Monday, March 02, 2015

Insulin detemir (1)

There is a certain belief structure within obesity research which maintains that the central action of insulin is to limit appetite. Obviously, not everyone agrees with this. I would like to do some wild speculating (any resemblance to real life events is purely accidental) about this paper:

Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats

The paper is very interesting, partly for what they failed to reproduce but mostly for the affiliations of the authors.

The first thing to say is that, if you work in the pharmaceutical industry, you want drugs which work. Hardcore. It’s no good fudging your results when working in pharmaceutical R&D because you’re going to get caught out as soon as anyone tries to actually use your drug. Which is guaranteed to happen. The drug has GOT to work. Industry has no fudge factor. You might have to lie, evade, obfuscate, misplace computer files and massage data to hide the serious adverse effects of your functional patented drug, but you wouldn’t want to have to do this for a molecule which is ineffective in the first place. Statins are very, very effective. At lowering cholesterol. The fudge factor comes from whether this does any good for any person and what multiple adverse effects the drugs might generate.

So I have respect for the integrity, within certain defined limits, of a drug company R&D team. The managers and PR crowd are another matter altogether. Think Dilbert.

Let’s look at the authors of this paper:

There are three. Jessen is the first author, so probably did the bulk of the work and wrote much of the paper. She works in the department of insulin pharmacology at Novo Nordisk, the company which makes insulin detemir. Bouman is last author so is possibly Jessen's line manager and also works for Novo Nordisk. Insulin detemir is interesting because it is the only insulin ever to have been shown to cause weight loss in any patient group. OK, this is limited to morbidly obese (BMI>40) type two diabetics and the weight loss is very small. But it does happen. Quite amazing really and quite different to any other insulin formulation on the market, all of which reliably cause weight gain. Hence I suspect the project at Novo Nordisk was to find out the hows and whys of this strange effect.

Jessen and Bouman will have started with generous (by academic standards) funding, because the drug industry will work at a potentially rewarding idea in a rather more motivated manner than an academic department. Neither author has any track record of publishing on the central anoretic effect of exogenous insulin. Their job is to get reliable and repeatable results about how insulin detemir is special. In this project they failed to achieve any sort of anorectic effect of insulin detemir, or of any other sort of insulin, within the brain. Mucho problemo.

Clegg is middle author and works in the Department of Psychiatry, University of Cincinnati. She has a vast number of publications, several of which feature the successful anorectic effect of insulin when administered directly in to the brain. In at least one such study she is the lead author.

Jessen has co published with Clegg back in 2001 on a non insulin related subject, presumably before Jessen moved to work for Novo Nordisk. They know each other and have worked together before.

I have this image of two industrial pharmacologists setting out to investigate the CNS effects of their rather promising systemic drug, insulin detemir, comparing it to routine and more obesogenic neutral insulin. They fully expect central insulin to be anorectic because they've read all of the papers. That's their job. They expect insulin detemir to be extra effective. In the first run of experiments using intra cerebral administration they failed to get any effect, of any type of insulin, on food intake. None.

This is big. And bad. EVERYONE in obesity research KNOWS that insulin, within the brain, suppresses appetite (excepting the few people who think this idea is bollocks of course, there are always a few people who think logically).

Jessen and Bouman probably think they have made a mistake somewhere along the line. They know that Clegg can, in academia at least, deliver results that show a suppression of appetite in rats following centrally administered insulin. They call her over from of Cincinatti to trouble shoot their problems.

In a hard nosed, financially driven situation, she can't do it. From the abstract of the study:

“Although we varied rat strain, stereotactic coordinates, formulations of insulin and vehicle, dose, volume, and time of injection, the anorectic effect of intracerebroventricular insulin could not be replicated”.

It seems to me that there are differences between academia and industry. It’s the difference between holding a religious belief in the central anorectic effect of insulin and looking for an effect which might suggest a marketable drug which will actually work to assist weight loss. I would call the latter "The Real World".

