Metabolic Health
Metabolic health and non-communicable disease.
It is hard to argue that we find ourselves in the midst of a significant health crisis with ever more people suffering from non-communicable diseases (NCDs). The latest numbers published by WHO from September 2023 suggest that NCDs account for 74% of all deaths world-wide translating to 17 million people annually. Topping the charts are cardiovascular disease followed by cancer, but there are many others as we know and many different contributing factors, mainly associated with our lifestyle and environment. One thing these diseases have in common is low grade chronic inflammation and metabolic alterations such as insulin and leptin resistance. NCDs hardly existed two hundred years ago so something has gone very wrong in our modern way of living. We have covered some of the factors leading to low grade inflammation in a previous blog so let s now take a look at the metabolic consequences.
Metabolism and health – the role of insulin.
Metabolism is how your body burns food. There are two parts to metabolism; burning food for energy or using foods to grow tissue, including fat tissue. Burning of foods to make energy or ATP mainly takes place in the mitochondria, whilst growing tissue is primarily driven by insulin. Insulin is a hormone that is released from the beta cells in the pancreas into the blood stream in response to food and the amount secreted depends on how high your blood sugar goes after a meal. The higher the blood sugar the more insulin is required to pack glucose into the cells and return blood levels back to normal physiological levels. This is why eating a balanced diet is so important to maintain healthy blood sugar and insulin function.
Insulin resistance
Insulin resistance (IR) can occur when blood glucose levels are persistently excessive leading to a constant demand for insulin. This ultimately results in a down regulation of insulin receptors and consequently lowered sensitivity to insulin. When the sensitivity goes down the demand for insulin goes up and therefore insulin in the blood increases in a bid to compensate for the poor signal reception. Ultimately, this can result in type 2 diabetes (T2D) when the insulin signal is no longer able to move glucose out of the blood stream effectively. T2D is a case of insulin resistance at the level of the liver, but it is important to know that insulin resistance can occur in various organ tissues contributing to the many different manifestations of IR we see in NCDs. For example, insulin resistance at the level of the heart leads to cardiovascular disease, insulin resistance at the level of the ovaries leads to polycystic ovarian syndrome whilst insulin resistance at the level of the brain can contribute to Alzheimer s disease. It follows also that insulin resistance is closely associated with inflammation.
What causes Insulin resistance?
Food choices are the obvious place to start when discussing insulin resistance since eating a diet high in table sugar and other refined carbohydrates will obviously increase blood sugar leading to a higher demand for insulin and over time a much higher risk of developing insulin resistance. Furthermore, excess sugar is converted to fat in the liver and transported for storage in adipocytes for later use, so high sugar intake is a key cause of obesity. However, although there is an association between obesity and IR; not everyone who is obese is IR and slim people can be IR too. This is important because there is a tendency to blame obesity and assume that slim people are safe from IR – but this is just not the case. Obesity is a risk factor but not a cause of IR and whether someone develops IR has less to do with their BMI and rather depends on where their fat is stored; under the skin or in important organs such as the liver and the pancreas, the former being entirely safe whilst the latter being the central cause of IR. There seems to be a personal threshold for storing subcutaneous fat, which may be genetically determined, and when this threshold is reached, fat is stored in the organs instead. That is how someone can be slim on the outside but fat on the inside. In the context of NCDs it is the IR that is a key factor in causing disease, not the obesity in itself.
Non-alcoholic fatty liver disease (NAFLD) – prime cause of IR.
Fatty liver disease is a prime cause of IR because the liver is a central target for insulin signalling and a fatty liver is really where it all starts, yet it is invisible to the eye. When the liver becomes fatty, it no longer responds to insulin normally and the pancreas must work much harder thereby increasing insulin secretion. The excess fat then spills over into different areas of the body such as into the pancreas where the fat starts to switch off normal insulin production ultimately causing beta cells to malfunction., According to Professor Roy Taylor from Newcastle University, who has led several studies into T2D notes this process sets the scene for IR. We therefore need to start to think of NAFLD and fat in the pancreas as the true causes of T2D.
Prior to the 1980s fatty liver disease was mainly associated with alcoholism, but that is no longer so. One quarter of the world population suffer with fatty liver disease today and they are not all alcoholics. Even children are no longer safe from fatty liver disease. So, what is the cause of non-alcoholic fatty liver disease (NAFLD)? Sugar is the key answer, but not any sugar. Fructose specifically drives fatty liver disease according to Dr Robert Lustig, an American paediatric endocrinologist with a special interest in metabolic disease.
The deeper dive into NAFLD.
