Gizmag: Injectable nanoparticles maintain normal blood-sugar levels for up to 10 days.

Fascinating technology featured in Gizmag & posted by someone HERE.

The nano-network that releases insulin in response to changes in blood sugar

"The injectable nano-network is made up of a mixture that contains nanoparticles with a solid core or insulin, modified dextran (which is commonly used to reduce blood viscosity), and glucose oxidase enzymes. When exposed to high levels of glucose, the enzymes convert glucose into gluconic acid, which breaks down the modified dextran to release the insulin. The gluconic acid and dextran, which are biocompatible, dissolve in the body, while the insulin brings the glucose levels under control.

The nanoparticles are given a positively or negatively charged biocompatible coating so that when they are mixed together, they are attracted to each other to form a “nano-network.” The positively charged coatings are made of chitosan, a material found in shrimp shells that has also found applications in self-healing car paint, while the negatively charged coatings are made of alginate, a material normally found in seaweed."

Wow! Cool bananas!

When the only tool in the box is a hammer...

Everything that needs fixing looks like a nail.

What are the action and reaction forces when a hammer hits a nail?

Diabetics are issued with blood glucose meters - and nothing else.

For people with type 1 diabetes, that's fine. They lack insulin, so they have to inject insulin in the right amounts & types to keep their blood glucose levels within reasonable limits. Applying Bernstein's Law of small numbers by reducing carbohydrate intake to a minimum keeps blood glucose levels within reasonable limits (between 3 & 7mmol/L) most of the time.

For people with type 2 diabetes and a fat belly (~85% of type 2 diabetics), that's not fine. Their disease is a disease of excess, causing dyseverythingaemia (hyperglycaemia, hypercholesterolaemia, hypoHDL-cholesterolaemia, hyperNEFAaemia, hypertriglyceridaemia, hyperuricaemia, etc). However, because the only tool in their box is a blood glucose meter, their disease looks like a disease of high blood glucose level (hyperglycaemia) only. Applying Bernstein's Law of small numbers by reducing carbohydrate intake to a minimum keeps blood glucose levels within reasonable limits, but makes everything else worse if energy from carbohydrates is replaced by energy from fats.

EDITED to include information in the comments: Only if energy from carbohydrates is reduced to a minimum AND energy from fats isn't increased to compensate (i.e. eat a PSMF or a Modified PSMF), does carbohydrate restriction help people with type 2 diabetes.

Can very-low-carb diets impair your mental faculties?

I wanna tell you a story...

In 2006, I had a test done on my pituitary gland*, called an Insulin Shock Test. It was pretty much what it said on the tin. I laid on a hospital bed, I was injected with an overdose of insulin and I was monitored for blood glucose and growth hormone levels every 30 minutes.

My blood glucose fell and fell and fell and fell until it reached ~1.5mmol/L (~27mg/dL). What happened was interesting. I came out in a cold sweat and developed a tremor. Apart from that, I felt fine. The consultant in charge was chatting to me and I was chatting to him. Eventually, I was given a sandwich, a yoghurt and a banana to eat.

Some time later, when I had stopped sweating and shaking, the consultant returned and told me that I had become confused. My brain had ceased to function correctly due to a lack of blood glucose (the insulin had totally suppressed serum FFAs and ketones, so there were no other brain fuels available), but I was too mentally-impaired to know that I was mentally-impaired. As far as I was concerned, everything was fine & dandy. This is the Dunning-Kruger effect.

Referring to Blood Glucose, Insulin & Diabetes, as blood glucose falls due to either starvation or a lack of dietary carbohydrate, insulin falls and glucagon rises, stimulating the liver to convert liver glycogen into glucose for export to the blood. Eventually, liver glycogen becomes depleted and blood glucose falls again. The pituitary gland notices this and secretes AdrenoCorticoTropic Hormone (ACTH) which stimulates the adrenal cortex to secrete cortisol. The adrenal glands are also stimulated to secrete adrenaline (a.k.a. epinephrine). Cortisol increases the conversion of amino acids and other substrates into glucose by the liver and kidneys. If blood glucose continues to fall, the pituitary gland secretes growth hormone (GH), which has an anti-insulin effect.

