA because I have diabetic neuropathy. I have no idea how it works, or really, if it does (it does seem to work), but I doubt that the reason is merely that "it's an antioxidant." Something more specific, surely.

Will it shorten my life? Hmm. If it makes me less likely to get a diabetic foot wound that won't heal, it may lengthen my life.

Guillermo Fernandez said...

Hi Peter, very nice post series as usual. With regard to alpha lipoic, I think it`s a good example on how something leading to improvements in one health aspect may be well worsening others; in this case improving memory and glutathione levels at the cost of shortening life span. Although we can discuss about life quality during ageing and the different tradeoffs on that, I think many of us are looking for both (quality AND life extension) when taking our own daily decisions, such as taking antioxidants. You mention that you stick to a life based around beta oxidation, normoglycaemia and a little superoxide signaling (as many of us! ); my question would be what would you look at to ensure yourself that decision is actually working? What would be your minimum set of preferred health key performance indicators to monitor? Fasting blood glucose? Hb1c? Blood pressure? Etc…….Would you include blood lipids on the panel? I think being holistic and not “treating a lab number” is important but also think you should monitor something else than simply “feeling better” to be preventive. I would like to read your thoughts on what would you include on the list and why (some kind of mechanistic reason to monitor that). I know the interpretation of such panel would require a careful analysis and many discussions may arise on the conclusions on such a list but I think it would be nice to have something on that too, whenever you have time to post about it.
Your second post on insulin detemir was just brilliant, I keep admiring the way you are able to connect different concepts in one single explanation, thanks for keep sharing your thoughts!

Kindke said...

ive seen many papers that are at odds with each other on different topics, seems to be a common theme that agenda dominates "science" research these days.

btw i dont think that trigs blocking leptin phenomenon is at all useful. leptin resistance is not the cause of obesity and insulin resistance is not the cause of diabetes.

infact Friedman himself showed that hyperleptinemia was the cause of leptin resistance.

i expect the reason obese people have hyperleptinemia is purely because of hyperinsulinemia, insulin stimulates leptin.

also peter dont know if you saw this but incase your interested, ancient hormone secreted from GI tract in fasting suppresses insulin secretion, "limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity."

Peter said...

Hi Ilaine, it's also worth noting that I know nothing about why SAMP8 age rapidly. And of course, I doubt whether we know too much about why ALA helps with diabetic neuropathy either. Life is full of unanswerable questions... Severe pain or reduced pain? What's the cost of the pain reduction? A hard one to call.

Guilliermo, it's very, very difficult to know what to measure. Even HbA1c +/- insulin are rather hard to interpret in the context of fat based, low carb metabolism. My main problem with lipids is that they have been wrong so badly, right from the start, that I'm loathe to give them any sort of validity by worrying about them. Or use my time following trails which lead to subjects such as oxidised cholesterol, the manipulation of which probably requires a low carbohydrate high saturated fat diet...

Kindke, yes, lots of conflicting research, I just like the direct contrast here, even in the titles. I'd not heard of limostatin or neuromedin U, but they are clearly interesting molecules. Looking at some of the reviews I tend to think, on first glance, that they resemble FIAF without the bacterial component. And another facet on why you need to carb load if you are a LCer about to take an OGTT....


Amy B. said...

Thanks for the news about alpha-lipoic acid. I'm writing a book about low-carb & ketogenic diets for Alzheimer's, and I recommend lipoic acid as, you guessed it, a great antioxidant for the brain. Might have to revise that...

Really interesting stuff on a personal level: after doing some research on lipoic acid, I decided to try it out, myself. Took it on 3 separate occasions, and each time, it turned me into an emotional wreck/basketcase. I'm not normally sensitive, or a crier, but man, that stuff threw me for a loop. It's the only thing that was different, and the only thing I've been able to connect those episodes to. (For the record, it was Designs for health's Lipoic Acid Supreme, which has 300mg ALA, plus 4mg biotin (which is a ton), and 500mg taurine, so I can't say whether it was the ALA alone, or the interaction/combination with the other ingredients.

August said...

I've tried R-ALA and found it, like many of these compounds that are supposed to improve blood glucose make me hungry and irritable. Berberine did this too. It seems to me insulin resistance- whether pathological or simply as a result of a low carb diet- is a symptom and the sort of thing you just go and fiddle with with a drug.

August said...


I meant to say IR shouldn't be fiddled with via a drug, but that whatever underlying issue is causing the IR should be addressed instead.

Puddleg said...

Fundamentally the main reason I stick with the LCHF diet is the freedom from pain.
Go to bed, legs don't hurt. Wake up in morning, joints don't hurt. Have a migraine occasionally but head doesn't hurt anymore. Eat food, guts don't hurt.
Hurt myself, doesn't hurt for long.
Amazing that people put up with and medicate more or less unsuccessfully, dangerously, or expensively, with drugs and supplements pain that can be turned right down by limiting carbs.

Alpha-lipoic acid - this basically is the rotor arm in the TCA cycle enzymes. You are speeding these up, and by doing so increasing demand for thiamine, biotin and so on, and pushing protons at an excessive rate.
This is unlikely to be antioxidant over the long haul.

karl said...

One point about antioxidants - there is yet to be a conclusive test to tell if something is an antioxidant in vitro

Most of what passes for an antioxidants are based on food storage work - things that keep fats from oxidizing - becoming rancid. But many of these things can become pro-oxidants in vitro. There are a couple of tests that the food-storage folks used to look at the antioxidant ability - and even these tests don't always agree - yet these tests are the basis for the grossly misleading claims that x,y and z are antioxidants worth taking as a supplement - based on someones BS.

Then there is the case of Vitamin C - mostly claimed to be an antioxidant, it can act as a pro oxidant in the presence of iron.