Remember table sugar consists of glucose and fructose. It turns out that excess fructose has three major ways of impacting liver health; firstly, unlike glucose, fructose does not get stored as glycogen in the liver (noting here that glycogen storage is not damaging to the liver). Instead, fructose overwhelms the mitochondrial capacity in the liver to produce ATP and CO2 and the excess gets thrown off as citrate, which via the citrate shuttle then exits the mitochondria and becomes cytoplasmic citrate and ends up as very low density lipoprotein or VLDL. Secondly, the VLDL formed from fructose needs to be transported out of the liver. The apolipoprotein B100 (apoB100) is responsible for this and is choline dependant (for phosphatidylcholine). Choline deficiency is common in modern day processed diets and when paired with excess fructose intake, research suggests, leads to a fatty liver; VLDL stays in the liver when choline is low, and the amount of fat is directly proportionate to the amount of choline. Thirdly, non-enzymatic glycation of fructose happens at 7 times the rate of that of glucose, increasing oxidative stress and inflammation in the liver itself. Glutathione is the major antioxidant protecting the liver from oxidative stress but is often found in insufficient levels, due to low intake of methionine orexcessive demand given our toxic environment. Genetic variants can also lead to lower production of glutathione.
So, in short, a high sugar (fructose) diet is toxic to the mitochondria, increases fat production, oxidation and inflammation in the liver and ultimately leads to fatty liver and IR. The substrate (fructose) is the critical consideration when addressing fatty liver. Thus, from a nutritional point of view, decreasing fructose from table sugar fruit juice and processed foods is important. Fresh fruits are not of great concern due to their fibre content. Alcohol is of course a consideration for some.
Chronic stress, chronic inflammation and IR
Aside from eating a high sugar diet, chronic stress can also lead to IR. During an acute stress response, stress hormones, notably noradrenaline and cortisol are produced. Noradrenaline binds to beta-adrenergic receptors on adipocytes causing lipolysis releasing free fatty acids and glycerol, which are then used for beta-oxidation and ketone production respectively. Hence, acute stress triggers fat loss.
Also, during acute stress, cortisol signals to the liver to release glycogen and initiate gluconeogenesis to provide glucose for ATP production which is then distributed preferentially to those organs which are most important for surviving the threat. These organs include the brain, the cardiovascular system, the muscles and the immune system. This alteration in energy distribution happens at the expense of all other organs, which will therefore be suffering a temporary energy deficit mainly achieved by inducing transient IR in those organs. These metabolic changes return to normal once the stressor has passed, restoring homeostasis.
When stress becomes chronic something else important happens. Alongside NA, another hormone called neuropeptide Y (NPY) is secreted. NPY functions as a break on the sympathetic nervous system and when it binds to its receptor on adipocytes it leads instead to pre- adipocyte proliferation and adipocyte differentiation, in other words an increase in fat. Thus, chronic stress can cause fat gain contributing to reaching the fat threshold as discussed above.
Furthermore, persistent cortisol production results in cortisol resistance at the level of the immune system enabling inflammation to persist. During an inflammatory response the immune system takes priority in terms of energy and uses organ specific IR to redirect energy to itself. Thus, chronic stress, chronic inflammation and IR in various organs go hand in hand.
Note also, that much of the de novo glucose synthesised and circulated during an acute stress response is destined to be taken up by the working muscles. Whilst ancient stressors which laid the foundations for these dynamics usually involved movement, such as looking for food and water, building shelter or running away from predators - modern day chronic stressors do not; psychosocial stress, herbicides, pesticides, nanoparticles, processed foods etc. Hence muscle activity doesn t soak up the extra glucose produced. In today s society, prolonged sitting time is an important cause of IR!
Testing
It should now be clear that simply testing fasting glucose and HbA1C does not reveal the full picture when determining if your client may be IR. It is important to also test fasting insulin to understand how much insulin is needed to produce the glucose result you are looking at and which enables you also to calculate beta cell activity (HOMA-2) and insulin resistance. Continued glucose monitors can be a great asset as part of understanding how diet is affecting an individual s glucose levels, but they do not tell you how much insulin the person is producing to maintain the glucose where it is.
We have discussed IR in this blog, but there are other important markers to consider when assessing metabolic health. Leptin, uric acid, triglyceride/HDL ratio are all important biomarkers to understand a person s overall metabolic health. As we were unable to find this combination of markers offered in one test, Colab Services recently created and launched some new exciting testing options – the Metabolic Assessment Panels or MAP series enabling you to dive deep into your client s metabolic workings.
METFLEX:
Leptin, cholesterol (total + components), triglycerides, HbA1c, Uric acid, glucose, insulin, insulin resistance.
METFIT:
METFLEX + full blood count, kidney/liver function, ferritin, adiponectin, Omegacheck
METFIT+
METFLEX + full blood count, kidney/liver function, ferritin, adiponectin, Prodromescan
Check out also our MAP series combination panels combining the MAPs with a number of other relevant panels.