From http://anthonycolpo.com/boosting-growth-hormone-with-diet-training-fact-or-fiction-part-2/:-
"after the zero-carb phase, subjects reported symptoms of hypoglycemia that included weakness, irritability, mental confusion, nausea, hunger, cold sweating and disturbed co-ordination. GH levels were higher during exercise after the low-carb phase, but so too were levels of other fuel mobilizing hormones such as epinephrine, glucagon, and cortisol." Epinephrine, glucagon, and cortisol are stress hormones. Chronically-high blood levels of stress hormones disrupt sleep and cause irritable, aggressive behaviour.

Ethanol inhibits gluconeogenesis in the liver (possibly also in the kidneys) resulting in worse hypoglycaemia. Worse hypoglycaemia results in more ACTH & adrenaline secretion and worse hypercortisolaemia, which can adversely affect the hippocampus, impairing memory.

In conclusion, if you want to eat a very-low-carb diet, long-term:-1) Don't do much high-intensity exercise. See "Funny turns": What they aren't and what they might be.
2) Don't drink much (if any) booze.

See also Can Low-Carb Diets Make You Crazy?

*My pituitary gland failed the test by secreting only 40% the amount of GH that it was supposed to. For six months, I was given GH to inject using a special pen with a 8mm x 0.3mm needle. By the end of the six month trial, I had perfected the art of painless injection. The trial was discontinued due to lack of any noticeable benefit (17 days supply of GH @0.3mg/day cost £120!).

Hyperinsulinaemia and Insulin Resistance - An Engineer's Perspective.

Another techie post.

From http://en.wikipedia.org/wiki/Negative_feedback_amplifier

There's been some arguing discussion over whether Hyperinsulinaemia (HI) causes Insulin Resistance (IR). My answer is...Yes and No.

HI increases IR long-term. See Downregulation and upregulation: The Insulin Receptor and Insulin oscillation.

HI doesn't increase IR short-term. How can I claim this? The above diagram represents a Negative Feedback Control System, which is how Blood Glucose is regulated.

"Input" represents Glucose from digested sugars and starches. The arrow pointing at AOL represents Blood Glucose (BG). The triangle containing AOL represents pancreatic beta cells. "Output" represents Insulin Secretion (ISec). More BG = More ISec.

The box containing ß represents three things that work in parallel to reduce Blood Glucose.
1) The Liver. More ISec = Less BG Production.
2) Muscle mass. More ISec = More BG imported to Muscle mass, via Glu-T4.
3) Fat mass. More ISec = More BG imported to Fat mass, via Glu-T4.
The three things aren't of equal strength, but they provide overall negative feedback.

If overall negative feedback is halved due to doubling of overall IR in the above three paths, ISec doubles. If you don't believe me, see Idealised Negative Feedback Inverting Amplifier using an idealised op amp on WolframAlpha. Double the value of resistance 2 (the negative feedback resistor Rf) from 10,000ohms to 20,000ohms and the output voltage on the inverting amplifier doubles from -10V to -20V.

The idealised Negative Feedback Inverting Amplifier using an idealised op amp on WolframAlpha is interesting in that an idealised op amp (the triangle with + and - inputs) has infinite gain and infinite voltage on its power supplies. As a result, there is zero volts (output voltage divided by infinity) between the idealised op amp's + terminal and its - terminal. If the idealised op amp's + terminal is connected to 0V (a.k.a. "Earth"), its - terminal is at 0V (a.k.a. "Virtual Earth") and has zero variation, whatever the input voltage. An actual op amp has a voltage gain of ~140dB (~10,000,000), so an output voltage of -10V can be achieved with a voltage of 1uV (one millionth of a Volt) on its - terminal.

If pancreatic beta cells had a zero threshold and infinite gain like an idealised op amp, BG would be zero and have zero variation with varying Glucose input. Pancreatic beta cells actually have a positive threshold and low gain, so BG is positive and has significant variation with varying Glucose input.

