Selenium And Cancer

Resistance Versues Endurance Training: Insulin Sensitivity

Insulin Resistance And Oxidative Stress

Insulin resistance is a likely driver of weight gain. Insulin resistance is characterised by a deterioration of the strength of the signal elicited by insulin on the cell, and as a result the insulin signal becomes less efficient at stimulating the transport of glucose from the blood into the cell. This causes fasting blood glucose levels to rise, a condition known as hyperglycaemia. In response to the higher than normal fasting blood glucose levels, the body's homeostatic mechanisms, controlled by the hypothalamus, increase the release of insulin to counter the effects of too much glucose in the blood. The pancreas therefore releases more insulin and this raises fasting insulin levels, a condition known as hyperinsulinemia. It these changes to the insulin system that need to be reversed in order to cause successful long term fat loss, as body fat levels cannot be brought under control with raised levels of insulin. This is because insulin stimulates the fat accumulation pathways inhibits the fat breakdown pathways.

The role of oxidative stress in insulin resistance has be suspected for some time based on the observation that antioxidant nutrients improve insulin sensitivity. Oxidative stress is a condition that describes a state in cells and tissues whereby free radical activity is chronically increased above normal physiological levels. Free radicals are chemicals with unpaired electrons, and these unpaired electrons cause the molecules to be very reactive. Free radicals therefore react with components in the body, and this causes these components themselves to become free radicals, setting up a chain reaction that damages tissues and cells and leads to disease. Free radicals are generated naturally by metabolic activity, but they are kept in check at manageable levels by a network of antioxidants, some of which are vitamins and some of which are naturally produced in the body. Possibly the most important exogenous antioxidants are vitamin C and vitamin E and the most important endogenous antioxidant is glutathione.

Overproduction of free radicals leads to oxidative stress, and this may cause interference with the insulin signal cascade, the metabolic steps that describe the transfer of the insulin signal from the membrane to the interior of the cell. Alternatively the oxidative stress may disrupt the membrane structure and interfere with the binding of insulin to its receptor. Oxidative stress can result from either an increase in free radical production or from a depletion of the antioxidants that normally prevent oxidative stress. Sources of free radicals include pollution, food components, inflammatory, stress and intense physical activity. All of these factors contribute to the production of oxidative stress. In such a circumstance, an increase in antioxidants will be required to prevent the metabolic damage from the increased free radical generation. Antioxidant vitamins and plant antioxidants have therefore been shown to be beneficial at improving insulin sensitivity through their inhibitory effects on cellular oxidative stress.

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Fibre And Insulin Resistance

Nutrient overload is one of the primary, if not the primary drivers, of insulin resistance. Too much energy in the form of fructose can overload the hepatocytes of the liver with energy and this stimulates the de novo lipogenesis pathway. The resulting fatty acids may accumulate in skeletal muscle and liver tissue where they cause insulin resistance by interfering with the insulin signal cascade. In addition, too much energy in too short a period of time overloads the cells with energy, including glucose and fatty acids, and as a result oxidation of the energy proceeds at an accelerated rate leading to the generation of free radicals. As a compensatory mechanism, the insulin receptor is desensitised in order to prevent further nutrient uptake by the cells. Refined carbohydrates, including refined crystalline sugar and refined crystalline fructose contribute to this nutrient overload as the fibre in the original plant material, which normally controls the rate of digestion and absorption, is absent.

Low fibre diets high in refined carbohydrates are therefore one of the contributory factors in nutrient overload. This explains the association between the typical Western diet, which is high in refined carbohydrate, and insulin resistance and obesity. Fibre is protective of insulin resistance because it can limit the rate at which the starch in carbohydrate foods is digested and absorbed. In this way fibre slows the rate of absorption of the glucose that is digested from the starch, and this prevents nutrient overload. Soluble fibre appears to be particularly effective in this regard because when in the gut it absorbs water and forms a gel. This gel acts as a physical barrier between the starch and the digestive enzymes required for its digestion, slowing the rate of digestion considerably. In addition this gel creates a barrier on the walls of the gut to inhibit the passage of glucose from the gut to the blood. The fibre in plant foods may also slow the gastric emptying rate, further reducing the rate of starch digestion.

