FAO the over-fat and/or those with metabolic syndrome: Big breakfast, medium lunch & small dinner is beneficial.

Breakfast like a King/Queen.

Go to work on an egg.

According to High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women.
"High-calorie breakfast with reduced intake at dinner is beneficial and might be a useful alternative for the management of obesity and metabolic syndrome." See the other PubMed studies listed in the above study, which corroborate it.

What about all the "artery-clogging" cholesterol in egg yolks? See Eat Whole Eggs All Day and Throw Your Statins Away? 375x Increased Dietary Cholesterol Intake From Eggs Reduces Visceral Fat & Promotes Healthy Cholesterol Metabolism.

Resistance is useless!

...said the Vogon guard. If that means nothing to you, watch this...


You probably know all about Insulin Resistance (IR) if you've read my blog for some time, as I may have mentioned it once or twice ;-) There's also Leptin Resistance (LR) in the brain, which reduces the amount of appetite suppression that leptin is supposed to produce. Robb Wolf's just written about Adrenaline Resistance (AR?) and chronically-high serum cortisol seems to induce Cortisol Resistance (CR?) in the hippocampus, resulting in poor short-term memory.

When the level of "X" in the blood is low most of the time, "X" receptors in the body up-regulate, so when the level of "X" in the blood goes high, it has an effect. When the level of "X" in the blood is high all of the time, "X" receptors in the body down-regulate, so when the level of "X" in the blood goes higher, it has a reduced effect.

The above suggests that regularly "grazing" on food is not a good idea, as this results in a fairly constant slightly elevated serum insulin level. Eating a meal, not eating for a few hours then eating another meal results in high serum insulin while the meal is being absorbed and low serum insulin for the rest of the time.

Impaired Glucose Tolerance: also between a rock and a hard place.

A high percentage of people with excessive visceral adiposity (belly fat) have Impaired Glucose Tolerance (IGT). This post is about them.

Image from http://carbsanity.blogspot.co.uk/2013/03/insulinproinsulinetc-in-normal-igt-and.html

IGT is caused by excessive NEFAs spewing into the blood and/or deficiencies and/or sedentariness.

If nothing is done about it, IGT will progress to full-blown Type 2 Diabetes, which will get worse and worse as per the graphs to the right of the IGT one.

To do something about it, see http://nigeepoo.blogspot.com/2011/02/insulin-resistance-solutions-to.html

Type 2 diabetes: your good signalling's gonna go bad.

A little bit of Tammy Wynette.

 

Good signalling:

There's a famine. You've got nothing to eat. Your body's glycogen stores have just run out. What happens next? As food intake is zero, serum insulin level is minimised, so lipolysis (fat mobilisation) is maximised. Serum NEFAs are maximised. High serum NEFAs provides fuel for tissues that utilise NEFAs and a "stop utilising glucose!" signal, in conjunction with low serum insulin. High serum NEFAs also increase ketogenesis in the liver, to give the parts of the brain that can utilise ketones an alternative choice of fuel, to reduce glucose utilisation to a minimum. Glucose utilisation must be minimised during a famine, as it's generated by the liver & kidneys from glucogenic amino acids, obtained from lean body mass (LBM) by hypercortisolaemia.

Gone bad:

You're a type 2 diabetic with a fat belly. For reasons that I don't understand (blood supply? Proximity to liver?), belly fat deposits spew NEFAs into the blood at a much higher rate than arm, boobs, love-handles, bum & thigh fat deposits. On a very-low-carb diet (50g/day carbs), serum insulin level is minimised, so lipolysis (fat mobilisation) is maximised. Serum NEFAs are maximised. High serum NEFAs provides fuel for tissues that utilise NEFAs and a "stop utilising glucose!" signal, in conjunction with low serum insulin. A type 2 diabetic with a fat belly already has underlying insulin resistance, due to over-full muscle, adipose and/or liver cells (making the liver spew glucose into the blood at too fast a rate and the muscles & adipocytes take it out of the blood at too slow a rate). The very-low-carb diet makes the underlying insulin resistance worse and high serum NEFAs in a milieu of caloric sufficiency wreak havoc. Serum fasting glucose level increases. Serum LDL-c level increases. Serum TG level increases. Serum just about everything level increases, except for serum HDL-c level, which decreases.

Type 2 diabetes: between a rock and a hard place.

About 85% of type 2 diabetics have excessive visceral adiposity (belly fat). This post is about them.

Which is better - the rock or the hard place?

1) The rock:

This is serum glucose. People with type 2 diabetes can measure their own serum glucose. Eating carbohydrates makes serum glucose increase, the rate of increase being proportional to the glycaemic index and the magnitude of the increase being proportional to the grams of carbs consumed. By limiting the intake of dietary carbohydrates, large spikes in serum glucose can be avoided. The occasional spike above 7.8mmol/L (140mg/dL) doesn't hurt. It's spending long periods of time above 7.8mmol/L that's harmful (by glycation).

A low-carb diet (~100g/day of carbohydrate) halves serum glucose fluctuations compared to a higher-carb diet (~200g/day of carbohydrate). A very-low-carb diet (~50g/day of carbohydrate) further halves serum glucose fluctuations compared to the low-carb diet. This seems like an improvement, at first glance.

2) The hard place:

This is the invisible "elephant in the room", as it's not measured by doctors and people with type 2 diabetes can't measure it themselves. It's serum Non-Esterified Fatty Acids, or NEFAs (a.k.a. Free Fatty Acids, or FFAs). Serum NEFAs are high when fasting and fall after eating foods that raise serum insulin (carbs & certain proteins). People with type 2 diabetes and excessive visceral fat (belly fat) have higher-than-normal serum NEFAs due to adipocyte insulin resistance (IR). See Insulin Resistance: Solutions to problems.

Just like with serum glucose, there's nothing wrong with serum NEFAs going up & down. It's chronically-high serum NEFAs that's harmful (except during periods of caloric restriction). See Showing posts sorted by relevance for query NEFA "type 2 diabetes" .

See Fig. 1 in Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet. On a very-low-carb (less than 50g/day carbs) diet that's not calorie-restricted, serum insulin remains low all of the time. To insulin-haters, that sounds like a good thing. Unfortunately, it means that there is no insulin spike to suppress serum NEFAs by shifting the balance of NEFAs going in/coming out of fat cells. Serum NEFAs stay high all of the time, which is harmful.