If ISec becomes zero (as in type 1 diabetes), there is zero negative feedback and BG goes up a lot. The same thing happens to the voltage on the idealised op amp's - terminal if its power supplies are 0V instead of infinite.

If ISec becomes insufficient (as in type 2 diabetes), there is insufficient negative feedback and BG goes up a bit. The same thing happens to the voltage on the idealised op amp's - terminal if its power supplies are 5V.

Having established that ISec is proportional to overall IR, what would happen if overall IR was proportional to ISec? If ISec doubled, overall IR would double, which would double ISec, which would double overall IR, ad infinitum. ISec would increase to maximum. THIS DOESN'T HAPPEN. Therefore, IR doesn't increase in proportion to ISec, short term.

Long-term, increased ISec increases IR for a variety of reasons, one of them being that increased ISec increases the rate at which cells fill with glycogen. Once full of glycogen, cells must down-regulate their import by down-regulating Glu-T4 and Glu-T2 (fat and liver cells also up-regulate their export of stuff) or rupture.

So, deplete your cells of glycogen by eating a diet that results in you unconsciously eating less and moving more. Also, do some higher-intensity exercises. Chris Highcock emailed me a link to Muscular strength and markers of insulin resistance in European adolescents: the HELENA Study.

A comment, a simile and insanity.

A lot of my recent titles contain three items.

1) The comment: I'm just about to leave the following comment on Peter (Hyperlipid)'s blog post Insulin and the Rewards of overfeeding. I thought that it was so good at summing-up, I'll post it here first!

"All,

Insulin increases the amount of glucose & FFAs entering fat cells, muscle cells & the liver.

Insulin decreases the amount of glycerol & FFAs exiting fat cells & the amount of glucose exiting the liver.

Hyperinsulinaemia (which can produce sedation) results when one or more of the following tissues loses insulin sensitivity:- fat cells, muscle cells & the liver.

So, why do people keep saying that hyperinsulinaemia locks nutrients away in fat cells only, thus robbing other cells of nutrients, thus causing lethargy?

The relative insulin sensitivity of tissues determines the relative partitioning of nutrients into those tissues.

When tissues lose sensitivity to insulin, blood glucose control becomes impaired. This results in a roller-coaster blood glucose level after eating high-glycaemic carbohydrates. A rapidly-falling blood glucose level can cause ravenous hunger. I have experienced this during medically-monitored tests (OGTTs & an insulin shock test).

Low-carb/ketogenic diets don't result in a roller-coaster blood glucose level and therefore don't cause ravenous hunger. Simples!

Over-eating due to ravenous hunger is NOT gluttony, just as under-moving due to sedation is NOT sloth.

THIS is gluttony."

EDIT: This didn't go in my comment but should have:- "Low-carb/ketogenic diets result in the avoidance of moreish & calorific foods such as sweets, chocolate, cake, biscuits, pizza, Pringles etc. A single bite of such foods has a negligible effect on blood glucose & insulin levels, but encourages another bite and another and another ad nauseam due to Food Reward.

2) The simile: I use similes. I used the simile "As happy as a pig in shit" in a comment somewhere on Woos blog. Now, you may (or may not) have noticed that my user-name is Nigeepoo. We Brits are obsessed by two things - The weather and our bowel movements. I find things to do with poo and farting amusing (schoolboy humour, I know!). I used the simile "As happy as a pig in shit" because it is amusing to me.

3) The insanity: According to Woo in the following comment:-

"Re: the comment...Sorry, not convinced.
You are basically refusing to admit your choice of words implied moral judgement. The phrase "happier than a pig in shit" is always applied to examples of people being content in immorality/bad behavior particularly gluttony and sloth... unless it is used ironically. Only an autistic or a non-english speaker would believe this crap."

Woo, you are as mad as a March hare. IMO of course, like everything I write. Duh!

How eating sugar & starch can lower your insulin needs.

