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. If left untreated, it can deteriorate into Type 2 Diabetes (T2D). See Type 2 diabetes in the UK.

IR & T2D can cause:-

High fasting & postprandial serum glucose, which increases the risk factor for Coronary Heart Disease, Retinopathy, Neuropathy & Nephropathy (Kidney failure), amongst other things. 
High fasting & postprandial serum triglycerides, which increases the risk factor for Coronary Heart Disease. See Lifestyle Intervention Leading to Moderate Weight Loss Normalizes Postprandial Triacylglycerolemia Despite Persisting Obesity.
High serum cholesterol, which 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 & Uric acid Kidney stones.
Hypertension, which raises the risk factor for Coronary Heart Disease, Strokes & Kidney failure.
Excessive appetite after eating high-GL carbohydrates, leading to overeating & obesity.
Lethargy/sleepiness after eating almost anything, but especially after eating high-GL carbohydrates, due to postprandial hyperinsulinaemia.


Possible causes (IR is multi-factorial) and solutions:

1. "Bad" genes. My genes aren't particularly good, but it is possible to change the expression of genes. See below.

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. FFAs, 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 is transported by Glu-T5 transporters which are insulin-independent & taken up by 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.

The Protein-Sparing Modified Fast (PSMF) depletes liver glycogen and liver & pancreatic fat rapidly. See also Reversing type 2 diabetes, the lecture explaining T2D progression, and how to treat it.

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 blood 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 activity is compulsory. See Physiological and health implications of a sedentary lifestyle.

See also Increased Glucose Transport–Phosphorylation and Muscle Glycogen Synthesis after Exercise Training in Insulin-Resistant Subjects , 
Improvement in Glucose Tolerance After 1 Wk of Exercise in Patients With Mild NIDDM (hat-tip to Go Kaleo) and
Move More: Solutions to problems. Excessive sedentariness was a secondary contributor to my IR.

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. FFAs & 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. FFAs & 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.

3. Empty (of glycogen) cells.
If carbohydrate intake is too low (say, less than 50g/day), physiological Insulin Resistance develops in order to spare glucose for the brain (as parts of the brain run on glucose only) and red blood cells. This is reversible on increasing carbohydrate intake. People who are on ketogenic diets are advised to increase their carbohydrate intake for a few days prior to taking an Oral Glucose Tolerance Test. See HIGH CARBOHYDRATE DIETS AND INSULIN EFFICIENCY.

4. 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/Metabolic Syndrome/Prediabetes (fasting serum glucose = 5.8mmol/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 carbohydrate-induced comas. I was also about the same weight that I was in 2003, so the improvement wasn't due to weight loss. Hypovitaminosis D was the primary contributor to my IR.

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.

5. Deficiency in Magnesium.
See Magnesium and type 2 diabetes. For the top 999 foods highest in Magnesium per 200kcal serving, see HERE. I've been taking ~4g of Epsom Salts/day (~400mg Mg/day, dissolved in 2 litres of fluids that I drink each day, to avoid laxative effects) since 2003 as it reversed osteoporosis in my lumbar spine.

6. Deficiency in Vitamin K2.
See Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial and 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 was taking 15mg/day of MK-4 since 2003, as it reversed osteoporosis in my lumbar spine. I'm now 15mg of MK-4 three times a week as a maintenance dose.
Note: Warfarin/Coumadin works by depleting Vitamin K, so lots of Vitamin K2 makes Warfarin/Coumadin ineffective.

7. 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.

8. 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.

9. 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.

10. Excessive intake of man-made trans-fats.
Base your diet on minimally refined produce rather than over-refined &/or moreish food products.

11. Excessive intake of chemicals.
Don't swallow toothpaste (fluoride) or disclosing tablets (as they may contain iodine). Don't hold till receipts between your lips (may be coated in BPA).

12. More than one of the above. See A tale of the unexpected & an analogy.

Any other ideas?

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. EDIT: Mum passed away in April 2013, so although it's possible to slow the progression of Lewy Body Dementia and reduce the symptoms of it, it's not possible to cure it.

Fats: Spawn of Satan or Dogs' Doodads?

