Keep 'em tight, Part 2.

Keep 'em tight was about the ramifications of excessive gut permeability, a.k.a."Leaky Gut".

Graphic From: www.leakygutcure.com

Almost as an afterthought, I added to that post a link to Physiology and Immunology of Digestion. As this article is interesting & informative and since only 706 people have read the first post since it was published (the link was added quite some time later), I thought that I'd give it another airing, with a picture to make the post more attractive.

Doctor, every time I do *this*, it hurts!

The correct response is either:-

1) Go to hospital and get that broken finger fixed, or
2) Stop doing *that*!

There seem to be a lot of people out there who are having problems with wheat gluten (gliadin), casein and other proteins. As Matt Lalonde said in The Science Behind the Paleolithic Diet, some proteins are harder to digest than others.

Here's a hard to digest protein:-


It's raw albumin (egg white protein). As mentioned in As sure as Eggs is Eggs....., raw albumin is poorly absorbed, compared to cooked albumin. To digest the above protein requires peptidase enzymes (pepsin, trypsin and chymotrypsin) to break the peptide bonds. This has to be done from the outside inwards, so a large, heavily-folded protein takes a long time to break down into individual amino acids. Cooking albumin changes the 3-D structure - this is called denaturing. Cooked albumin digests much faster than raw albumin, which is why it's much better absorbed. Cooked proteins are generally faster to digest than raw proteins, unless they're burned to a crisp on a barbecue!

In a person with a healthy gut, partially-digested proteins are not absorbed, as the molecules are too large to pass through the tight junctions in the small intestine. They just ferment, producing malodorous wind. In a person with impaired gut permeability, partially-digested proteins pass through the loose junctions and get into the blood, provoking an immune response. This is not good, so Keep 'em tight.

People who suffer ill-effects after eating certain proteins may either have the wrong genes (e.g. coeliac disease), or have impaired gut permeability. The former isn't fixable but the latter may be. In the meantime, if eating "X" hurts, don't eat "X"!

Keep 'em tight.

Wheel nuts? Nope!

Image from http://suppversity.blogspot.de/2012/11/shedding-some-light-on-the-leaky-gut.html

I'm referring to Tight Junctions. As mentioned at the end of Wheat? Oh, dear! , 10% of the people who are healthy enough to donate blood have gut walls permeable enough to let gliadin fragments pass into the blood.

Tight junctions are important, as they keep the contents of the gut inside the gut and out of the blood. If you read Food Combining: What's THAT all about?, you'll see that during digestion, proteins are broken down into individual amino acids & very short peptide chains*. Amino acids & very short peptide chains are small enough to pass through tight junctions. Peptide chains longer than about 3 amino acids are too big to pass through. See also Physiology and Immunology of Digestion.

Carbohydrates are broken down into monosaccharides, which are small enough to pass through. Disaccharides are too large (except for Trehalose, which Jay Bryant told me about as a treatment for Alzheimer's Disease).

Fats are broken down into glycerol and fatty acids. Glycerol is small enough to pass through. Fatty acids and other fatty molecules such as Vitamin D, Co-enzyme Q10, Vitamin K2, curcumin, berberine etc are transported across.

The consequences of having loose junctions are not good. Stuff that's not supposed to get in to the blood gets in and stimulates the immune system to produce antibodies against it. That in itself is not a problem, unless the stuff that the body's produced antibodies against happens to resemble parts of your own body.

Diseases of autoimmune origin such as Coeliac disease (gut), Eczema (skin), Dermatitis herpetiformis (skin), Sjögren's syndrome (mucous membranes), Cerebellar ataxia (Purkinje cells in the brain), Multiple sclerosis (myelin sheaths of nerves), Type 1 Diabetes (pancreatic beta cells), Rheumatoid arthritis (joints), Asthma (lungs), Lupus erythematosus (various), Autoimmune thyroiditis (thyroid), LADA (pancreatic beta cells) etc are caused by the body's immune system mistakenly attacking the body. Autoimmune diseases can also occur after bacterial & viral infections.

The other day, I found Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism.

See also Stronger Intestinal Barrier May Prevent Cancer in the Rest of the Body, New Study Suggests.

So, how do we keep 'em tight? See Vitamin D.
See also Dietary Fat Can Modulate Intestinal Tight Junction Integrity.
See also Shedding Some Light on the Leaky Gut <> Exercise Connection. Plus: 20+ Things You Should or Shouldn't Do to Protect and Restore the Integrity of Your Intestinal Wall.


In other news....
I had a phone call from mum's GP this morning. Having read my evidence, he's agreed to test mum's serum B12, 25(OH)D and Calcium and give her supplements accordingly. He's also happy with me giving mum a Ketogenic diet and will also advise the nursing home to exercise mum as often as she is able. Result!

I put four cubes of liver pâté out for Sooty & Sweep (I don't know which one is which as they're identical) and a Magpie swiped two of them. We also have seagulls. I put the other two cubes out of sight in a box.


So far, so good!

P.S. What fuel can be extracted from decomposing seagulls?
.
.
.
Wait for it...
.
.
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Petrel! (From Petrol Direct, a joke site in case anyone's wondering).