This is a bookmarking post. Jason Sandeman is a chef who has a couple of web-sites at Well Done Chef! and Jason Sandeman — Real Food For Your Life. He has Latent Autoimmune Diabetes of Adulthood (LADA), which has resulted in a total loss of his pancreatic beta cells which means that he has to take insulin.

Now, it's generally believed in low-carb circles (and by myself) that people with Type 1 Diabetes Mellitus (T1DM) should minimise their intake of sugary & starchy carbohydrates as these promote wild fluctuations in blood glucose. See The problem with Diabetes.

Jason wrote the following comment on Richard Nikoley's blog. The relevant part is as follows:-
"Even more weird – now that I have introduced the starches into the diet – I have actually got better control now. I thought my insulin needs would go up – but they haven’t. They’ve gone down."

To which I replied:-"How about this for an explanation? You now have a well-controlled glucose input to your circulation via diet, which has suppressed the poorly-controlled glucose input to your circulation via hepatic glucose production."

Hepatic glucose production (HGP) is increased by Glucagon, Cortisol & Adrenaline/Epinephrine. These are secreted as blood glucose level falls below certain values in order to keep our brains alive. See Blood Glucose, Insulin & Diabetes.

As keeping our brains alive is rather important (!), the mechanism is fairly crude in operation and blood glucose can overshoot in a positive direction, as a bit of glycation is less harmful than brain death. See "Funny turns": What they aren't and what they might be. Hyperglycaemia requires insulin to lower blood glucose back to the normal range.

Therefore, eating some (but not too much) sugar & starch can result in lower blood glucose level and lower insulin secretion. Eating fibre/fiber (a carbohydrate) is also good for keeping blood glucose low, as only just mentioned in Fiber and Insulin Sensitivity. Ain't the human body weird?

At first I was afraid, I was petrified...

My titles are becoming increasingly blatantly song-orientated. No YouTube video, this time.

I just read Hans Wu's latest post Alzheimer's and Dementia and had a few thoughts.

1) In the early stages of mental decline, there is still self-awareness and the process is frightening. Constant reassurance is the best thing for somebody in this state. As self-awareness fades, one becomes happy. An example of this is HAL-9000 as his memory modules were being unplugged in the film "2001 a space odyssey". My mum is in this state, thank goodness.

I entered this state temporarily during an Insulin Shock Test on my pituitary gland, when my serum glucose fell to 1.5mmol/L (27mg/dL) under medical supervision. I was blissfully unaware of my confusion. Too much alcohol in the blood also causes loss of self-awareness. I entered this state last week while socialising with a friend. After half a bottle of White Zinfandel, I was blissfully unaware of my merriness!

2) When I see "arterial stiffness", I think "inappropriate calcification" and "Vitamin K2".

3) Transient Ischaemic Attacks (TIAs a.k.a. mini-strokes) cause loss of blood flow to parts of the brain, resulting in amnesia. There may be some permanent brain damage, depending on how long the TIAs last. TIAs can be caused by spasms in arteries within the brain. Ditto migraines.

When I see "spasm", I think "magnesium".

How stuff works, Part 2.

I'm the kind of person that likes to analyse everything to death (and make lists).

1) Here's what I wrote on Synthesis: Low-Carb and Food Reward/Palatability, and Why Calories Count:-
"I’m going to stick my neck out here and state that fat, sedentary people do better on low-carb diets because:-

Fat, sedentary people have severe muscular insulin resistance.
This results in chronic hyperinsulinaemia and acute hyperinsulinaemia on eating carbs (which causes lethargy & increased sedentariness).
Chronic hyperinsulinaemia impairs the Phase I insulin response.
This impairs the stability of the blood glucose control system, resulting in large fluctuations in blood glucose level on eating carbs.
A rapidly-falling blood glucose level causes severe hunger pangs (I’ve experienced this under medical supervision).
Severe hunger pangs cause overeating, resulting in increased fatness.
GOTO 1

Low-carb diets reduce the large fluctuations in blood glucose level. Once normal blood glucose control has been restored by bodyfat loss & exercise, low-carb diet is no longer required."