Low fibre diets such as the typical Western diet are associated with obesity and insulin resistance. Therefore adding more fibre to the diet should provide benefits to weight loss because dietary fibre has the potential to improve insulin sensitivity. Soluble fibre is present in high concentrations in oats and legumes, and this may explain the weight loss, blood glucose and insulin lowering, as well as the insulin sensitising effects of these foods. Fruits are high in fructose, which would suggest they may contribute to insulin resistance. However, fruits also contain the soluble fibre pectin, which may neutralise the damaging effects of fructose in fruits. Vegetables also contain soluble fibre in the form of pectin, as well as cellulose and other insoluble fibres. Whole plant foods such as fruits and vegetables and whole grains have been shown to produce weight loss effects when they replace refined carbohydrates in the diet. Supplemental fibre may not be as effective as that from whole plant foods.

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Algal DHA Versus Fish DHA and EPA

Is Oxidative Stress The Maid Driver of Insulin Resistance?

Obesity, cardiovascular disease and type 2 diabetes are all aetiologically linked through the metabolic syndrome. The observation that all three diseases are associated with oxidative stress, has lead some to speculate that oxidative stress is the causative factor in metabolic syndrome. In fact evidence suggests that free radicals and oxidative stress are indeed a causative factor in insulin resistance and the development of insulin resistance then causes the development of secondary diseases characterised by the metabolic syndrome including cardiovascular disease, obesity and type 2 diabetes. Since Denham Harman first postulated about the role of oxidative stress in ageing and disease, many studies have confirmed the link between high levels of oxidative stress and disease and the aging process. It is not known what causes the generation of the oxidative stress that leads to the development of insulin resistance, but stress, poor diet, recreational drugs both legal and illegal as well as pollution may play a role.

However, adipocytes may generate free radicals through exposure to excessive energy. As energy, particularly in the form of free fatty acids and glucose, accumulates in the adipocytes, the energy pathways of the cell overproduce acetyl CoA and this in turn increases production of energy donors such as reduced NAD (NADH). As the electron donors accumulate, they increase the hydrogen ion membrane potential in the mitochondria, and this inhibits the flux of electrons down the electron transport chain. Inhibition of complex III of the electron transport chain increases the half life of the free radical intermediates of coenzyme Q and this results in superoxide generation. As superoxide accumulates it leads to the formation of oxidative stress. Over time, the generation of superoxide radicals would deplete the body of cellular antioxidants, which may explain the association between obesity and low antioxidant status. This theory also explains nicely why animals on reduced energy intakes have longer lifespans.

Accumulation of free fatty acids in adipocytes may also reduce the translocation of glucose transporters (GLUT4) to the cell membrane surface and this may inhibits the efficient uptake of glucose to the cells, causing insulin resistance. This process may be a reaction by the cell to prevent further uptake of energy in order to limit the production of free radicals. Insulin resistance can therefore be thought of, if this theory is correct, as a compensatory mechanism to prevent the cellular generation of oxidative stress. Refined carbohydrates and fructose may therefore be a source of free radical generation as they cause an overload of energy in the blood following consumption. Whole grains prevent this as the fibre content slows the absorption of the glucose and other sugars. Further, beta cells of the pancreas may be particularly susceptible to oxidative stress as they have low levels of endogenous antioxidants such as catalase, superoxide dismutase and glutathione peroxidase.

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The Major Fat Constituents in the Typical Western Diet

The typical Western diet is the modern diet of the developed nations of North America, Western Europe and Australasia. Evidence suggests that insulin resistance is caused by consumption of the typical Western diet, and this relates to the presence of refined and processed foods within the diet that can alter the biochemical balance of the body through changes to normal metabolic regulation. Of the food components that may contribute to these metabolic changes, dietary fats have been identified as playing a role. The typical Western diet is generally high in both cholesterol and saturated fat, and these have been blamed for both the cardiovascular disease epidemic that is currently sweeping through developed nations and for the rise in the rates of obesity. However, this might be unfair and a gross oversimplification of human nutrition as both dietary cholesterol and saturated fat have been part of the human diet since history began, but the cardiovascular disease and obesity epidemics are only recent phenomenon.