Time to discard the idea that centrally acting insulin is an anorectic agent? Kudos to the researchers for publishing.


Saturday, February 21, 2015

Random musings on carbon monoxide

There are occasional days at work when I get a lunch break. Sometimes it is long enough to get home and back, often it’s not. Given an hour of free time in the basement, what might you do?

Well, usually I go and have a look whether Nick Lane's group has any new publications up. Pondering the origins of life is a great relief from the problem solving with limited information that makes up clinical work.

In recent months I’ve usually had three browser windows open to try and get an accurate understanding of what he and his coworkers are specifically saying.

As a preamble to discussing those methanogens and acetogens which do not use cytochromes I would just like to lay it on with a trowel that these strict anaerobic organisms are not “living fossils” or in anyway primitive. They appear to be using a method of carbon fixation which is developed from that of the first prebiotic synthesis. That does not make them simple. If this is the first technique for carbon fixation it has been developing for well over 3 billion years. It’s still used nowadays because it works.

So lets go to Figure 1 sections a and b of An Origin-of-Life Reactor to Simulate Alkaline Hydrothermal Vents to have a look at the energetics of fixing organic carbon:

This shows that hydrogen is unable to reduce CO2 to formaldehyde at pH 7. However, if you introduce a pH difference across a thin FeS barrier, it appears to be possible to put an electron or two on to FeS clusters which can then drive the reaction. At the risk of spoiling the paper, it works. Yield is low, but it's there.

Of much greater interest (to me anyway) is the ability to reduce CO2 to CO. I've added these potentials to Nick Lane's diagram like this:

There is a lower barrier to be overcome and, given the suggested pH gradient, greater likelihood of the reaction proceeding. I think the group are interested in formate and formaldehyde because they have the potential to do many things other than generate acetate/methane plus the reactions from there onwards are exergonic.

I'm more interested in CO formation because the carbon monoxide dehydrogenase (CODH) enzyme appears to be core to carbon fixation and is conserved between archaea and eubacteria, certainly in the methanogens and acetogens which lack cytochromes and are strictly anaerobic in their metabolism. So too is acetyl CoA synthase, which is directly linked to CODH. This suggests that this enzyme complex, or the abiotic reaction is preserves, is very ancient. We need to look at Early bioenergetic evolution, Fig 2 section b for a suggestion of how prebiotic acetate synthesis might have occurred. This is the top section:

If we work down from the CO2 at the top of the dashed line rectangle we can see that CO2 is being reduced by electrons from a very low potential FeS cluster (just where it says +2[H]), generated as in my modification of the blue bar chart above, using the pH gradient across a thin FeS barrier. The FeS cluster on the right is the actual catalytic cluster and the green sphere is a Ni atom crucial to its function.

The CO diffuses to a second FeS catalytic cluster which is doped with two more Ni atoms, shown as two green spheres. This reaction does not need a low potential FeS group, so I'm not sure why the black/yellow cluster is shown to the left of the "Ni" in the diagram, excepting that modern ACS does have an FeS cluster covalently attached to the FeNiS catalytic cluster. Doesn't make the diagram particularly easy to interpret. Anyhow, the CO binds to one of the two Ni atoms and waits for a methyl donor.

The methyl source is on the far left of the diagram, shown as CH3-X. This has to be of abiotic origin in an origin-of-life scenario and the simplest is undoubtedly CH3-SH. This methyl group attaches to the CO on the Ni atom and we then have CH3-CO- attached to the catalytic site. Thiolysis using a source of sulphydryl (shown as HS-R in the diagram, below the CH3CO-Ni, still within the dotted rectangle) generates a thioester of acetate, shown (outside the rectangle) as CH3CO-SR.

We've already speculated the availability of CH3-SH in vent fluids to supply methyl groups, so we could simply replace HS-R with HS-CH3 i.e. CH3-SH can provide both the methyl group and the sulphydryl group for the above reactions. The only step requiring any energy input is the initial reduction of CO2 to CO using a low potential FeS cluster.