I added a hot-link that wasn't in the original comment. Thanks to Sam Knox for linking to that study.

Lethargy & increased sedentariness result in very few calories burned (BMR/RMR + TEF). Eliminating (lethargy & increased sedentariness) greatly increases calories burned without conscious effort (BMR/RMR + TEF + TEA + NEAT/SPA). This is why people on low-carb diets can eat more and still lose weight. The Energy Balance Equation still applies.


2) I've noticed that people conflate Food Tastiness with Food Reward. Here's my opinion:-

Excessive reward = Moreish. What your food tastes like is only vaguely relevant. Avoid eating moreish foods, unless you're a body-builder who's trying to bulk.

Here's what I wrote on Food Reward: “There’s Always Room For Dessert”:-
"I believe that obesity is physiological AND neurological (the proportions varying from person to person).

For example, one chocolate doesn’t disturb my blood glucose & insulin, but I still crave another. And another. Ad nauseam."

Physiological cravings take hours to kick-in.
Neurological cravings take seconds to kick-in.

Emily Deans wrote:-
"Multiple times I’ve used naltrexone (an opiate blocker) to stop binge eating. The cravings go away. It only takes a few weeks. It’s a nice way to undo addiction/reward without starving someone… not FDA approved."

That's pretty damning evidence for the existence of Food Reward. How can naltrexone block something that doesn't exist?

Finally Monsieur, a waffer-thin mint.

We are not all the same.

Cont'd from Everyone is Different.

Lyle (McDonald) brought the following study to my attention to illustrate that "We are not all the same":- Some Metabolic Changes Induced by Low Carbohydrate Diets. On a very-low-carb diet, one subject’s total cholesterol rose to 12.9mmol/L (500mg/dL in US units). The others didn't.
See also LDL cholesterol goes sky high on fatty diet.

I posted the study in various blogs to make the above point. Here are some of the replies I got:-
"Lyle? Lyle McDonald? Is that where you got that study, Nigel?" and... "I’m usually a pretty polite guy, Nigel. But based on this quote from the beginning of the study you mentioned, the people who wrote this study were a bunch of f**kwads, and really don’t deserve our attention. It’s a hatchet job."
"That was a weird study (1967) what I could make of it." and... "The men did all the stages but the women only did 3 stages of the diet."
"The fats were mostly omega-6 PUFA 13-35 grams worth..."
"The report you cite is so old and out of date that it makes me cry..."

My point was well & truly missed. I got the distinct impression that people thought I was criticising very-low-carb, high-fat diets. I wasn't. The simple fact is that there is no "One True Diet" that suits absolutely everybody. In the olden days everywhere & in poor countries nowadays, people that ate/eat the wrong diet for their body died/die young. Nowadays in rich countries, they get put on drugs e.g. oral hypoglycaemics (to lower blood glucose) & hypolipidaemics (to lower blood cholesterol/triglycerides).

Please note that omega-6 PUFAs tend to lower serum cholesterol rather than raise it, as per Fig. 2 of Types of Dietary Fat and Risk of Coronary Heart Disease: A Critical Review. However, don't rush off and eat shed-loads of omega-6 PUFA (e.g. corn oil) in the mistaken belief that it will make you live any longer. See (1971) Incidence of cancer in men on a diet high in polyunsaturated fat - Pearce.

Finally, for a little light relief, here is the latest result for Google Fight between "Healthy "low-fat diet"" and "Healthy "low-carb diet"". Oh, YES!

Cont'd on Everyone is Different, Part 2.

The problem with Diabetes.

Referring to Blood Glucose, Insulin & Diabetes, a healthy person regulates his/her blood glucose level so that it doesn't go too high or too low. See Control of blood sugar levels.

Someone who has diabetes either has insufficient/no insulin secretion (type 1) or has insulin secretion but it's ineffective (type 2). People with type 1 diabetes have to inject various types of insulin and monitor their Blood Glucose (BG) with a BG meter. Here lies the problem. Consider the following analogy:-

Blood glucose control is like driving down a road cut into the side of a mountain. If you steer too far to the left (low blood glucose), you fall off the edge of the road and die. If you steer too far to the right (high blood glucose), you smash yourself against the side of the mountain. Injecting insulin/taking oral hypoglycaemic agents is like pulling on the steering wheel to the left. Eating sugary/starchy carbs is like pulling on the steering wheel to the right. Exercising is like pulling on the steering wheel to the left.