From https://ajcn.nutrition.org/content/65/5/1628S.full.pdf

Fats get a lot of bad press in the media. There are so many adverts with "X% fat-free" or "only 1g of fat per Jaffa Cake" as if that's going to stop you from getting fat when you "om nom nom" your way through a whole box of the things!

Saturated fats are usually described as "bad" and polyunsaturates are usually described as "good". This is simplistic. Everything is bad in excess, even polyunsaturates. The thing about fats is that there are four basic types (saturates, monounsaturates, ω-6 polyunsaturates and ω-3 polyunsaturates) and they need to be consumed in roughly the right proportions for optimum health. Suffice it to say, the majority of people in the West do not eat them in anywhere near the right proportions. So, what exactly are fats?


Fats

Fats are an ester of glycerol (CH₂OH-CHOH-CH₂OH) & 3 fatty acids, and are also known as triglycerides (TG's) or triacylglycerols (TAG's).

1 molecule of glycerol + 3 molecules of fatty acid = 1 molecule of triglyceride + 3 molecules of water.

It's the fatty acids that determine whether a fat is saturated, monounsaturated etc. The four different types of fatty acid have a CH₃ at one end and a COOH at the other. The difference is in the middle section.

Saturated fatty acids have a middle section consisting of CH₂'s. Here's a diagram for Stearic acid (the predominant fatty acid in beef):-

__H H H H H H H H H H H H H H H H H O
H-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-O-H
__H H H H H H H H H H H H H H H H H


Monounsaturated fatty acids have one C=C bond in the middle, which is usually (but not always) 9 from the left-hand end, resulting in monounsaturates often being referred to as ω-9's, as ω is the last letter of the Greek alphabet. Here's a diagram for Oleic acid (the predominant fatty acid in olive oil):-

__H H H H H H H H_____H H H H H H H O
H-C-C-C-C-C-C-C-C-C=C-C-C-C-C-C-C-C-C-O-H
__H H H H H H H H H H H H H H H H H


ω-6 polyunsaturated fatty acids have two or more C=C bonds in the middle, with the last one always being 6 from the left-hand end. Here's a diagram for Linoleic acid (the predominant fatty acid in sunflower oil):-

__H H H H H_____H_____H H H H H H H O
H-C-C-C-C-C-C=C-C-C=C-C-C-C-C-C-C-C-C-O-H
__H H H H H H H H H H H H H H H H H


ω-3 polyunsaturated fatty acids have three or more C=C bonds in the middle, with the last one always being 3 from the left-hand end. Here's a diagram for Alpha-linolenic acid (the predominant fatty acid in flax-seed oil):-

__H H_____H_____H_____H H H H H H H O
H-C-C-C=C-C-C=C-C-C=C-C-C-C-C-C-C-C-C-O-H
__H H H H H H H H H H H H H H H H H


These diagrams are slightly misleading. Where there is a C=C bond, there are two H's on the "underside" only of the molecule. This asymmetry causes the H's to repel each other and bend the molecule into a V-shape at each C=C bond. C=C bonds with H's on the same side are known as "cis" bonds. The above molecule is really cis, cis, cis (c,c,c) Alpha-linolenic acid. The other type of C=C bond is known as "trans" and looks like the following diagram:-

__H H H___H H___H H___H H H H H H H O
H-C-C-C=C-C-C=C-C-C=C-C-C-C-C-C-C-C-C-O-H
__H H___H H___H H___H H H H H H H H


This is a diagram of trans, trans, trans (t,t,t) Alpha-linolenic acid. As the H's are on opposite sides of the molecule, they do not repel each other and the molecule is straight, as shown above. Note that saturated fatty acid molecules are naturally straight. Therein lies the problem with trans-fatty acids. They're straight, like saturated fatty acids, but they have unsaturated bonds, which are prone to peroxidation. See https://www.cyberlipid.org/perox/oxid0002.htm WARNING! Heavy-duty organic chemistry!