So when you supply CO and CH3-SH to a slurry of FeS and NiS you get CH3CO-S-CH3 of abiotic origin. This was done back in 1997 by Huber and W√§chtersh√§user. The trick of reducing CO2 to CO is the hard knot to pick and which needs FeS and a proton gradient, not available in the slurry.

The thioester can hydrolyse to heat and acetate but more interestingly it carries enough energy to form a phosphate derivative which retains slightly more available energy than ATP.

After translating this in to a system which has developed genes and proteins, we still the have remnants visible.

Let's now look at the lower section of Figure 2 section b. The complex series of reactions down the left is how modern acetogens generate their methyl donor source, down the right is the system from methanogens. These are both replacing the speculated abiotic CH3-SH. These pathways are not particularly relevant to any origin of life speculation but clearly are interesting in their own right as they also support CO2 reduction by H2. There are some interesting speculations as to why tungsten or molybdenum are required cofactors... Today it's still the central rectangle we are interested in:

This is the modern version of what we have been looking at previously, with the two Ni doped FeS clusters on the right hand side. The reduction of CO2 to CO is no longer accomplished using a proton gradient, in fact these archea and eubacteria use a sodium gradient rather than a proton gradient. Instead, a low potential ferrodoxin protein with two FeS clusters is generated in the cytoplasm using electron bifurcation from molecular hydrogen (not shown, discussed here, that's the third window in my browser!). The systems used differ between methanogens and acetogens but the core energy currency for both is still reduced ferredoxin. This ferredoxin looks, to me, like a fossil of the FeS on a proton gradient which provided reducing power in the initial scenario.

The transport of CO to the second FeSNi cluster is down a molecular tunnel in the modern enzyme but the binding to a Ni atom at the end of that tunnel persists. Source of the methyl group is quite different between archaea (methanogens) and eubacteria (acetogens). This differing arrangement suggests development after the divergence of the two lineages.

The use of CH3-SH to form a thioester has been replaced by the use of coenzyme A, giving us the familiar acetyl-CoA (shown as CH3CO-SCoA) below the rectangular box. This can be used for substrate level phosphorylation of ADP to ATP or can be used as a source of cell carbon for metabolism. There is a lot of interest along these lines in this paper: The stepwise evolution of early life driven by energy conservation.

There are some interesting ideas which stem from this believable scenario.

Substrate level phosphorylation is clearly very ancient. There are suggestions from the speculated origins of ATP synthase that ATP usage may have been common before this enzyme complex was developed.

The possibility of generating an ATP-like moiety was present when all that was available was a proton gradient derived reduced FeS cluster and some CH3-SH.

Carbon fixation does not appear, initially, to have involved proton translocation, though the gradient was essential.

Carbon monoxide is utterly intrinsic to the formation of life. Strange, that.


Thursday, February 12, 2015


People may have seen this quote on Facebook. Lovely to see Steven Rentaquote Nissen publicly acknowledging that the death toll from cardiovascular medicine's lethal low fat diet has finally been halted by a couple of investigative journalists. Thank you Mr Taubes and Ms Teicholz. Oh, he missed that bit...... Here's the quote:

Steven Nissen, chairman of cardiovascular medicine at the famed Cleveland Clinic: For years, "we got the dietary guidelines wrong. They've been wrong for decades."

Advice to avoid foods high in fat and cholesterol led many Americans to switch to foods high in sugar and carbohydrates, which often had more calories. "We got fatter and fatter," Nissen says. "We got more and more diabetes."

Recent studies even suggest that longtime advice on saturated fat and salt may be wrong, Nissen says.

Personally I feel a little contaminated, unclean, by Nissen's falling in to line with what any sensible person with a laptop and net access realised fourteen years ago. Yeugh. Anyway: I thought I would help out by sketching out his next press release:

Steven Nissen, chairman of cardiovascular medicine at the famed Cleveland Clinic: For years, "we got the cholesterol guidelines wrong. They've been wrong for decades."