Not monitoring BG regularly is like driving down the above road with your eyes shut most of the time. You have no idea where you are on the road. Every time you monitor BG, you open your eyes.

A high-carbohydrate diet + high-medication regimen (e.g. ADA & Diabetes-UK) is like pulling on the steering wheel very hard, which results in diabetics veering all over the road. As diabetics don't want to fall off the edge of the road and die, they steer too far to the right (high average blood glucose) and damage themselves by glycation.

A low to very-low-carbohydrate diet + low to very-low-medication regimen (e.g. Bernstein, Christie, Ruhl, Cooksey, Shwarzbein etc) is like pulling on the steering wheel very gently, which results in diabetics steering a reasonably straight course down the middle of the road.

As low blood glucose is potentially fatal, that's why Studies show that a high average blood glucose level has lower mortality than a more normal average blood glucose level.

Everybody knows.........Part 2

.........that ketogenic diets like the Atkins diet destroy your kidneys and rot your bones, right? Wrong!
.........that the Atkins diet causes ketoacidosis which is a very dangerous condition requiring urgent hospital treatment, right? Wrong!

There's a lot of nonsense spoken about ketogenic diets by people who really should know better. I suspect that they have been taught wrongly at uni or med school as per the quote in Everybody knows.........Part 1.

Benign Dietary Ketosis is NOT Ketoacidosis.

Consider the following four cases:- Note: Figures are from "Introduction to Nutrition and Metabolism" By David A Bender (Senior Lecturer in Biochemistry, UCL)

1) Healthy human, fed state: Glycogen stores are replete. Serum glucose = ~5.5mmol/L. Serum fatty acids = ~0.3mmol/L. Serum ketones = 0mmol/L. No gluconeogenesis is taking place. Amino acid pool is replete. Cortisol level is normal so there is no loss of muscle mass.

2) Healthy human, fasting for 7 days: Glycogen stores are depleted. Serum glucose falls to ~3.5mmol/L. Serum fatty acids rise to ~1.2mmol/L. Serum ketones (mainly D-3-hydroxybutyrate) rise to ~4.5mmol/L (not high enough to cause acidosis). Gluconeogenesis is occurring. Amino acid pool is depleted. Cortisol level is high, causing slow loss of muscle mass. This is bad ketosis.

3) Healthy human, low-carbohydrate diet: Glycogen stores are depleted. Serum glucose falls to ~5mmol/L.
Serum fatty acids rise to ~1.2mmol/L. Serum ketones (mainly D-3-hydroxybutyrate) rise to ~4.5mmol/L (not high enough to cause acidosis). Gluconeogenesis is occurring. Amino acid pool is replete (due to protein intake). Cortisol level is normal so there is no loss of muscle mass. This is good ketosis.

4) Human with untreated type 1 diabetes: Glycogen stores are depleted. Due to lack of insulin, the Glu-T4 transporters in cells cannot move to the surface so glucose cannot enter cells. Serum glucose = >20mmol/L. This causes major damage to kidneys, arteries, eyes, nerves etc by cross-linking with proteins (glycation) resulting in major disability and eventual death. As the body is forced to run on fatty acids & ketones, metabolic processes are out of control and ketones rise to much higher levels than in 2) or 3) (I don't know how high exactly) resulting in acidosis and eventual death. This is ketoacidosis.

Conclusion: Low-carbohydrate, very-low-carbohydrate & ketogenic dieting is similar to fasting in that serum glucose levels are lower than normal and glycogen stores are depleted. The body is encouraged to burn less glucose and more fatty acids & ketones, but the metabolic processes are all under control. The big difference between low-carbohydrate dieting and fasting is in the amino acid pool and cortisol levels.

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.