The main problem identified with saturated fat is the amount of calories that it contains. We are told that this increases the risk of overeating and this is turn increases the risk of weight gain. However, as we have seen previously, the energy balance theory of weight gain is not established as the cause of weight gain or obesity. While it is possible to overeat saturated fat, it is just as likely that carbohydrate could be overeaten, and there is with carbohydrate, particularly that which is refined, good reason to suspect that it can cause metabolic dysfunction. Many of the detrimental effects of saturated fats on human physiology have also been, either deliberately or mistakenly, attributed to plasma levels of fasting triglycerides, the largest contribution to which originates not from the diet, but from the de novo lipogenesis pathway using carbohydrate as a substrate. That the Massai of Africa eat large amounts of saturated fat but are not overweight also argues against its role in weight gain.

A number of modified fats are present in the typical Western diet. These include oxidised fats that are the products of lipid peroxidation and trans fats that are the result of the hydrogenation of vegetable oils. Both of these groups of fats are novel dietary additions that were not present in the human diet in great quantities before the mass processing of food, and as such are a relatively new addition to the nutritional research. Increasingly oxidised and trans fats are being identified as possible metabolic poisons. In particular, they may lead to inflammation, oxidative stress and this may subsequently lead to a decrease in insulin sensitivity. Both trans fats and oxidised fats may therefore contribute towards the development of insulin resistance. Interestingly, trans fats may be responsible for some or all of the detrimental effects of saturated fats. This relates to some earlier research that did not differentiate between trans and saturated fats in studies, but simply grouped them together as a single category.

The last group of fats that make up the typical Western diet are the unsaturated fats. There are two nutritional groups of unsaturated fats and these include the monounsaturated fatty acids and the polyunsaturated fatty acids. Unsaturated fatty acids have one or more double bond in their carbon chains, and this gives the molecules less stability in the presence of oxygen, heat and light when compared to saturated fat. This means that unsaturated oils are prone to rancidity, and when consumed in their rancid state, can cause specific health problems. Olives contain high amounts of monounsaturated fatty acids, and vegetable oils such as sunflower, rape, safflower and corn oils contain high amounts of polyunsaturated fatty acids. Because of their chemical structure unsaturated fats tend to be liquid oils at room temperature in contrast to saturated fats which tend to be solid at room temperature. Some animal products such as lard and fish contain high amounts of unsaturated fatty acids.

One subgroup of polyunsaturated fats are the omega-3 and omega-6 categories of fatty acids. These groups are championed by alpha linolenic acid and linoleic acid, the parent compounds and the omega-3 and -6 metabolic pathways, respectively. Both alpha linolenic acid and linoleic acid have vitamin like effects, as they are both essential nutrients and they are required to form short-lived hormone molecules called eicosanoids. Generally the typical Western diet contains too many omega-6 fatty acids and too few omega-3 fatty acids and this causes an imbalance in eicosanoid formation in cells. As eicosanoids regulate inflammation, and imbalance of omega-6 to omega-3 fat in the diet leads to a proinflammatory state, and this subsequently causes oxidative stress and associated metabolic damage. Trans fats also interfere with essential fat metabolism. Metabolites of alpha linolenic acid in the diet include eicosapentaenoic acid and docosahexaenoic acid from fish.

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What Is A High Quality Diet?

Brown Versus White Fat

There are two main types of adipose tissue in human physiology. These are designated white and brown adipose tissue (BAT). Discussion of their different physiological roles is important in any exploration of weight gain and fat loss. White adipose tissue is the most well known sort of fat. If anyone has cooked and eaten a joint of red meat they will have seen the white adipose tissue of the animal around the meat. The distinctive white colouration can be seen. The fat is humans is very similar to this and quantitatively white adipose tissue makes up most of the fat we carry on our frames. The white nature of this tissue relates to its low concentration of mitochondria, because it is metabolically not very active. The physiological function of white adipose tissue is mainly as a store of energy, but white fat does fulfil other roles such as acting as a shock absorbed to delicate structures such as internal organs and joints. When we gain weight, it is the white adipose tissue that becomes engorged with triglycerides.

Brown adipose tissue is much less common in humans. Babies possess a fair amount of brown adipose tissue, but as we age the amount we carry seems to diminish. The presence of brown adipose tissue in babies confirms the conclusions of scientific studies, that brown adipose tissue is a source of heat. The brown colour of the tissue is related to the presence of a high number of mitochondria in the cells of brown adipose tissue, and this makes the cells very metabolically active. Brown adipose tissue is able to perform a special metabolic trick called uncoupling, which it achieves with the help of special uncoupling proteins. In normal cells when glucose or triglycerides are oxidised, a high energy compound called ATP is produced and this adds to the energy content of the cell. Only the workings of the cell can remove this energy. However, uncoupling proteins uncouple the glucose and triglycerides from the production of ATP, and instead divert the resulting energy to produce heat.