Therefore, people who have type 2 diabetes and excessive visceral fat and who are permanently on a very-low-carb diet that's not calorie-restricted are harming themselves.

Type 2 diabetes in the UK.

From Insulin usage in type 2 diabetes mellitus patients in UK clinical practice: a retrospective cohort-based analysis using the THIN database:-

"Importantly, this analysis has been conducted using routine data from UK clinical practice, which allows an insight into how patients are managed in current UK practice. In summary, this study demonstrates a persisting delay both in oral therapy escalation and insulin initiations in patients with type 2 diabetes, with a relative reduction in the effectiveness of oral therapy escalation. There is an apparent threshold HbA1C of > 8.5% beyond which additional oral therapy in routine practice appears unlikely to achieve an HbA1C target ≤ 7.0%.
This study thus highlights the need for more timely escalation of glucose-lowering therapy, including insulin initiation, in order to limit unnecessary patient exposure to hyperglycaemia and associated serious consequences, such as macro-vascular and micro-vascular complications."

An HbA1C of 7.0% still results in macro-vascular and micro-vascular complications. If someone develops type 2 diabetes in the UK, the NHS isn't going to save them. They have to save themselves.

See also Having Diabetes and Car Insurance and Applying for a Driving Licence and Informing the DVLA. Basically, developing type 2 diabetes in the UK sucks.

People who have Impaired Glucose Tolerance need to take action to prevent their condition from deteriorating into full-blown Type 2 diabetes. See http://nigeepoo.blogspot.co.uk/search/label/Diabetes.

The unusual suspects.

In The usual suspects., I banged on about deficiencies in Vitamin D3, long-chain omega-3 fatty acids (EPA & DHA) and Magnesium.

It's the one on the right. Our right, not their right.

According to Jane Karlsson, the iron-manganese ratio and the zinc-copper ratio are also very important. Very-low-carb diets can in theory cause iron overload (if lots of red meat is eaten) and deficiencies in manganese and copper. This may be why people on such diets often find that their glucose tolerance doesn't improve.

Dietary copper and risk of coronary heart disease.
Meat diets and fragile bones: inferences about osteoporosis.
PubMed search for Klevay LM[Author]

For the top 999 foods highest in Manganese per 100g serving, see HERE.

For the top 468 foods highest in Copper per 100g serving, see HERE.

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!

Obesity is multi-factorial, spectra and other stuff.

This post is a hotch-potch of thoughts that are currently whizzing around in my brain.

1) Obesity: Like just about everything in life, obesity is multi-factorial. Each factor may have only a small impact on obesity. Tackling one factor alone won't solve the problem. Every factor has to be tackled, one at a time.

So, New York City Mayor Michael Bloomberg announcing a ban on sales of sugary drinks larger than 16 ounces in restaurants, delis, sports arenas, and movie theaters won't solve the obesity problem, but it will help.

EDIT: In shops and supermarkets in the UK, tobacco products now have to be kept out of sight. I'd like to see the same thing happen to Crap-In-A-Bag/Box/Bottle (CIAB).

2) Spectra: As also mentioned in my first link, there is a spectrum of fatness in the general population which probably follows a bell distribution curve. From skinniest to fattest, there are people who are:-
Extremely skinny. Very skinny. Skinny. A bit skinny. Average. A bit fat. Fat. Very fat. Extremely fat.

If you take somebody in a category who isn't currently consuming CIAB and introduce CIAB to their diet, what happens? They move to a category to the right. Therefore, it's possible for there to be very skinny people who consume CIAB. Therefore, anybody who (or should that be Wooo?) states that the existence of very skinny people who consume CIAB is proof that Food Reward doesn't exist is wrong.

3) Other stuff: I am concerned with people overlooking postprandial (a.k.a. nonfasting) triglycerides (a.k.a. triacylglycerols a.k.a. TAGs a.k.a. TGs) after eating large amounts of fat. According to Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women, serum TGs 2-4 hours post-meal are very significantly associated with Cardiovascular Events (fully adjusted hazard ratio [95% confidence interval] for highest vs lowest tertiles of levels, 4.48 [1.98-10.15] [P < 0.001 for trend]).

After 4 hours post-meal, serum TGs are cleared from circulation by being burned by muscles and/or by being stored in fat cells. See Figure 3B in Extended effects of evening meal carbohydrate-to-fat ratio on fasting and postprandial substrate metabolism.

How care homes are starving their residents to death.

Now that I have your full attention (!), care & nursing homes give their residents plenty to eat & drink, so they are not starving them to death in the conventional sense.

So, what am I talking about? Clue:- UVB cannot penetrate window glass. Watch this video.


I'm talking about Vitamin D starvation.

At this time of year, care home residents are dying like flies. My sister (who worked in a care home years ago) told me that this is normal. Three died at mum's care home in the same week recently. All of the residents have one thing in common. They're all pale.

Old people feel the cold, so if they do go outside between March and September, they're covered from head to toe in clothes. They synthesise minimal Vitamin D in their skins for their bodies to store. Then, between September and March, their bodies use up those stores. Vitamin D levels decay exponentially , with a half-life of about 60 days. As Vitamin D levels fall, the risk of getting viral infections greatly increases, mood worsens, aches and pains worsen, blood glucose control worsens, the risk of getting cancer greatly increases. Need I go on?

As Dr. Richard M. Cooper (Private GP, Harley Street) pointed out, ALL of his patients were low in Vitamin D and they were active people who could go outdoors. Many care home residents can't go outdoors. They can get a paltry 400iu Vitamin D from an Adcal-D3 chewable tablet, but they're huge things that taste like sweetened chalk and cause constipation (mum hated them).

Death by Vitamin D starvation is a long, drawn-out process that reduces the quality & length of life for care home residents. Something needs to be done about it. All care home residents should have their serum Vitamin D levels tested and be given Vitamin D3 accordingly. I have broached this subject with the manager of mum's care home.

Mum's on 5,000iu/day of Vitamin D3. Although she is now fairly non compos mentis, she still smiles a lot and laughs at my dreadful jokes. She is also infection-free.

