Metabolic Syndrome 5 Part Deep Dive part II

Oct 22, 2023

Part II - From metabolically healthy to metabolic syndrome – the mechanics

As I eluded to before in the previous article, the main issue with Metabolic Syndrome (MtS)/Insulin Resistance (IR) is the dysregulation of insulin. The point I want to make clear right from the get go is, that by the time lab tests pick up that your blood glucose levels aren’t been managed well, and to the point where you have now have type 2 diabetes (T2D) which is classified as “when the body doesn’t produce enough insulin (beta cells in the pancreas are “burnt out”) to function properly, or the body’s cells don’t react to insulin.
This means glucose stays in the blood and isn’t used as fuel for energy”. Your insulin levels have been high in the back ground trying to control your blood glucose levels for quite some time, maybe even a decade or more! So, we need to pay more attention to insulin levels a lot earlier and get the right blood tests done, and do something about it.

For example, I have a friend who is in his early 50’s and his uncle just passed away from cardio vascular disease and his dad needs a bypass, so he is concerned about his health and his fate.
He sent me some blood tests he got done a year ago, he had all the markers for MtS/IR, high triglycerides (TG), lower HDL-C, large amount of belly fat, with a BMI that would classifies him as obese, HBA1C (blood glucose measurement) high, and his TG/HDL-C ratio was above the normal and this marker is a good indicator of insulin resistance. However, his doctor suggested to lose some weight, that he might need to go onto a cholesterol lowering medication and to get a scan to see how his heart is going. This is all great, however when looking through the lens of insulin resistance we might see the results a little different.

So, in this article we will discover what metabolic flexibility is, and then look at the mechanisms to which someone would go through to get to metabolic Syndrome/Insulin resistance.

Let’s start with the definition again of Metabolic: Relating to the chemical changes in living cells by which energy is provided for vital processes and activities and new material is assimilated.

Metabolic flexibility describes the ability to respond or adapt to the changes in metabolic or energy demands. To generate chemical energy and key metabolites either aerobically or by using anaerobic respiration to give it greater versatility and metabolic flexibility to respond and adapt to environmental changes. (8)
Said in simpler terms, metabolic flexibility is the ability to switch between burning carbs and burning fat. Someone with great metabolic flexibility can burn carbs when they eat them, they can burn fat when they eat them or in a fasted state. They’re able to switch from carbohydrate metabolism and fat metabolism with relative ease. (9)

The other end of the spectrum of less metabolic flexibility can have consequences like:

  • You get sleepy after eating carbs
  • You can’t go five hours between feedings
  • You get the midday crash after lunch
  • You must snack to sustain your energy levels
    • Fasting is difficult, and if you manage to power through the discomfort, you get worse results than you were expecting (muscle loss, very little fat loss) (9)


      Now let’s look at the mechanism from flexibility to how you become inflexible and get insulin resistance and metabolic syndrome.

      We will be looking at carbohydrates mainly here as they have the biggest effect on insulin, protein raises insulin a little, and fat raises insulin insignificantly.

      When we eat carbohydrates that contain glucose or can get broken down into glucose which is most carbohydrates. Processed and refined carbohydrates raise your blood glucose levels the most, this includes things like:

      • White grains which are a refined source of carbs, like breads, pastas and cereals. Baked goods like muffins, cookies, cakes etc.
      • Sugar-sweetened drinks like soft drinks, sports drinks and other drinks with added sugar.
      • Starchy vegetables have less fibre than other vegetables and raise blood glucose more, and quicker.
      • Processed foods can have hidden added sugar like non-dairy milks (which can be very high in sugar), low fat options as more sugar is usually added to add flavour in replace of fat, salad dressing and other packaged foods.

      When we eat carbs that convert to glucose, our pancreas releases insulin and the glucose then gets stored in skeletal muscles and the liver as stored glycogen to be used as energy when it needs it. In a healthy individual, 80-90% of consumed glucose is stored as glycogen (in muscle and liver). (10) It also tells the liver to stop gluconeogenesis (the making of new glucose from fat or protein), so, glucose production goes down in the liver.

      pathogenesis of hyperglycaemia in type 2 diabetes
      Picture from Gerald Shulman

      If we eat too many carbs that spike our insulin it promotes de novo lipogenesis (converts excess carbohydrates into fatty acids in the form of triglycerides), so triglycerides go up. Insulin also stimulates Lipoprotein lipase (fat storing hormone) thereby increasing circulation of free fatty acids by up to two-fold and facilitating entry of fatty acids into muscle cells

      It’s when the muscle cells start getting fat in them that it impairs the glucose transport into the cells. So now the glucose can’t get into the muscles as well and glucose is still floating around, so more insulin is produced to try and cram it in.

      glucose path with or without insulin resistance
      In this picture you can see that excess sugar is turned into fat in the form of triglycerides. Lipoprotein Lipase increases due to increase in insulin, increases fatty acid building up in the muscle cell which impairs glucose uptake and glycogen stores in muscle go down. Picture from Gerald Shulman

      As this process happens it causes impairment of mitochondrial (the power plant in every cell that generates most of the chemical energy needed to power the cell) fat oxidation (breaking down of fat), promotes fat accumulation in the liver and increases susceptibility to insulin resistance (11)

      So, the first stage of insulin resistance happens when we eat too many carbs that turn to glucose in the blood, which raises insulin levels, to normally store 80-90% of the glucose as glycogen in the muscles and the liver. We normally only need about 5 grams of glucose in the blood at any time, which really isn’t much when you think about it. When insulin runs high for prolonged periods it increases fat storing hormones, increases triglycerides, increases fat to build up in the muscle which defects the glucose transport in the cells and doesn’t let the glucose into the muscle. This will impair our powerplants in our cells to use fat as energy and promotes fat accumulation in the liver.
      metabolic associated fatty liver disease MAFLD
      This picture describes the above process. You can see the yellow dots which are fat accumulating in the muscle and the liver. Fat in the liver will increase the chances of getting Non-Alcoholic Fatty Liver Disease (NAFLD) or what Gerald Schulman calls Metabolic-Associated Fatty Liver Disease (MAFLD) Picture from Gerald Shulman
      muscle and liver glycogen in insulin sensitive and insulin resistance
      Stage 1: Gerald and his team discovered that while insulin-sensitive and insulin-resistant participants were able to store similar amounts of the ingested carbohydrate as liver glycogen, the insulin-resistant participants were able to store much less glycogen in muscle (11) Picture from Gerald Shulman
      liver fat and hepatic de novo lipogenesis
      In this Figure the insulin-resistant participants (yellow) also stored more fat in the liver and synthesized more fat from the ingested glucose (de novo lipogenesis) Picture from Gerald Shulman

      We might leave it here for this article, as I know there is a lot of information. I hope I have put it in a way that makes it a little easier to understand. On my journey of learning more about chronic diseases and in particular insulin resistance and metabolic syndrome, there is a lot of basic information out there which can leave you asking more questions, then there is the super technical journal articles to sieve through and a few amazing doctors and diabetologists who go into so much detail it’ll make your head spin, I’ve tried to bridge the gap here and paint a picture incorporating the science in an easier to digest way.

      In the next article we will pick up with stage two and how the liver becomes insulin resistant and how that can affect someone’s health.