Advice to take drugs to lower cholesterol led many Americans to pay for statins which made them diabetic and increased their cancer risk. "We got sicker and sicker,” Nissen says. "We got more and more dementia.”

Recent studies even suggest that longtime advice in favour of statins was a bad as that against saturated fat and salt, Nissen says.

Y'all know it's coming! You saw it here first.


Saturday, February 07, 2015

Ketosis and Protein

I just wanted to throw out a few comments about the inhibition of ketogenesis by protein. The obvious effect, that of stimulating gluconeogenesis, appears to be at best a partial explanation of what happens.

I've long been interested in how amino acids feed into (and are derived from) the citric acid cycle and related pathways. Clearly any amino acid which metabolises to oxaloacetate within the liver is simply going to remove that void in the citric acid cycle (oxaloacetate deficiency) which results in acetyl-CoA being diverted to ketogenesis. Aspartate is one such. Those metabolising to pyruvate are also going to do essentially the same thing. There is no need for increased gluconeogenesis in this scenario. Gluconeogenesis may happen at a increased rate. It may not. Providing a source of oxaloacetate in the liver mitochondria will stop ketogenesis, whatever gluconeogenesis does, whatever insulin does.

Personally I am very ketoadapted. I've drifted in and out of ketosis since just after that start of the current century, probably around the summer of 2001 if I recall correctly. I find carbohydrate restriction effortless. Limiting to 30-40 grams per day is easy. Protein limitation is much more difficult. With about 20grams of protein in each breakfast and a few grams derived from cream, chocolate or macadamias at lunch time this does not leave a huge allowance for meat intake at suppertime. At around 65kg bodyweight nowadays keeping to 1g/kg is not the easiest target. A decent steak and I miss it. Life is too short to stress about this, but I certainly don't eat steak every day. Urinary ketones are always there at the + or ++ level. Exercise (distance walking) usually gives +++ as does the evening meal post prandial period, unless there have been excess chips with supper or I've gone significantly over my protein limit.

So I've limited protein, mildly, for years. My degree of keto adaptation still allows free generation of ketone bodies, certainly to a level where I can detect acetoacetate in my urine.

For some reason the concept of amino acids being derivatives of (and inputs towards) the TCA pulls me back to Nick Lane's ideas, the origin of life and the throwing together of metabolism. I'm willing to buy the reduction of CO2 by H2 to give formate as the starting point of metabolism. There is an energetic cost to this initial step but once going it's all down hill, energetically, to pyruvate. Many amino acids are formed from pyruvate and close derivatives. This makes sense. Evolution doesn't plan but does progress within the framework of what is available.

In modern biology DNA doesn't do very much other than replicate (I simplify). RNA is much more active, it carries the message out, assembles itself in to ribosomes and does all of the picking and choosing of amino acids etc to make a protein. I like to think of DNA as a rather stable "hard copy" of the information which was originally carried by the less stable RNA. As such DNA is the fossilisation of the amino acid preferences of primordial RNA. Written in to DNA are the remnants of what was probably a chemical associations of RNA with specific amino acids. If DNA specifies a cytosine at the start of a triplet then the amino acid chosen via transport RNA will be derived from alpha-ketoglutarate, if an adenine the coded amino acid will be oxaloacetate derived, if thymine it comes from pyruvate and if guanine the amino acid will be derived from any one of several possible small molecules. The second base specifies how hydrophobic/hydrophilic the chosen amino acid might be and these two cover a high proportion of the biological amino acids. The third base is degenerate, i.e. it doesn’t carry any specific information but does allow a wider pool of amino acids to be selected.

I'm afraid this is all rather cool to me.