EDIT: Here's a transcript of the important bits from the above video:-

"At this care home, they're proud of their varied menu. Even so, the Government recommends supplements for the over 65's as well as children under 3 and women who are pregnant or breast-feeding. But health charities are demanding clearer guidelines and better advice. Because research into Vitamin D deficiency has revealed associations with all sorts of conditions, including Multiple Sclerosis, Diabetes, Arthritis, Osteoporosis, Heart Disease and even some cancers."

Dr Carrie Ruxton (Nutritionist) said:-
"What I think the Government should do is promote its own policies. It had a policy for years to recommend Vitamin D supplementation for vulnerable groups, like elderly, housebound and pregnant & lactating women and children but at the moment, that's not being done. In my own example, I was pregnant twice and nobody told me to take Vitamin D supplements."

This is unacceptable. As the manager at mum's care home is not responsible for the residents' supplementation, I will be taking this up with the MP for the area.

Update: I spoke to the nurse on Friday 2nd March about mum's medical history. Before Vitamin D3, mum had a Urinary Tract Infection in the previous 9 months. Since Vitamin D3, mum has had no medical problems and she has been happy & contented. Her serum Vitamin D level is in the normal range.

Does it really matter?

I mean, does it really matter exactly how & why low-carb diets work? My thoughts...



There's a lot of in-fighting on the internet about low-carb & paleo diets etc. Which is "best", exactly how they work and so on. I don't believe that there is a best diet. Everyone is different (in genetics, environment, activity etc). To boil it down to the basics:-

1) Eat real food that hasn't been buggered-about with too much. Grains that have had the outer husk removed (e.g. white rice) are O.K. Grains that have been rolled flat or inflated to a large size by heating to >100°C are O.K. Grains that have been ground into dust are not O.K.

2) If eating "X" causes you problems, stop eating "X". If certain proteins cause you problems, you either have a genetic condition (e.g. coeliac disease) or excessive gut permeability. The first isn't fixable but the second may be. If certain carbohydrates cause you problems, you either have a genetic problem or insulin resistance. The first isn't fixable but the second may be.

The real enemy here is the food manufacturers. They don't want people to stop eating their highly-profitable Crap-in-a-Bag/Box/Bottle (CIAB), as it's bad for business. They also influence Governments. So let's stop fighting amongst ourselves and attack the real enemy any way that we can. Lead by example.

You pusillanimous pipsqueak!

Who said that? To whom? Answer HERE.
We're all insignificant in the scheme of things. Here's another Eric Idle classic.


"And pray that there's intelligent life somewhere up in space, 'cause there's bugger-all down here on Earth." LOL.

Sometimes, I get the feeling that I'm invisible. I write about stuff and a few weeks later, people are arguing about stuff that I've written about. For instance...

What becomes Insulin Resistant first? Liver, Muscle or Fat-mass?
CarbSane says "Where does insulin resistance start? The adipose tissue."
Stephan Guyenet says "I'm not so sure that insulin resistance begins in adipose tissue."

So who's right? They both are. As Lyle McDonald says "It all depends." Referring to Insulin Resistance: Solutions to problems, whatever fills up first becomes IR first. Or have I got it all wrong? Comments, please!

Am I even more insignificant because I have an Engineering Degree but zero qualifications in the field of diet & nutrition? Dr Richard K Bernstein used to be an Engineer. He's done very well as a doctor.

Bearing in mind the title, I'd better put a picture of me below.

Inflammation: Is omega-6 really to blame?

Take a look at the following diagram from Tripping Lightly Down the Prostaglandin Pathways showing the omega-6 and omega-3 pathways.


Omega-6 pufas result in the production of Series 1 prostaglandins (anti-inflammatory) and Series 2 prostaglandins (inflammatory). Omega-3 pufas result in the production of Series 3 prostaglandins (anti-inflammatory).

Now, see Are diets high in omega-6 polyunsaturated fatty acids unhealthy?

"Insulin sensitivity might be the common factor relating disease to fatty acid metabolism — both within and between the fatty acid pathways. A high linoleate to arachidonate concentration occurs in insulin resistance, in diabetic complications and also in some tumours."

"Current epidemiological and clinical evidence supports the regular consumption of cold-water fish as part of a balanced diet, in which attention to lifestyle and the quantities eaten (to prevent obesity and the insulin resistance syndrome) may be more critical than the nature of the fatty acids consumed."

Do you see where I'm going with this? If you have insulin resistance, don't change your diet (low in carbs & avoiding omega-6) to suit the insulin resistance. Tackle the insulin resistance!

This isn't an open invitation to start guzzling high-pufa oils. Stick to oils that have been squeezed out of things that grow in hot climates. I include Extra-Virgin Olive Oil in this category. Check the label, as the pufa contents of different EVOOs vary. Solesta from Aldi contains only 6.6% pufas.

EDIT: In addition, your brain depends on omega-3 to function properly. Too much omega-6 can "fry" it. See Mental Health and Omega 3/6 Ratio, A New Review.

Vitamin D is anti-inflammatory. Fish oils are also anti-inflammatory.


I just spotted this on Anthony Colpo's Blog: The Adventures of Chris “Razzi” Razwell and Other Assorted Internet Psychos. Oh, my!


And finally: I made mum a CD of "Dare" by The Human League (I bought it in vinyl years ago) and played it on the CD/Record player in the lounge at the nursing home. She loved it and was moving her arms in time with the music. This is her favourite track from that album.

Insulin Resistance: Solutions to problems.

Before I start on what may be the most important thing that I've ever written, here's "Don't Stop Movin" by S Club 7. It's a clue to what's coming.


The problem:
Insulin Resistance (IR) is a major problem for a significant percentage of the population in the developed world. It can cause:-

High fasting serum glucose, which increases the risk factor for Coronary Heart Disease.
High post-prandial serum glucose, which increases the risk factor for Coronary Heart Disease, Retinopathy, Neuropathy & Nephropathy (Kidney failure) amongst other things.
High serum cholesterol.
High serum triglycerides, which in conjunction with high serum cholesterol increases the risk factor for Coronary Heart Disease.
High serum Free Fatty Acids (a.k.a. FFAs a.k.a. NEFAs) from IR fat cells, which increases the risk factor for Sudden cardiac death and also worsens IR in liver & muscle cells.
High serum uric acid, which increases the risk factor for Gout & urate Kidney stones.
Hypertension, which raises the risk factor for Coronary Heart Disease, Strokes & Kidney failure.
Excessive appetite after eating high-GL carbohydrates, due to rebound low serum blood glucose, leading to overeating & obesity.
Lethargy after eating almost anything, but especially after eating high-GL carbohydrates, due to compensatory hyperinsulinaemia.
If IR is left untreated, it can deteriorate into type 2 diabetes. See Type 2 diabetes in the UK.

