Humans evolved in the setting of periodic food scarcity during which we developed the ability to rapidly switch between different fuel sources.  We are designed by evolution to burn fat in our fasting state and to burn primarily carbohydrates in our fed state in order to generate energy in the form of ATP.  All of this occurs in our mitochondria.  But with the development of the modern industrial food environment and ready access to overnutrition combined with less energy expenditure compared to the conditions under which we evolved, we find ourselves overnourished and at odds with our evolutionary design.  One consequence of this mismatch is impaired fuel switching in the mitochondria—we lose the ability to easily switch between lipids and glucose that marks a healthy metabolism.  As a result, our engines are inefficient, we have trouble burning fat while fasting, we are hungrier sooner after a meal, we eat more and find ourselves in a feed forward loop.  Eventually we develop obesity and the diseases related to insulin resistance such as diabetes, metabolic syndrome, NAFLD and ultimately cancer.   At least these are the claims.  What follows is an abstract of a good review paper published earlier this week that examines the concept of metabolic flexibility.

How and why does metabolic inflexibility occur?  

With chronic overnutrition (aka the Standard American Diet), cells become overstuffed and congested with macronutrients, overwhelming the enzymatic mechanisms of metabolism and leading to accumulation of incompletely oxidized substrates–the details of this process are probably not as interesting for our purposes as are the consequences.  These substrates harm mitochondria through oxidative stress from free radical damage and acetylation / protein modification due to acetyl coA accumulation.  The damage actually reduces the number of mitochondria as well as changing their functional morphology–the mitochondria look different and their performance is degraded.   The plasticity of the fuel switch deteriorates, leading to a sluggish metabolic response to nutritional cues.  Imagine a hybrid vehicle whose gas motor is flooded and so it can only use electricity.  And maybe the gas tank is expansile and is ever filling.  (I wish I could think of a better metaphor but I’m a poor mechanic).

At the same time, the overfed state also requires increasing amounts of insulin to push glucose into cells via insulin dependent glut4 transporters.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  The pancreas is the hose pump in this analogy, and with prolonged pressure, it can fail leading to diabetes.  Meanwhile glucose that should be going into the muscles and fat cells is instead taken up by the liver in an insulin independent process and converted to fat through de novo lipogenesis, ultimately leading to NAFLD–now the leading cause of liver failure.  The very high circulating levels of insulin cause sodium retention in the kidney, creating the phenotype of salt-sensitive hypertension.  Insulin is also a growth factor, and high levels are associated with carcinogenesis.  This is the backstory of the American healthcare system.

Insulin resistance and metabolic inflexibility are intertwined and it’s not clear which comes first, but they relate to each other and are both a consequence of overfeeding.  One reason this topic is of clinical interest is that people with metabolic inflexibility have problems burning fat in the fasting state.  They get hungry sooner and have trouble with fasting.   The intracellular availability of glucose determines the nature of substrate oxidation in human subjects (1).  If there is an excess of glucose, the cell will preferentially oxidize the glucose.  Otherwise it will turn to fat.

How do we treat this metabolic rigidity?

1. Diminish the nutrition going into the cell
   1. Caloric restriction: since the problem begins with too much energy, an energy deficit, regardless of macronutrient balance, is a reasonable first step toward relieving substrate competition.  I don’t think you need to go low carb or keto, though some people may find it easier to do so in order to manage their hunger.  Calorie restriction permits cells to decongest themselves of unused substrate and restore normal membrane potential across mitochondria.  Losing weight is the best and perhaps only valid treatment for fatty liver and can reverse insulin resistance and DM2 in its early stages.  So eating less is how to repair the metabolic inflexibility which derives from eating too much–it feels like an astute observation of the obvious, but there may be a special way of eating less that is especially effective.  Fasting.
   2. Fasting: starvation has benefits beyond calorie restriction alone.  We evolved to cope with periods of starvation and the metabolic program triggered by fasting has diverse benefits beginning with exhaustion of liver glycogen stores and initiation of ketosis. Burning ketones is metabolically healthy for a number of reasons, particularly as we age.  At the cellular level, fasting induces autophagy to remove damaged proteins, mitochondrial biogenesis and mitophagy.  The issue of fasting is, of course, a larger one and care must be taken to preserve lean muscle mass, but the rationale to starting a diet with a fast is that lipid oxidation is kickstarted by more rapidly inducing metabolic flexibility.
   3. SGLT2 inhibitors:  SGLT2 (sodium glucose cotransporter-2) inhibitors force the kidneys to spill glucose in the urine leading to a condition that mimics caloric restriction.  These drugs have been shown to be kidney protective, to reduce weight, to reduce blood pressure and to improve outcomes in congestive heart failure.  It turns out that they also promote beiging of adipocytes (in mice)—the brown fat that generates heat and burns calories in the process.  Unclear if this is relevant in humans.  At the mitochondrial level, SGLT2i’s permit the cell to decongest itself of the metabolic substrates that have caused all the damage.  Taking SGLT2i at night, according to the authors, amplifies the effects of an overnight fast.

2. Improve factors that mitigate mitochondrial stress
   1. Restoration of glutathione with glyNAC to counter oxidant stress
   2. Carnitine based acetyl-group buffering: theoretical. I don’t see any evidence that carnitine supplementation is of value at this point.

3. Increase energy expenditure
   1. Aerobic exercise, particularly zone 2 exercise is the best way to improve the number of mitochondria and their function. There is a strong association described between exercise and metabolic flexibility.  Even after one episode of exercise, insulin resistance and mitochondrial function improve.
   2. Resistance training: bigger muscles means a bigger glucose sink, a greater buffer to accommodate nutrient load in the fed state.

Footnote

(1) https://journals.physiology.org/doi/abs/10.1152/ajpendo.1996.270.4.e733