I love these glimpses in to the early mish-mash of chemicals and how they might have interacted before life became seriously organised. What you can and cannot say about LUCA, the last universal common ancestor, and the first steps away from prebiotic chemistry, is largely determined by such biochemical fossils.

All of this random musing came from wondering whether amino acids might supply oxaloacetate and so suppress ketosis. Some do.

Well. Eating a steak is not very ketogenic. It’s hard to separate this from the origins of metabolism and of life, for me anyway,


Saturday, January 31, 2015

Shewanella and electrons

Have we found alien life? This interview did the rounds via Facebook recently. There is only one answer.


We have found bacteria that can run their electron transport chain using an electrical connection to an external electron acceptor. In more ordinary bacteria electrons travel down the ETC to complex IV where, under oxidative metabolism conditions, they are passed to oxygen as the terminal acceptor, still within the cell.

Bacteria are the most sophisticated metabolists on Earth. To stick a series of cytochromes together to form a wire, from the end of an electron transport chain to an extracellular acceptor of electrons, is no big deal. Once a bacterium is using such a wire (which will, undoubtedly, be using quantum tunnelling effects much as the FeS clusters of complex I do) to access extra cellular terminal acceptors it is absolutely no problem to make that terminal acceptor anything with an appropriate redox potential.

Under these conditions a cathode electrode will allow the metabolism of NADH from the cytosol, via complex I and the CoQ couple down the ETC and out along the cytochrome wire. A cathode electrode, whatever it is made of, is an electron acceptor. That's the definition.

So growing bugs on a cathode is utterly unremarkable. NADH comes from "food". Electrons from NADH drive the ETC to make ATP and are dumped out-of-cell on to the cathode.

Where things get slightly interesting is that you can also apply a negative voltage to the end of the wire, making it an anode, a net supplier of electrons. Certain types of bacteria can function under these conditions without any carbon input. From the article:

“A lot of organisms that can put electrons onto an electrode can also do the opposite and take electrons from one”—though not at the same time—Rowe says. That ability to reverse course surprises me, and Rowe, too. “I’d think it would be really hard on the organisms. You’re basically stealing energy from them. But they do okay.”

This is incorrect, it lacks perception.

It is perfectly possible to run the ETC in reverse. Bacteria do this on occasions, for reasons best known to themselves, especially if their normal metabolic substrates cannot generate NADH directly. Usually ATP is used to drive ATP synthase in reverse to maintain the membrane potential. Electrons flow in reverse to reduce NAD+ to NADH which can then be used for anabolism. All that Shewanella spp need to do is to use the negative voltage of an external electrode to facilitate reverse electron flow and they can be generating NADH for anabolism without any carbon source. About a third of a volt does the trick, from the interview.

Whether this process would allow the fixation of atmospheric carbon dioxide to actually allow growth is irrelevant. What matters is that there is absolutely nothing about these bacteria living on "pure electricity" which suggests anything other than a clever piece of wiring added on to the end of a  fairly normal ETC.

This is what Shewanella oneidensis looks like with its complex I and CoQ couple:

A clever bacterium? Yes, with very busy periplasm. But anyone who thinks that any bacteria are simple is stupid. What if you think that these particular ones are alien life forms?

"Kenneth Nealson is looking awfully sane for a man who’s basically just told me that he has a colony of aliens incubating in his laboratory".

It is only an alien life form if aliens developed the same electron transport chain as any Earthly organism which uses oxidative phosphorylation to chemical acceptors.

How much does Nealson know?


Saturday, January 17, 2015

GSD IIIa, ketones, MAD and Veech again

I mentioned the high protein/exogenous ketone approach to Glycogen Storage Disease IIIa in a recent post. It's very nice that an effective treatment can actually be achieved through a Modified Atkins Diet (MAD at <10g of carbs per day) involving food, w/o faking ketosis though those exogenous synthetic ketones.