The cause and solutions:
1) "Bad" genes. My genes aren't particularly good, but it is possible to change the expression of your genes.

2) Full cells. A full cell is an IR cell. Consider Liver, Muscle and Fat cells:-

a) Liver cells: Liver cells are a 2-way street. "Stuff" (e.g. NEFAs, Glucose & Fructose) goes in and "stuff" (e.g. Ketones & Glucose) comes out. Glucose normally comes out of the liver at a rate of ~5g/hour to fuel the brain, but this can increase a lot under the control of Insulin, Glucagon & Cortisol. If more stuff goes in than comes out, liver glycogen stores fill up and vice-versa. When liver glycogen stores become full, liver cells down-regulate processes that produce liver glycogen e.g. hexokinase & Glu-T2 transporters. Liver cells effectively become IR to stop more stuff from going in.

However, fructose uses Glu-T5 transporters which are insulin-independent & fructokinase which has a high affinity for fructose, so fructose effectively "barges its way in" to the liver. This is why fructose is a problem for people who have permanently full liver glycogen stores.

b) Muscle cells: Muscle cells are a 1-way street as far as Glucose is concerned, though Amino Acids can go in & come out. Muscle glycogen cannot be used to produce serum glucose - it can only be used by muscles. When muscle glycogen stores become full, muscle cells down-regulate processes that produce muscle glycogen e.g. hexokinase & Glu-T4 transporters. Muscle cells effectively become IR to stop more stuff from going in.

As per It's all in a day's work (as measured in Joules), muscle cells use mostly fat at rest & lowish-intensity exercise. Glycogen usage increases rapidly as exercise intensity increases. Now do you see the significance of the music video above? Intense exercise (e.g. Running, Sprinting, Resistance training with weights, parts of High-Intensity Interval Training a.k.a. HIIT, parts of Tabata & parts of Zumba) depletes your muscle cells and makes them Insulin Sensitive.

This means that exercise is compulsory. I have been in denial for years. Then, Uh-oh! There may be trouble ahead... happened. See Increased Glucose Transport–Phosphorylation and Muscle Glycogen Synthesis after Exercise Training in Insulin-Resistant Subjects and Improvement in Glucose Tolerance After 1 Wk of Exercise in Patients With Mild NIDDM (hat-tip to Go Kaleo). See also Move More: Solutions to problems.

However, don't overdo it! You may have a funny turn, keel over & hurt yourself. See "Funny turns": What they aren't and what they might be.

c) Fat cells: Fat cells are a 2-way street. Fat cells are a bit like balloons that are full of holes. As stuff (e.g. NEFAs & glucose) goes in, the balloon expands to accommodate it. As more stuff goes in and the balloon gets bigger, the internal pressure increases and the holes get bigger, so stuff (e.g. NEFAs & glycerol) comes out at a faster rate. At some level of fullness, stuff comes out as fast as it goes in. At that point, fat cells are effectively IR. So, don't overstuff your fat cells by getting too fat. If you are already too fat, medium intensity exercise (e.g. Walking, Power Walking, Jogging, "Aerobics", parts of High-Intensity Interval Training a.k.a. HIIT, parts of Tabata & parts of Zumba) depletes your fat cells and makes them Insulin Sensitive.

Dress appropriately so that you don't feel cold. Feeling cold is what stimulates your appetite, not exercise. See Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. I go for a 30 minute walk each evening.

3) Deficiency in Vitamin D3.
See Hypovitaminosis D is associated with insulin resistance and ß cell dysfunction.
The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults.
The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men.
Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals.
Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial.

In January 2003, I had impaired Glucose Tolerance (fasting serum glucose = 6.8mmol/L & 2 hours post-75g glucose load serum glucose = 8.7mmol/L). A sandwich used to send me to sleep.

By September 2008, I had normal Glucose Tolerance (fasting serum glucose = 5.0mmol/L & 2 hours post-75g glucose load serum glucose = 3.7mmol/L). I also no longer suffered from hyperinsulinaemic drowsiness. I was also about the same weight that I was in 2003, so the improvement was not due to weight loss.

So, either use a UVB sun-lamp as per instructions to receive a sub-erythemal dose (not quite going pink) or get tested by your GP and supplement with Vitamin D3 accordingly. I take 5,000iu of Vitamin D3/day.

4) Deficiency in Magnesium.
For the top 999 foods highest in Magnesium per 100g serving, see HERE. I take ~4g of Epsom Salts/day (~400mg Mg/day). 

5) Deficiency in Vitamin K2.
See Vitamin K₂ prevents hyperglycemia and cancellous osteopenia in rats with streptozotocin-induced type 1 diabetes. Good sources of Vitamin K2 can be found HERE. I take a Vitacost Ultra Vitamin K with Advanced K2 Complex/day. Note: Warfarin/Coumadin works by depleting Vitamin K, so lots of Vitamin K2 makes Warfarin/Coumadin ineffective. 

6) Deficiency in Manganese. See Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion. For the top 999 foods highest in Manganese per 100g serving, see HERE.

7) Deficiency in, or excess of Copper w.r.t. Zinc. See Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose stimulated insulin secretion. For the top 468 foods highest in Copper per 100g serving, see HERE.

8) Deficiency in, or excess of Zinc w.r.t. Copper. See Zinc, pancreatic islet cell function and diabetes: new insights into an old story. For the top 999 foods highest in Zinc per 100g serving, see HERE.

9) Excessive intake of man-made trans-fats.
Base your diet on Real Food rather than manufactured food products.

10) Excessive intake of chemicals.
Don't swallow toothpaste (fluoride) or disclosing tablets (may contain iodine). Don't hold till receipts between your lips (may be coated in BPA). Don't slather too many chemicals on your skin.

Any other ideas for normalising insulin sensitivity?

Finally, the obligatory picture. Hannah Spearritt is rather nice. :-p

I nearly forgot! Today, when I arrived at mum's nursing home, I found her reading a book. She hasn't done that for over a year. She even knew that it was Wednesday. Ketogenic diet for the win. Mum now has a dual-fuel brain.