This uncoupling of energy has two important consequences in the body. The first is that the cells can manufacture heat from stored energy and in this way can increase the temperature of the body. Small animals that have relatively small surface areas use this trick to maintain warmth, and as a result small mammals have high amounts of brown adipose tissue. Babies too have a small surface area and so require brown adipose tissue. The adult human has less need for this process because they have a larger surface area and also because they are able to move themselves from the cold to the warmth. Adaptive thermogenesis describes the ability of brown adipose tissue quantity to upregulate following chronic exposure to cold. Another consequence of the ability of brown adipose tissue to uncouple energy production is the fact that this allows the wasting of energy. Brown adipose tissue can be stimulated through the release of hormones such as adrenaline, to waste energy, and the consequence of this is a reduction in body fat.

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Do I have Metabolic Syndrome?

The metabolic syndrome is a cluster of metabolic disorders that are likely caused by the insulin resistance that characterises the condition. These metabolic disorders include, but are not limited to, changes to plasma lipoproteins, raised levels of fasting blood glucose, raised levels of fasting insulin, systemic inflammation, oxidative stress, immune dysfunction, the development of nonalcoholic fatty liver, high blood pressure and weight gain, particularly around the waist. The changes to plasma lipoproteins that occur with development of the metabolic syndrome include increases in plasma triglycerides (also called very low density lipoprotein (VLDL)), increases in the small dense low density lipoprotein (LDL) particle, and decreases in the high density lipoprotein (LDL) particle. While developing one or two of these disorders in no way confirms the metabolic syndrome, they can be used as a guide to determine if the disorder is present. This is because there is no defined medical definition for the metabolic syndrome.

Diagnosing the metabolic syndrome can therefore be very difficult without a detailed clinical examination and careful analysis of blood tests. However, there are a number of easy ways to determine if the metabolic syndrome is likely present without detailed biochemical tests. A simple oral glucose tolerance test is one of the best ways to determine the health of the insulin system. Following an overnight fast, a glucose drink is consumed and then periodically blood glucose measurements are taken using a finger prick lancet and a simple blood glucose measuring device. Under normal circumstances, following ingestion of glucose, there will be a rapid increase in blood glucose, and then as insulin is released, that blood glucose will fall to baseline over the course of around 90 minutes. Blood glucose falls because the insulin facilitates the transport the glucose into the cells. If insulin resistance in present, the glucose stays in the blood for longer and blood sugar may not return to baseline for some hours.

Another of the classic signs of insulin resistance that strongly suggests that the metabolic syndrome might be present is a large amount of deep abdominal fat. This gives the individual a rotund appearance, and this characteristic body shape is described as android or apple shaped. Measuring the waist to hip ratio of an individual is a good indicator if they have such a body composition. This can be done by dividing the waist measurement in cm by the hip measurement is cm. A waist to hip ratio of above 1.00 or 0.85 strongly suggests that insulin resistance is present in men and women, respectively. Abdominal fat is associated with insulin resistance, but the cause and effects are not fully understood. The storage of fat preferentially in the viscera of the abdomen may relate to changes in hormones that occurs during the development of the metabolic syndrome. Much of the metabolic damage that occurs from the presence of the metabolic syndrome results from the accumulation of visceral fat in and around the liver.

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Vitamin D From Sunbeds

How Do Trans Fats Contribute to Insulin Resistance?

Oxidised fats can interfere with insulin resistance because they initiate free radical chain reactions that can lead to oxidative stress. This oxidative stress then interferes with the insulin signal cascade decreasing the strength of the insulin signal reaching the interior of the cell. This then leads to a decrease in the uptake of glucose from the blood to the cells. Trans fats are another group of modified fats that may decrease insulin sensitivity. Like oxidised fats, trans fats may decrease insulin sensitivity through the generation of oxidative stress. However, unlike oxidised fats, trans fats are not thought to decrease insulin sensitivity through the direct initiation of free radical chain reactions, but through an indirect immune related mechanism. The ability of trans fats to initiate oxidative stress likely relates to their ability to interfere with the metabolism of the essential fatty acids alpha linolenic acid and linoleic acid that belong to the omega-3 and omega-6 families of fat, respectively.