Gluten - more than just a pain in the guts?

Remember the advert "I'm feeling a bit bloated". "Here, have some Bifidus Digestivum!"? I wonder what percentage of the population suffers from bloating, gas pains, constipation, IBS or some degree of failure to absorb the nutrients from their food?

People with Coeliac Disease (CD) or Dermatitis Herpetiformis (DH) (intensely itchy spots on pressure points) have to avoid gluten as much as possible, as it produces an auto-immune response with antibodies that attack their own bodies. However, gluten is also implicated in other conditions due to molecular mimicry. Sjogren's syndrome (dry eyes & other bits) and cerebellar ataxia (brain damage) are mentioned in a huge article by Loren Cordain Cereal Grains: Humanity’s Double-Edged Sword.

This article suggests that there are conditions other than CD & DH which can be helped by switching from gluten-containing grains (wheat, rye, oats, barley & spelt) to non gluten-containing ones (rice, corn, quinoa, buckwheat, millet & amaranth). Luckily, supermarkets like Tesco, Waitrose and Sainsbury's now have a large "Free from" section, which makes finding gluten-free substitutes for breads, cakes, biscuits & breakfast cereals etc a lot easier.

EDIT: See also Keep 'em tight.

Blood Glucose, Insulin & Diabetes

Diabetes is afflicting an increasing percentage of the population as time goes by. Even athletes like Sir Steven Redgrave can get it. This article tries to explain the workings of the body's blood glucose (BG) regulation system and what can go wrong with it.

How does the body regulate blood glucose?
At any given moment, there's about 4.5g of glucose circulating in your blood (5mmol/L x 180g x 5L). As the brain alone uses about 6g of glucose per hour in the absence of ketones, blood glucose (BG) level could fall to zero within an hour if we ate no sugary/starchy carbs. If we ate a mere 5g of glucose, BG level could double. As very low BGs are fatal and very high BGs damage proteins by a process called glycation (a bit like caramelisation), the body keeps BG levels within fairly tight limits by the use of a negative feedback (NFB) control system.

How does a negative feedback control system work?
NFB systems consist of a non-inverting (more in → more out) part, which in this case are the islet cells of Langerhans (a.k.a. pancreatic beta cells), as increasing BG level results in increasing insulin secretion. It's actually a bit more sophisticated than that. Beta cells can store insulin and dump it into the blood if there is a sudden increase in BG level. This is analogous to the accelerator pump in a carburettor, which dumps petrol into the engine if you slam your foot on the accelerator pedal, i.e. it produces a rapid response. The dumping of insulin from beta cell storage is known as the Phase 1 insulin response. If this (or the accelerator pump) fails, there is a lag in the response; this will become significant below.

Increasing BG level results in increasing insulin secretion from beta cells and is known as the Phase 2 insulin response.

The other part of a NFB system is the inverting (more in → less out) feedback part, which in this case is split into three parts, all working in parallel. They are:

1. Liver - increasing insulin level results in decreasing Hepatic Glucose Production.
2. Muscle cells - increasing insulin level shifts GLU-T4 transporters which shuttle glucose from the blood into cells, decreasing BG level.
3. Fat cells - increasing insulin level shifts GLU-T4 transporters which shuttle glucose from the blood into cells, decreasing BG level.

What can go wrong?
There are three main types of diabetes:

1) Type 2 diabetes. This is by far the most common (about 95% of all cases) and is usually caused by abdominal obesity. Type 2 diabetes has two main mechanisms going on. The first is a progressive insulin resistance of target tissues, possibly caused by increased levels of saturated fatty acids being fed to the liver from abdominal fat stores, chronically-high BG and insulin levels caused by chronically over-consuming high glycaemic load carbohydrates, possibly accompanied by large amounts of saturated fat and/or large amounts of omega-6 fat. A sedentary lifestyle lowers the sensitivity of muscle cells to insulin. Insulin resistance also has a hereditary link. It may also be linked to a Vitamin D deficiency, see here.

Insulin resistance weakens the feedback in the NFB system, resulting in further increased BG and insulin levels (hyperinsulinaemia). Increased BG level causes increased damage to beta cells by glycation. Increased insulin level causes further insulin resistance as target tissues become increasingly insensitive (a bit like louder and louder music making you progressively deafer and deafer). Eventually, beta cells become too damaged to secrete sufficient insulin and insulin levels begin to fall. This results in a massive rise in BG level and this is now full-blown Type 2 diabetes. There are five main treatments for Type 2 diabetes:

1. Lifestyle interventions - reduced intake of high glycaemic load carbohydrates and/or increased intake of omega-3 fats and/or increased intake of Vitamin D3 and/or increased intense exercise and/or loss of abdominal fat.
2. Sulphonylureas - drugs which stimulate beta cells to secrete even more insulin. Unfortunately, that's a bit like flogging a dying horse as it doesn't address the problems caused by weakened feedback and eventual beta cell failure is inevitable, resulting in the need for insulin injections.
3. Biguanide drugs such as Metformin - increase insulin sensitivity in target tissues. This strengthens the feedback in the NFB system, which results in reduced BG and insulin levels. This combined with lifestyle interventions can return the NFB system to normal operation.
4. Thiazolidinediones - also increase insulin sensitivity in target tissues, e.g. muscle and fat, as well as possibly improving the secretory function of beta cells.
5. Insulin injections take the strain off beta cells, but may worsen insulin resistance.