Uh-oh! There may be trouble ahead...

I won't deny that I'm not very active. On days that I don't visit my mum, I spend many hours reclining on a sofa with a lap-top on a small table, surfing the internet. I make sloths look hyperactive!

I thought that this wasn't a problem as I also don't eat very much (as I'm so engrossed rummaging through the vast amount of information out there) and I'm maintaining a relatively stable weight.

Then I read Sedentary Physiology at Obesity Panacea which lead me to Sedentary Physiology Part 1 – Not Just The Lack of Physical Activity , full study HERE.

"Hamburg et al. (2007) examined the effect of 5 days of complete bed rest on metabolic health in 22 adult volunteers. Study participants remained in bed for over 23.5 h per day, rising only for matters of personal hygiene. At the completion of the study, despite no changes in body weight, they experienced significant increases in total cholesterol, plasma triglycerides, glucose, and insulin resistance. The changes in carbohydrate metabolism were particularly pronounced, with participants experiencing a 67% greater insulin response to a glucose load following the 5-day intervention."

The thing is, I've never liked sports & formal exercise. In infant school, exercise involved running around in the playground. That, I could do. In primary school, exercise involved running around in the playground, some PE and some outdoor sports (rounders & cricket, using a tennis ball). That, I could also do, although my short legs made me rubbish at running. In secondary school, in addition to PE, there were sports such as football, rugby, cricket, hockey, tennis, swimming & cross-country running. That, I utterly hated (tennis was just about bearable) and so to avoid doing them, I developed an art for forging sick notes in my mum's handwriting. This improved my normal handwriting, so some good came of it. So, what to do?

As toilet breaks force me off the sofa, I shall drink more to make me wee more often. I shall also use the upstairs toilet during the day and the downstairs toilet during the night. See also Eat Less, Move More: Solutions to problems.

I was just thinking......

On a messageboard in a galaxy far far away, someone suggested that as many as one in three people in the UK could have impaired carbohydrate metabolism. This set me thinking.

London is 51degrees North of the Equator, so the sun has to pass through ~45% more atmosphere to reach us, compared to the Equator.

According to Elina Hyppönen & Chris Power, (edited) "The prevalence of hypovitaminosis D was highest during the winter and spring, when 25(OH)D concentrations less than 75nmol/L were found in 87.1% of participants, respectively; the proportion was 60.9%, respectively, during the summer and autumn."

Note that 75nmol/L was insufficient to give me normal Insulin Sensitivity. See Chiu, Chu, Go & Saad. However, greater than 160nmol/L was sufficient, but that was only obtained after I supplemented with 5,000iu/day of Vitamin D3 (25 x RDA).

A deficiency of omega-3 EFAs can cause Insulin Resistance (poor Insulin Sensitivity). See Ghafoorunissa, Ahamed Ibrahim, Laxmi Rajkumar & Vani Acharya, Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG & Pascoe WS and Yam D, Bott-Kanner G, Friedman J, Genin I, Klainman E & Shinitzky M.The typical omega-6:omega-3 ratio in the British diet is ~15:1. This is partly due to the fact that animal produce from grain-fed animals contains a lot more omega-6 and a lot less omega-3 than it used to. See Is food less nutritious than it used to be? Andre Purvis investigates. In addition, people eat grains, nuts, seeds, oils & spreads high in omega-6 and don't eat much oily fish, powdered Flax-seeds (a.k.a. Linseeds) or Purslane (a plant that's relatively high in omega-3).

With all of these problems, I wonder what percentage of the UK population actually do have some degree of impaired carbohydrate metabolism? It might be more than one in three.

According to The eatwell plate, one third of our total Calories are supposed to come from bread, rice, potatoes, pasta and other starchy foods. All of these foods raise blood glucose. Impaired carbohydrate metabolism makes for roller-coaster blood glucose levels which encourages over-eating, leading to obesity (see my Blog post on Blood Glucose, Insulin & Diabetes.)

I think that that's enough thinking for now.

Vitamin K

After Vitamin D, Vitamin K will be the "next big thing" you hear about in the media. Why? Just Google "Vitamin K" and see what comes up. At the top of the list is good ol' Wikipedia.

Vitamin K used to be thought of as only the blood clotting vitamin. Some new-borns have to be given Vitamin K injections to ensure proper clotting. However, Vitamin K is needed for the carboxylation of osteocalcin in Bone Matrix Gla Proteins. The what of what in what? In simple terms, Vitamin K is needed to ensure that dietary calcium goes into your bones, rather than into your artery walls, kidneys, brain etc. A lack of Vitamin K can cause osteoporosis. To prevent/treat osteoporosis, either Vitamin K1 (phylloquinone) or Vitamin K2 (menaquinone or menatetrenone) will do. I used 15mg/day K2 (plus Calcium plus Magnesium plus Vitamin D3) to reverse osteoporosis (bone density -2SD) in my lumbar spine.

However, only Vitamin K2 is effective at removing calcium from the media of artery walls. In The Rotterdam Study, "The relative risk (RR) of CHD mortality was reduced in the upper tertile of dietary menaquinone (K2) compared to the lower tertile (RR 0.43, 95% CI: 0.24, 0.77). Phylloquinone (K1) intake was not related to any of the outcomes." An RR of 0.43 means, on average, a 57% reduction in heart attack deaths. I've now put K2 in Cholesterol & Coronary Heart Disease.

Vitamin K2 is required for brain health. See Look after your brain.

See also Vitamin K₂ prevents hyperglycemia and cancellous osteopenia in rats with streptozotocin-induced type 1 diabetes and Vitamins D and K as Pleiotropic Nutrients.

Good food sources of Vitamin K2 can be found here.

Warfarin antagonises Vitamin K, so it can result in arterial calcification. Anyone taking warfarin should ask their GP for regular check-ups to keep an eye on this potential problem.

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.

Vitamin D

Vitamin D is known as the "Sunshine Vitamin" and it was once thought that a deficiency in it was rare and that it was only involved in calcium homoeostasis in bones and that a lack of it caused only Rickets. Recent research has shown that not only is Vitamin D involved in a whole host of bodily processes, but also that an insufficiency in it is very common, leading to a whole host of degenerative diseases.