The essential fatty acids alpha linolenic acid and linoleic acid are natural cis-structured fats which are essential to the health. When ingested in the correct ratios they form a number of short lived hormones called eicosanoids that can regulate cell function. One of the main functions they regulate in the cell is that of inflammation. For health to be maintained and for inflammation to be controlled the diet must contain roughly 1 gram of linolenic acid for every 3 grams of linoleic acid. By interfering with the metabolism of the essential fatty acids, trans fats negatively affect the delicate balance between the omega-3 and omega-6 fatty acids and this modifies production of the antiinflammatory eicosanoids. Ingestion of trans fats may therefore result in the generation of inflammation. Inflammation is detrimental to insulin sensitivity, because the inflammatory immune response is a sources of oxidative stress. Indirectly therefore trans fats lead to oxidative stress and this interferes with the insulin signal cascade.

Another possible mechanisms by which trans fats interfere with insulin sensitivity is though changes to the fluidity of membranes. The cell membrane fluidity is regulated by incorporation of different types of lipid into the cell membrane. Increasing the amount of long chain polyunsaturated fatty acids such as the omega-3 and omega 6-fatty acids derived from alpha linolenic acid and linoleic acid into the membranes increases their fluidity because these molecules have many double bonds that gives the carbon tails a pronounced kink. This means that packaging the fats together closely is more difficult, and the extra space within the membrane causes increase fluidity. High fluidity in the beta cells of the pancreas that release insulin as well as the target cells of insulin may increase insulin sensitivity. Trans fats have straight carbon tails, and ingesting trans fats increases their concentration in the cell membranes in place of the polyunsaturated fats, decreasing membrane fluidity and insulin sensitivity.

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Oxidised Oils

As well as trans fats the typical Western diet also contains a group of oils called the oxidised fats. Like all biomolecules, fats can react with a number of substances to produce derivatives that change their chemical and physical properties. In particular, fats and oils readily react with oxygen to form a range of chemicals in a process called lipid peroxidation. The products of these reactions can be put under the umbrella heading of oxidised fats. Some fats react more readily with oxygen, and the reactivity with oxygen is generally dependent on the number of double bonds present in the carbon chain of the fat. Polyunsaturated fats have many double bonds and so readily react with oxygen. Monounsaturated fats possess only one double bond and so are more stable than polyunsaturated fats. Saturated fats have no double bonds in their carbon chains and so are the most stable form of fatty acid. Oxidation of fats causes them to become rancid, and rancid fats are now thought to possess a significant detrimental effect on health.

Vegetable oils are generally polyunsaturated oils, and this means that they are highly susceptible to reaction with oxygen. However, fish oils are even more unsaturated than vegetable oils. The vegetable oils linoleic acid and alpha linolenic acid possess two and three double bonds, respectively. However, the eicosapentaenoic acid and docosahexaenoic acid in fish oils possess five and six double bonds, respectively. Fish oils are therefore highly susceptible to oxidation and rancidity and most sources of fish oils possess some concentration of oxidised fats. Although vegetable oils are generally more stable than fish oils, they are just as likely to contain oxidised oils and go rancid. This is because vegetable oils are often extracted from the seed with extreme heat and pressure that can increase the risk of reactions with oxygen occurring. In addition, the oils are often processed further and this involves further adulteration of the delicate polyunsaturated fatty acids in their oils.

Lipid peroxidation produces a number of reactive aldehyde chemicals including malondialdehyde and 4-hydroxynonenal that are able to react with cellular structures when ingested. This process occurs because the lipid peroxides can initiate free radical chain reactions whereby they steal electrons from cellular components to stabilise their own structures. This creates an unstable biomolecule within the tissues that then does the same to another biomolecule, which in turn, reacts with another and so on in a chain reaction. Antioxidants are able to quench such reactions through donation of an electron to the free radical, thus preventing further damage. High intake of oxidised fats, as are present in the typical Western diet, therefore increases free radical chain reactions leading to the development of oxidative stress. Oxidative stress is thought to be responsible for a number of diseases and may contribute to the development of insulin resistance and weight gain.

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