Many of the things claimed to be antioxidants by the 'health food industry' folks don't end up in circulation - our bodies dispose of them as fast as possible.

Then there is the claimed evil nitrates found in bacon - these are actually potent storage antioxidants - also found in many fruits and vegetables - but only vilified when in meat.

When I see something advertized as an antioxidant - I mentally replace the word antioxidant with lemon scented or new and improved.

Galina L. said...

Most of all I detest declarations that something is just "good for you" - it is how antioxidants are usually being praised without any coherent explanations what they are doing in a human body.
From my field observations - the foods which are recommended on the ground of their antioxidant content are often on the list to limit for the people who are prone to allergies. I am free from worries about asthma and eczema now, but consuming more often than occasionally chocolate, citruses, strawberries, red whine, cayenne pepper, tomato souses and some other foods wakes up my Rosacea.
I remember how, when my son was a toddler, red apple provoked his eczema, but not a green one, we were buying yellow, not orange carrots, white, not black or red, currant, and so forth. Even red-skinned potatoes were worse than white potatoes. Back then I thought he would be unhealthy without eating fruits and vegetables before he turned one year.

altavista said...

Peter, could you summarize why you "choose" to ignore the studies showing the adverse effects of cream? :)

I think there was another instance in the archive showing cream has an inflamatory effect, but you dismissed it, and didnt quite understand your explanation then.

Also I'd be interested to know what blogs/research etc. on nutrition/biochem you read to keep your confirmation bias in check?

This place is great but it can turn into an echo chamber.

Peter said...

Hi altavista, 'tinternet ate my comment! Bed time now, will try again when I get the chance!


Peter said...

OK, take two.

Do you mean Dandona’s work on ROS burst induction from PMNs? I feel his model is flawed as it produces results which, IRL, if you followed their indications, would be very counter productive. When compared to what cream actually does in intact humans on a low sucrose +/- low carb diet. Models are models. You need a reality check.

There are other studies on dietary fat endotoxin uptake too, but they have to be put in to a context of the benefits of endotoxin. It’s certainly far from all bad. But models almost never give the whole picture. I try to see whether the whole picture fits with my confirmation bias.

I don’t really read much on the net except Pubmed and Wooo, both of which seem to reinforce my problem. I pick up occasional post by various LC bloggers through Stan’s site but even here I see much simplification which makes me a little uncomfortable. LC is good, it’s not a panacea. But what are the alternatives for someone with complex I dysfunction?

Mostly I read what interest me. Currently it’s largely around the evolution of the ATP synthase complex… Other one liner posts come through Facebook links. I don’t have a Plan, I’m happy for others to save the world. They seem to be doing quite well at the moment.


altavista said...

Yeah, I was referring the Dandona paper a few years back.

My gut feeling (and experience growing up on a farm close to nature) is we didnt evolve in a high fat environment, and all the positives you identify through biochemistry, might be offset by negatives you "choose" to skip over due to biases etc. hence my question. Would be cool to have an honest "nemesis" going at it from the other side.

Like most of life, the answer might be unpleasant: most likely caloric restriction + FOOD is where it's at, and high-fat is the hedonistic 2nd best/less bad :).

Peter said...

The problem I have with Dandona’s model is the minimal ROS response following alcohol or orange juice ingestion. I don’t doubt that this is what he found. But his model suggests you might minimise ROS damage by avoiding drinking glucose and cream but be ok with vodka and orange. Dandona is a diabetologist. Is this the way he would approach managing a diabetic? I just can’t see how his model fits life.

There are, of course, many people who espouse a fat restricted, often vegan, approach to degenerative diseases. They currently suffer from any sort of evidence base by which I can convince myself they are correct. I don’t see amelioration of Parkinsons by 28 days on a low fat, low sugar approach. A ketogenic diet clearly does this. There are many more examples, as you are well aware.

On the fat front I’ve been wanting to post on Miki Ben-Dor’s paper

for some time.

Obviously the paper is not suggesting that Homo erectus was a LC-er, but it suggests a line of evolution I’m comfortable to follow. I loved his video from AHS. So dependent on his ideas, not his presentation style (which lacks a certain something!). When you compare this to a polished presentation, presenting bollocks in a highly believable manner, I’d go for the mumbled PhD thesis any day. But that’s just me and my lipophilia…


altavista said...


That is one well researched paper and a good read, but 35% protein and 37% plant is not high fat. Im holier than thou, though, since cutting fruit completely seems to do the trick for me. :)

The authors of the plant section remind me of the joke about the drunk who was searching his keys under the lamp post because thats where the light was. Using MQ data and extrapolating a straight line because what else are you gonna do? :)

I can see a scenario where we didnt evolve chewing grass and bark. I doubt fruit and tubers will modify your dentition at all.

Also hunting elephants with sticks on 2700 calories DEE? Saw a tabloid headline at the supermarket today, on Kardashian wolfing down 5400 calories/d.

Maybe if they watched a lions pride attack on elephants and the success rate of it. A healthy lioness is 2x human size, prob crushing 5 humans easily, and watch 10 of them fly through the air when they try something.

Also not sure how you cut elephants tendons "from behind" with stone flakes, even if you call them axes. I thought we hadnt invented metallurgy yet. :)

Other than that, I have no concerns:)

Thinking Aloud said...

I bought and read that SAMP8 / Lipoic Acid mouse study.

They were giving them 100mg/kg/day of ALA. That's like me taking 8g of lipoic acid a day.

That seems to be a preposterously high dose: what did they expect ? Also, the paper doesn't discuss the causes of early death, which I would expect to be cancer from such an obvious anti-oxidant overload.

To me, all this paper says is that "insane doses of ALA are ...insane". I'm not sure that it helps you form a view on the value of a reasonable dose.