What is Vitamin D?
There's a good overview on Vitamin D here.
Here's a presentation called Vitamin D deficiency: The Cause of Everything?
Here's a presentation called Vitamin D and Prevention of Chronic Diseases.
See also Use of Vitamin D in Clinical Practice and Vitamins D and K as Pleiotropic Nutrients.


How common is Vitamin D deficiency?
According to Hyppönen and Power, in a large sample of the white British population born in 1958, 60.9% of subjects had serum 25(OH)D (the active metabolite of Vitamin D) of less than 75nmol/L in Summer & Autumn, and 87.1% had serum 25(OH)D of less than 75nmol/L in Winter & Spring.
Here's my experience of Vitamin D3. For many years, I was struggling to cope with my job and I eventually took early retirement on the grounds of ill-health. In mid-2006 I was given a serum 25(OH)D test and the result was 73nmol/L. As the Reference Range for serum 25(OH)D is 50-200 nmol/L, I was technically not deficient in Vitamin D. Subsequent events suggested otherwise.
In January 2007, after reading the above study and a study by Vieth, Kimball, Hu and Walfish, I began to supplement with 2,000iu/day of Vitamin D3 and also used a UVB+IR lamp for 3 minutes each night. At first, nothing happened and I was pretty sceptical about getting any improvement. However, after about 8 weeks, I began to notice an awakening in my brain. This continued, and by March 2007, I was feeling quite perky. Friends commented on the fact that I had become very chatty and I was also waking early in the morning raring to go, totally unlike my former self. In May 2007, I had another serum 25(OH)D test and the result was 115nmol/L. Another interesting result was my serum triglycerides, something that's usually always higher than desirable. My TGs were 1.4mmol/L (RR less than 1.8mmol/L). This was the lowest result since tests began in 2002.

I began to get bored with standing around stark naked in front of a UV lamp for 3 minutes each night and I stopped doing this. Slowly, my brain began to go back to sleep. I couldn't understand why as I thought that 2,000iu/day of Vitamin D3 (10 x RDA) was more than enough. In November 2007, I had another serum 25(OH)D test. When I saw my endocrinologist in December 2007, I was quite shocked to see that the result was now 70nmol/L. I immediately increased my Vitamin D3 intake to 5,000iu/day (25 x RDA) and within 2 weeks, my brain started to wake up again. In May 2008, serum 25(OH)D was 173nmol/L and in September 2008 it was 163nmol/L. I'm still taking 5,000iu/day.

See also The urgent need to recommend an intake of vitamin D that is effective.


What foods contain it?
For a list of the foods highest in Vitamin D, see here. Beware of foods that have been supplemented, as Vitamin D2 may have been used. This is less effective than Vitamin D3 according to Armas, Hollis and Heaney. Vegetarians and vegans may not want to eat foods containing Vitamin D3 as this is sourced from animals (e.g. the lanolin from a sheep's coat). Eating the Standard English Diet, it is difficult to obtain 5,000iu/day of Vitamin D. The cheapest way to get a lot of it is by going out in the sun in a swimsuit for 20 or so minutes in the middle of the day in Summer and Autumn, which costs absolutely nothing. As Vitamin D is fat-soluble, the body can build up stores to keep itself supplied during Winter and Spring.


Vitamin D deficiency, Insulin Resistance and The Metabolic Syndrome and Type 2 Diabetes
According to Hyppönen and Power, there is a strong association between decreasing 25(OH)D, increasing BMI (Body Mass Index) and increasing HbA1c (glycated haemoglobin).
According to Khaw, Wareham, Bingham, Luben, Welch and Day, increasing HbA1c is associated with increasing Relative Risk of mortality, summarised here.
According to Chiu, Chu, Go and Saad, there is a positive correlation of 25(OH)D concentration with insulin sensitivity and a negative effect of hypovitaminosis D on ß cell function. Subjects with hypovitaminosis D are at higher Relative Risk of Insulin Resistance and The Metabolic Syndrome.

In January 2003, I had impaired Glucose Tolerance (fasting serum glucose = 6.8mmol/L and 2 hours post-75g glucose load serum glucose = 8.7mmol/L). A sandwich used to send me to sleep.
By September 2008, I had normal Glucose Tolerance (fasting serum glucose = 5.0mmol/L and 2 hours post-75g glucose load serum glucose = 3.7mmol/L). I also no longer suffered from hyperinsulinaemic sleeps. Result!


Vitamin D deficiency and Cancer
According to Lappe, Travers-Gustafson, Davies, Recker and Heaney, subjects receiving 1400-1500mg/day supplemental calcium and 1100iu/day supplemental Vitamin D3 have a Relative Risk of getting any type of cancer of 0.402 which is equivalent to a 60% reduction in the risk of getting cancer compared to the non-supplementing group. If the first 12 months results are discarded (to exclude any subjects who already had cancer when they started the study), the RR is 0.232 which is equivalent to a 77% reduction in the risk of getting cancer. I wonder what the result would have been had 5,000iu/day of Vitamin D3 been used.
See also Diaz, Paraskeva, Thomas, Binderup and Hague.


Vitamin D deficiency and Mental function
According to Vieth, Kimball, Hu and Walfish as mentioned above, supplementing with 4,000iu/day of Vitamin D3 produces a large reduction in the "Miserableness Factor" without affecting serum Calcium levels. According to Wilkins, Sheline, Roe, Birge and Morris, Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults.
According to Gloth, Alam and Hollis, Improvement in 25(OH) D is significantly associated with improvement in depression scale scores in a group of 15 subjects with SAD.
According to Cherniack, Troen, Florez, Roos and Levis, Hypovitaminosis D is prevalent among older adults, and several studies suggest an association between hypovitaminosis D and basic and executive cognitive functions, depression, bipolar disorder, and schizophrenia.

Vitamin D deficiency and High Blood Pressure
According to Forman, Giovannucci, Holmes, Bischoff-Ferrari, Tworoger, Willett and Curhan, plasma 25(OH)D levels are inversely associated with the risk of incident hypertension.


Vitamin D deficiency and the Immune System
According to Cannell, Vieth, Umhau, Holick, Grant, Madronich, Garland and Giovannucci, Vitamin D deficiency predisposes children to respiratory infections.
According to Ginanjar, Sumariyono, Setiati and Setiyohadi, The active form of vitamin D produces and maintains self immunologic tolerance.