Our bodies take trans-fatty acids and incorporate them into cell membranes as if they were saturated fatty acids. This results in atherogenicity (artery-clogging), damage to the immune system and other health problems. Trans-fatty acids are found in partially-hydrogenated vegetable oils, so any cooking/spreading fats which have the word "hydrogenated" high-up in the ingredients list should be avoided. These are bad fats.

There are naturally-occurring trans-fatty acids made by bacteria in the stomachs of ruminant animals, like Conjugated Linoleic Acid (CLA). This looks a bit like the diagram below:-

__H H H H H_____H___H H H H H H H H O
H-C-C-C-C-C-C=C-C=C-C-C-C-C-C-C-C-C-C-O-H
__H H H H H H H___H H H H H H H H H


This has one of the C=C bonds shifted to the left and also has one cis bond and one trans bond, so the molecule is always bent. CLA has possibly beneficial properties, but human trials show mixed results. It's certainly not artery-clogging, so don't let anyone put you off eating butter from grass-fed cows (e.g. Anchor or Kerrygold butter) by saying that it has trans-fats in it. CLA is a harmless trans-fat.


Saturated fat consumption should be about 10% of total calories. This is because, even though saturated fats are not essential (our bodies can synthesise them), this guarantees adequate synthesis of sex hormones. Total polyunsaturate consumption should be about 5% of total calories, with a ω-6:ω-3 ratio of between 1:2 and 4:1. As ω-3's are found in greater quantities than ω-6's only in flax-seeds (a.k.a. linseeds) and oily fish, and many people eat way too little or no oily fish (and who, other than body-builders and some vegetarians/vegans, eats flax-seeds?), the ω-6:ω-3 ratio in the West is ~20:1. This is due to the widespread consumption of meats, eggs & milk from grain-fed animals, grains, nuts and seeds. There are high rates of heart disease and other inflammatory diseases in the West, as ω-6's end up in series 1 & 2 prostaglandins, and series 2 prostaglandins are pro-inflammatory. ω-3's end up in series 3 prostaglandins, which are anti-inflammatory.

So eat up yer oily fish if you're not vegetarian or vegan. Otherwise, eat up yer ground-up flax-seeds!

Monounsaturates can make up about 15% to 35% of total calories, depending on activity levels. From the histogram in Everyone is Different, sedentary people, on average, burn twice as much energy from fats as from carbohydrates.

So, if 25% of energy comes from protein say, 25% of energy can come from carbohydrates, and 50% can come from fats, i.e. a 2:1 ratio of fats:carbs. The cyclists at the left-hand end of the histogram in Chapter 1 would do best on 25% protein, 15% carbohydrate, 60% fat, when sedentary, whereas the cyclist at the right-hand end of the histogram would do best on 25% protein, 60% carbohydrate, 15% fat, when sedentary. When active, more carbs are needed by everyone.

Which fats contain which fatty acids? See https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQcYggz8ORx7mdTT7_ngR-jKOG-2FB4sm5HZWFyJF7xFYlNn-XCkbs4tSIuFFaJFVUdFTw13Q5M2-Adu_jeVnu3O37NhPlK_XWrxIACJ_QT1KmVElpl1YoLO4nfBBoqJNI5FQlhSDh/s640/comparison-of-fats.gif for a Comparison of Dietary Fats.

For high-temperature cooking, saturates are the least likely to oxidise (when they're on fire, they're oxidising!), followed by monounsaturates, then ω-6's, with ω-3's being the most likely to oxidise. An oil doesn't have to be smoking, to be oxidising. Alpha-linolenic acid oxidises to varnish at room temperature without smoking, which is why linseed oil is used to varnish cricket bats and dilute putty. The best non-animal fat for high-temperature cooking is Coconut Oil, followed by Palm Oil and then Olive Oil.

Extra-Virgin Olive Oil (EVOO) has a lower smoke point than refined Olive Oil (due to higher levels of free fatty acids), but has higher levels of polyphenol antioxidants, which makes it heart-healthy.

Oils high in polyunsaturates shouldn't be heated to temperatures greater than 100°C, as polyunsaturates can change from the cis configuration to the trans configuration at 102°C. See https://www.harricksci.com/sites/default/files/pdf/application_notes/FatIR_App-Notes_ATR_Oil-Analysis.pdf