Robert gave me the heads up on the latest paper on GSD IIIa using MAD, available as a free text through Pubmed. It's rather good as, again, it shows that there are medics out there who think matters through and occasionally come to correct conclusions. I love the clinical details of compliance/non compliance too. And that the early hypoglycaemia, treated with corn starch (bleugh), was asymptomatic under ketosis.

That's nice.

He also sent me the full text of Veech's

The Determination of the Redox States and Phosphorylation Potential in Living Tissues and Their Relationship to Metabolic Control of Disease Phenotypes

which is a fascinating personal insight in to what it was like to work in Hans Krebs' lab, combined with the sort of hard core math which implies rather more understanding of biochemistry than simply adding MitoSOX red to some cells and looking for colour changes to show oxidative stress. That's some complex reading to work through when clinical and home life combine to give me a chance!


Palmitic acid and hyperglycaemia in diabetic heart failure (1)

I've been gifted a paper of great interest. The authors of the paper are very good in their explicit discussions of the limitations of their models, the reasons for the choices they made and the limitations of all current models and probes. This is good and, needless to say, there are an awful lot of "ifs, buts and maybes" to the data! On the down side the paper is an epub of the crudest type, retaining numbered lines, the figures at the very end of the whole paper and all of the captions in a lump between the references and the figures. So not easy reading for a very complex paper, with very complex figures and very complex captions. I spent a large amount of time on this paper over the Christmas vacation but never hit post on any of it. Here is an introduction.

Over the years we have seen, largely via Veech, the ability of ketone bodies alone to rescue myocardial function to give mechanical work performance comparable to the combination of insulin with a relatively normal level of glucose in the perfusion of isolated rat hearts. Equally there is the concept that ketones essentially bypass insulin resistance to rescue metabolism.

The hearts in Veech's study were perfused with oxygenated buffer which was devoid of the free fatty acids which are a normal metabolic substrate for heart muscle.

As a lipophile I have long wondered whether, outside of the neurons, palmitic acid might be a reasonable substitute for ketones in rescuing muscle metabolism damaged by hyperglycaemia.

From the start of the discussion section of Bhatt's paper:

"We investigated the role of substrate-driven redox status on the contractile/energetic performance of heart trabeculae from the T2DM ZDF rat. The main findings are: i) HG exerts a detrimental action on contractility of T2DM heart trabeculae that Palm is able to rescue; ii) Palm prevents oxidative stress exacerbated by HG, an effect independent from insulin action; iii) insulin appears to worsen the negative effect of HG through higher oxidative stress and lower GSH; iv) ZDF heart mitochondria emit less ROS and display higher ROS scavenging capacity of the GSH/Trx antioxidant systems; v) cardiac redox balance in HG appears to play a causal rather than correlative role in the preservation of contractile performance in ZDF trabeculae"

Palmitic acid will rescue hyperglycaemia induced myocardial contractility failure. OK, I'm happy.

This was the core finding in the paper. There are a whole slew of spin off concepts which grow from it but if I wait until I have them all sorted out it might be a very long time before I get another post out!

But here we have it. Hyperglycaemia is bad. Palmitic acid rescues hyperglycaemia induced dysfunction. A paradigm shift in glucose vs FFAs!


Thursday, December 04, 2014

ACCORD and musings on insulin

There are a couple of things I would just like to mention in passing. Jenny Ruhl has just posted a nice entry about ACCORD. This is very important. Lowering your blood glucose is significantly protective against CVD events. This is the exact opposite of the initial analysis of the results where a flawed interpretation of the data led to vociferous suggestions that lowering the HbA1c of diabetics might be actually dangerous. Hopefully this reanalysis will put an end to such stupid ideas which are still dangerously prevalent today.

Before Jenny posted the above I had been thinking about both metformin and insulin for the management of diabetes. I have posted on insulin, which is probably the ideal drug for diabetes management provided it is combined with low carbohydrate eating, in the past but it bears reiterating.