Vitamin D Deficiency and Falls
According to Dharmarajan, Akula, Kuppachi and Norkus, in the pilot study of older adults with gait imbalance and falls, vitamin D deficiency was observed in 54% of patients tested and previously unrecognised.


Vitamin D Deficiency and Chronic Pain
According to Plotnikoff and Quigley, all patients with persistent, non-specific musculoskeletal pain are at high risk for the consequences of unrecognised and untreated severe hypovitaminosis D.
According to Al Faraj and Al Mutairi, Vitamin D deficiency is a major contributor to chronic low back pain in areas where vitamin D deficiency is endemic.
According to Gloth, Lindsay, Zelesnick and Greenough, there may be a pain syndrome associated with vitamin D depletion that appears as hyperaesthesia worsened by light, superficial pressure or even small increments of movement.


But doesn't the sun damage the skin and cause skin cancer?
Inappropriate sun exposure can certainly damage the skin. Chronic overexposure to the sun (e.g. farmers and other outdoor workers) causes wrinkly, leathery skin and skin cancers such as Basal Cell Carcinoma and Squamous Cell Carcinoma. These are benign skin cancers which are easily removed and rarely fatal. Acute overexposure to the sun (e.g. people getting severe sunburn on foreign holidays) causes the much more serious Malignant Melanoma. This condition, if not caught early enough, has a very high risk of mortality.
However, sensible sun exposure has more benefits than hazards. See Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation. EDIT: See also Is Vitamin D Shooting Me in the Foot?


Is it possible to get too much Vitamin D?
It is possible to overdose with Vitamin D by supplementation. According to Vieth, published cases of vitamin D toxicity with hypercalcaemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intakes of greater than 40,000iu/day. See also Pharmacokinetics of vitamin D toxicity.
People suffering from Sarcoidosis, Primary Hyperparathyroidism, a history of Calcium Kidney Stones and Milk-Alkali Syndrome need to consult their GP before supplementing with Vitamin D. People prescribed Warfarin also need to be careful, as Warfarin is a Vitamin K antagonist, which can result in calcification of tissues.

It isn't possible to overdose by sun exposure, as the metabolic processes down-regulate when ~10,000iu has been produced. To find out when the sun is strong enough to produce Vitamin D in your skin, see the Vitamin D Synthesis in Human Skin Calculator.

EDIT: Insufficient Vitamin A can result in Vitamin D toxicity. See Is Vitamin D Safe? Still Depends on Vitamins A and K! Testimonials and a Human Study.

EDIT: Vitamins A & D are synergistic, not antagonistic. See New Evidence of Synergy Between Vitamins A and D: Protection Against Autoimmune Diseases.

I've found a cheap source of 5,000iu Vitamin D3 gelcaps. See http://www.iherb.com/Vitamin-D3-5-000-IU-360-Softgels/18335 That's a 1 year supply for about £10. First-time buyers can use discount code NIG935 to get $5 off their first order. Standard shipping is $4.

10,000iu Vitamin D3 gelcaps are also available. See http://www.iherb.com/Healthy-Origins-Vitamin-D3-10-000-IU-360-Softgels/21298

EDIT: See Cheapest Vitamin D3 yet. That's a 1 year supply for about £7.50.

Addendum:- Editorials, meta-studies and human Randomised Controlled Trials on Vitamin D and Vitamin D3 over the period 2005 to present.