2) Type 1 diabetes. This is much less common (about 5% of all cases) and is caused by an autoimmune disease. One possible mechanism is as follows: Due to an increase in Zonulin (see here ), the gut becomes more permeable than it should (a.k.a. Leaky Gut Syndrome) and allows protein fragments to pass into the blood. These are destroyed by antibodies. However, if a protein fragment happens to have the same sequence of amino acids as a protein in our own body, the antibodies then set about destroying parts of our own body. Examples of this are gluten (proteins found in wheat, rye, barley and oats) producing antibodies in the blood that can destroy the gut causing Coeliac Disease or skin cells causing Dermatitis Herpetiformis or mucous membranes causing Sjogren's Syndrome or brain cells causing Cerebellar Ataxia. As there is an association between the consumption of cows' milk and the incidence of type 1 diabetes (see here ), it's quite possible that, in susceptible individuals, fragments of casein protein enter the blood in this way resulting in antibodies that destroy pancreatic beta cells. Another possible mechanism is autoimmune attack after a viral infection. Once all of the beta cells are destroyed, no insulin is secreted and insulin injections are required. If some beta cells survive, there is a possibility that normal BG level can be maintained if sugary/starchy carbohydrate intake is reduced.

3) Latent Autoimmune Diabetes of Adulthood (LADA). The percentage of cases with this is unknown as it is often misdiagnosed as type 2 diabetes. This is a slow developing diabetes that is more like type 1 in origin (autoimmune with antibodies) but is often misdiagnosed as type 2 because of the age at diagnosis and the relatively slow progression of the disease (slow compared to type 1 but fast compared to type 2). See here. It is believed that Sir Steven Redgrave has this. Whether or not his autoimmune disease was triggered by a huge intake of milk (to build those Olympic-winning muscles), we will never know.

What else can go wrong?
As stated earlier, loss of the Phase 1 insulin response can occur. This usually happens when beta cells are chronically over-secreting insulin due to a chronically-high intake of sugary/starchy carbs and are unable to store any. This results in a lag in insulin response. This isn't a problem if low glycaemic load carbs are eaten and BG levels change only a little or very slowly. However, if high glycaemic load carbs are eaten, this produces a large and rapid rise in BG level. If a NFB loop with a lag in it is presented with a sudden change in input level, its output overshoots. This results in too much insulin being secreted, which eventually results in low BG levels! This is known as rebound hypoglycaemia. The solution? Stick to low glycaemic load carbs.

Where does blood glucose come from if I haven't eaten?
When no sugary/starchy carbs are being digested, BG starts to fall. Adrenaline and noradrenaline (catecholamine hormones) are secreted by the adrenal medulla into the blood and also by sympathetic neurons. Like glucagon (see below), they stimulate the mobilisation of glycogen and triacylglycerols (stored fats) by triggering the production of cyclic AMP (adenosine monophosphate). Adrenaline and noradrenaline differ from glucagon in that their glucose-producing effect is greater in muscle glycogen than in liver. They also inhibit the uptake of glucose by muscle. Instead, fatty acids released from adipose tissue are used as fuel. Adrenaline also stimulates the secretion of glucagon and inhibits the secretion of insulin. Thus, catecholamines such as adrenaline and noradrenaline increase the amount of glucose released into the blood by the liver and decrease the utilization of glucose by muscle.

Pancreatic alpha cells secrete glucagon. This hormone mobilises the conversion of liver glycogen into glucose. The liver only stores about 70g of glycogen, but when combined with water, a larger mass of glucose is generated. Eventually, liver glycogen stores become depleted and BG level falls again. Glucagon also stimulates gluconeogenesis in the liver & kidneys, which is the production of glucose from non-carbohydrate precursors, like the conversion of glucogenic amino acids, such as glutamine, into glucose. See Liver and Kidneys Synthesize Glucose. This causes slow muscle wastage unless there is sufficient protein intake to provide the necessary amino acids. When BG falls to about 3.3mmol/L, the pituitary gland kicks-in and secretes ACTH (adrenocorticotropic hormone) which stimulates the release of cortisol from the adrenal cortex. Cortisol further stimulates gluconeogenesis in the liver & kidneys. When BG level falls to about 2mmol/L, the pituitary secretes GH (Growth Hormone) which has an anti-insulin effect.

What else does insulin do?
Insulin has many metabolic effects in the body apart from lowering BG level. It's a very anabolic hormone and an insulin spike is usually desired post workout to maximise the uptake of glucose and amino acids by muscle cells. There's nothing wrong with the occasional short-term insulin spike. It's chronically-high insulin levels that cause long-term health problems like high blood pressure and clogging of arteries.