This is my opinion. If you can control your diabetes with metformin and wish to eat lots of carbohydrate, by all means get on with it, that's your choice. Not checking or not worrying about your blood glucose excursions might be a mistake. What you mean by good control might not involve HbA1c values in the 5% region or below.

If you need insulin to control your blood glucose, you have no choice. It's low carb. Live with it.


Some researchers (who write third rate papers using a rather inappropriate pancreatectomised dog model) are now starting to wake up to the fact that the pancreas secretes insulin in to the portal vein, not the subcutaneous tissues. In normal individuals insulin/glucose arrives at the liver via the portal vein and insulin facilitates transport of the glucose in to the liver, being metabolised in the process. Relatively little post pranial insulin or glucose penetrates to the peripheral circulation in a normal individual.

EDIT: Gretchen has kindly pointed out that the liver uptakes glucose through GLUT2, not GLUT4. The function of insulin, acting on its receptor (facilitating its degradation), is to suppress gluconeogenesis and hepatic glucose output. This is the correct function of the elevated portal insulin level. It makes no difference to the issues with peripheral vs portal insulin, but the correction is welcome. END EDIT

Once a person needs insulin to control their blood sugar levels they inject it subcutaneously. This will invariably elevate the systemic concentration of insulin. It will only modestly elevate the portal vein level. This is very important.

In the cited paper the dogs get a meal with 50% of calories from carbohydrate, 30% from fat and 20% from protein. In control dogs, instrumented but not pancreatectomised, the portal vein insulin after the meal is, at certain time points, ten times the peripheral systemic concentration. This is what is needed to allow the liver deal with the glucose load from the meal while simultaneously protecting the body from both hyperglycaemia and hyperinsulinaemia.

Subcutaneous insulin will make the rest of the body do the liver's job of clearing post prandial glucose, the liver can't manage because it never sees the requisite ten times the normal peripheral insulin concentration needed to deal effectively with the portal glucose load.

What happens when you use the rest of the body as a glucose sump? From the paper:

"Peripheral hyperinsulinemia is associated not only with increased risk of hypoglycemia, but also an increase in catechol and cortisol secretion and lipolysis [14], deleterious effects on vessel walls [6], ischemic heart disease, hypertension and hyperlipidemia [8], and abnormalities in hemostasis [10]"

As always, I would add that it's the obese, blind, legless person in the queue for dialysis who pays the bill for eating the carbohydrate.

This is the situation for all type I diabetics and the more advanced type 2 diabetics. The only route round it is to use intra peritoneal insulin which is, in part, absorbed through the mesenteric veins so is partially portal vein selective. There are, needless to say, a stack of complications to intra peritoneal insulin infusion. Tight control of glucose using subcutaneous insulin from a blood glucose controlled pump is no solution. Though glycaemia is better controlled it is still at the cost of too little insulin in the portal vein and too much in the periphery, using the body as a glucose sump. Over the years I have never been quite able to decide whether hyperinsulinaemia or hyperglycaemia is the primary factor which kills nerves and kidneys. It's a difficult call. And a fascinating discussion in its own right.

What happens if you eat a diet very low in starch?

Very little insulin is ever secreted by the pancreas, especially as glucokinase down regulates. Very little glucose ever needs to be taken up by the liver. Very little insulin will be metabolised by the liver. The insulin gradient between the portal vein and the systemic circulation will be as low as you can practically get it. If someone still needs to inject insulin alongside a very low carbohydrate diet, and many might not, injecting a very small amount subcutaneously will deliver an arterial concentration to the gut, pancreas and eventually to the portal vein and liver which is still quite close to what the portal vein might have supplied. If the body is not using insulin the tissues will not extract it, so portal and systemic concentrations will converge. Everything pans out at some near basal level.

A very low carbohydrate diet is not perfect for insulin dependent diabetics but it is streets ahead of anything else. What people do or do not consider a "normal" human diet will not get around this. Need exogenous insulin? You are not in a position to eat ancestral starch. It's a simple matter of anatomy, physiology and biochemistry.