The Role of Vitamin D in Cancer Prevention
Estimates of optimal vitamin D status.
Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.
The re-emerging burden of rickets: a decade of experience from Sydney.
An excess of widespread pain among South Asians: are low levels of vitamin D implicated?
Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients.
Vitamin D and prevention of colorectal cancer.
Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial.
Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial.
Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial.
Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study.
A system for improving vitamin D nutrition in residential care.
Impact of dietary and lifestyle on vitamin D in healthy student girls aged 11-15 years.
How much vitamin D3 do the elderly need?
Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS).
A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers.
Risk assessment for vitamin D.
Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations.
Serum 25(OH)D levels, dietary intake of vitamin D, and colorectal adenoma recurrence.
The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults.
Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis.
A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study.
Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: the Hoorn Study.
Fracture prevention with vitamin D supplementation: considering the inconsistent results.
A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer.
The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
A single dose of vitamin D enhances immunity to mycobacteria.
Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation.
Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women's Health Study.
Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.
Bone mineral density and bone markers in patients with a recent low-energy fracture: effect of 1 y of treatment with calcium and vitamin D.
Vitamin D deficiency in multicultural primary care: a case series of 299 patients.
Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents.
Vitamin D status and response to Vitamin D(3) in obese vs. non-obese African American children.
Vitamin D and skin physiology: a D-lightful story.
Additive benefit of higher testosterone levels and vitamin D plus calcium supplementation in regard to fall risk reduction among older men and women.
Rapid correction of low vitamin D status in nursing home residents.
Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.
Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease.
Exploration of association of 1,25-OH2D3 with augmentation index, a composite measure of arterial stiffness.
Vitamin D and prevention of colorectal adenoma: a meta-analysis.
The tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency.
Administration of oral vitamin D induces cathelicidin production in atopic individuals.
Estimation of the dietary requirement for vitamin D in healthy adults.
Changes in 25-Hydroxyvitamin D3 to oral treatment with vitamin D3 in postmenopausal females with osteoporosis.
Vitamin D or hormone D deficiency in autoimmune rheumatic diseases, including undifferentiated connective tissue disease.
High-dose oral vitamin D3 supplementation in the elderly.
A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men.
Vitamin D deficiency in older men.
Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial.
Vitamin D supplementation during Antarctic winter.
Vitamin D insufficiency and treatment with oral vitamin D3 in northern-dwelling patients with chronic kidney disease.
Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving.
Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial.
Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age.
Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers.
Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals.
Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk.
Effect of vitamin D supplementation in the institutionalized elderly.
Calcitriol ointment 3 microg/g is safe and effective over 52 weeks for the treatment of mild to moderate plaque psoriasis.
Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men.
Low parathyroid hormone levels in bedridden geriatric patients with vitamin D deficiency.
Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins?
Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.
Vitamin D and depressive symptoms in women during the winter: a pilot study.
Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial.
Vitamin D, parathyroid hormone and the metabolic syndrome in middle-aged and older European men.
Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial.
Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.
Meta-analysis of vitamin D, calcium and the prevention of breast cancer.
Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial.
Combination of alfacalcidol with calcium can improve quadriceps muscle strength in elderly ambulatory Thai women who have hypovitaminosis D: a randomized controlled trial.
Vitamin D(3) induces expression of human cathelicidin antimicrobial peptide 18 in newborns.
Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis.
No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year.
Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.
Vitamin D levels, lung function, and steroid response in adult asthma.
Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study.
Pandemic preparedness for swine flu influenza in the United States.
Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.
Vitamin D supplementation suppresses age-induced bone turnover in older women who are vitamin D deficient.
Suppression of C-terminal telopeptide in hypovitaminosis D requires calcium as well as vitamin D.
A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.
Milk fortified with the current adequate intake for vitamin D (5 microg) increases serum 25-hydroxyvitamin D compared to control milk but is not sufficient to prevent a seasonal decline in young women.
Vitamin D-vitamin K interaction: effect of vitamin D supplementation on serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, in Danish girls.
Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the Southeastern United States.
Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative.
Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.*
A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness.
The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland.
Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
Dairy calcium intake, serum vitamin D, and successful weight loss.
Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome.
A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency.
Serum 25-hydroxyvitamin D concentration is associated with functional capacity in older adults with heart failure.
Effect of vitamin D supplementation on testosterone levels in men.
Vitamin D production depends on ultraviolet-B dose but not on dose rate: a randomized controlled trial.
Vitamin D(3) is more potent than vitamin D(2) in humans.
Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis.
High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study.
Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill.
Effects of vitamin D supplementation on 25-hydroxyvitamin D, high-density lipoprotein cholesterol, and other cardiovascular disease risk markers in subjects with elevated waist circumference.
Changes in balance, functional performance and fall risk following whole body vibration training and vitamin D supplementation in institutionalized elderly women. A 6 month randomized controlled trial.
Diet induced thermogenesis, fat oxidation and food intake following sequential meals: influence of calcium and vitamin D.
The response of elderly veterans to daily vitamin D3 supplementation of 2,000 IU: a pilot efficacy study.
Meta-analysis: Circulating vitamin D and ovarian cancer risk.
Relation of vitamin D level to maximal oxygen uptake in adults.
Vitamin D status in patients with stage IV colorectal cancer: findings from Intergroup trial N9741.
Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies.
Burning daylight: balancing vitamin D requirements with sensible sun exposure.
Relationships between vitamin D status and cardio-metabolic risk factors in young European adults.
Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis.
Vitamin D status and early age-related macular degeneration in postmenopausal women.
Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study.
Annual high-dose vitamin D3 and mental well-being: randomised controlled trial.
Vitamin D status and outcomes in heart failure patients.
The impact of vitamin D status on periodontal surgery outcomes.
The role of paricalcitol on proteinuria.
Effects of weight loss on serum vitamin D in postmenopausal women.
Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies.
Vitamin D intake and risk of cardiovascular disease in US men and women.
Meta-analysis: Serum vitamin D and colorectal adenoma risk.
Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial.
Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial.
Vitamin D supplementation for prevention of mortality in adults.
The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial.
New clinical trials with vitamin D and analogs in renal disease.
The relation between vitamin D deficiency and fibromyalgia syndrome in women.
Interventions for latent autoimmune diabetes (LADA) in adults.
Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults.
Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis.
Vitamin D3 and the risk of CVD in overweight and obese women: a randomised controlled trial.
Low 25-hydroxyvitamin D is associated with increased mortality in female nursing home residents.
Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects with type 2 diabetes.
Vitamin D supplementation in infants with chronic congestive heart failure.
Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis.
Consumption of vitamin D-and calcium-fortified soft white cheese lowers the biochemical marker of bone resorption TRAP 5b in postmenopausal women at moderate risk of osteoporosis fracture.
Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients.
Vitamin D supplementation in the treatment of atopic dermatitis: a clinical trial study.
Effect of vitamin D repletion on urinary calcium excretion among kidney stone formers.
25-Hydroxyvitamin D levels and the risk of stroke: a prospective study and meta-analysis.
Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes.
Treatment of vitamin D insufficiency in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing three regimens.
Therapeutic effects of calcium & vitamin D supplementation in women with PCOS.
Higher vitamin D dietary intake is associated with lower risk of alzheimer's disease: a 7-year follow-up.
Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance.
Comparison of narrowband ultraviolet B exposure and oral vitamin D substitution on serum 25-hydroxyvitamin D concentration.
The relation between sunscreen layer thickness and vitamin D production after ultraviolet B exposure: a randomized clinical trial.
Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.
Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study.
The effect of combined calcium and cholecalciferol supplementation on bone mineral density in elderly women with moderate chronic kidney disease.
Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis.
Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults.
Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial.
Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials.
An open label, randomized controlled study of oral calcitriol for the treatment of proteinuria in patients with diabetic kidney disease.
Ergocalciferol from mushrooms or supplements consumed with a standard meal increases 25-hydroxyergocalciferol but decreases 25-hydroxycholecalciferol in the serum of healthy adults.
Narrowband ultraviolet B three times per week is more effective in treating vitamin D deficiency than 1600 IU oral vitamin D₃ per day: a randomized clinical trial.
Vitamin D intake is inversely related to risk of developing metabolic syndrome in African American and white men and women over 20 y: the Coronary Artery Risk Development in Young Adults study.
Vitamin D and gestational diabetes: a systematic review and meta-analysis.
Associations between 25-hydroxyvitamin D and weight gain in elderly women.
Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus.
A pooled analysis of vitamin D dose requirements for fracture prevention.
Determinants and effects of vitamin D supplementation on serum 25-hydroxy-vitamin D levels in patients with rheumatoid arthritis.
Vitamin D is a major determinant of bone mineral density at school age.
Effect of vitamin D and inhaled corticosteroid treatment on lung function in children.
Serum 25-hydroxyvitamin D3 and D2 and non-clinical psychotic experiences in childhood.
Vitamin D deficiency in postmenopausal, healthy women predicts increased cardiovascular events: a 16-year follow-up study.
Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies.
Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill.
A 12-week double-blind randomized clinical trial of vitamin D₃ supplementation on body fat mass in healthy overweight and obese women.
Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.
Relation of severe deficiency of vitamin D to cardiovascular mortality during acute coronary syndromes.
Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.
Interventions for preventing falls in older people in care facilities and hospitals.

*See Vitamin D and UV fluctuations for an explanation.

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