The Difference Between Flexible and Inflexible Metabolism

Metabolic Flexibility

Metabolic flexibility (MetF) is the ability to rapidly switch between the use of carbohydrates and fats for energy needs based on nutrient availability [i]. MetF allows for the storage of fuel when food obtainability is high and utilization of that stored energy when food is not available. This metabolic elasticity is critical to human survival during periods of scarcity and allows for the enjoyment and celebration of food when in abundance.

Insulin is a key player in orchestrating the modulation of the type of calories we burn for energy. When a meal with carbohydrates is eaten, insulin increases. Insulin stimulates the use of glucose for energy as well as storage of both carbohydrates and fatty acids from the food we eat. When food intake matches fuel expenditure, an individual will neither gain nor lose weight. When caloric intake exceeds fuel needs, excess calories are stored as fat to be accessed at a future date when we need more calories for energy that we have eaten.

Historically, humans have repeatedly experienced periods of both feasting and famine. Food availability changed seasonally each year with winter months of food scarcity and summers of abundance. People also experienced extended intervals of low caloric intake during lean years and excess consumption during plentiful years. This variation in caloric intake is also seen on a much smaller scale in the daily cycle of the fasted/fed states.

On a daily basis, it is common for people to fast overnight for roughly 10-12 hours. Glucose from a carbohydrate meal stays in the bloodstream for no longer than about 5 hours.  This means that in an overnight fast we need energy from our fat storage.  In lean healthy individuals, fat from storage is easily accessed for fuel during the overnight fasted state. Following a meal with carbohydrates, these individuals secrete insulin, thereby suppressing fat burning and shifting metabolism to primarily glucose [ii]. The daily fast/fed cycle in this example demonstrates metabolic flexibility.

When healthy lean people are exposed to prolonged fasting or prolonged exercise, fatty acids and ketones increase and energy is maintained despite an imbalance of  fuel intake and expenditure. These are other examples of how MetF maintains optimal function despite environmental unpredictability.

Metabolic Inflexibility

Metabolic inflexibility (MetIF) is a modern malady linked to Metabolic Syndrome and to many chronic diseases. While it may seem obvious that overconsumption of calorie-dense food is the root cause, it turns out to be much more complicated. Other key contributory insults include poor sleep combined with high stress, environmental toxicants (chemicals that are detrimental to health), poor exercise habits and a mismatch of activity to circadian rhythms. To reinstate metabolic flexibility in metabolically ill people, all these factors must be addressed.

Insulin, the conductor of metabolic fuel modulation, does not have the same impact on people who are obese and insulin-resistant. Contrary to metabolically well people, this metabolic type shows a reduced ability to burn fat in general, a lack of increase in fat burning during the fasted state and minimal suppression of fat metabolites with an increase in insulin. These people end up with excess fuel in their blood stream and in storage but lack the ability to easily burn either glucose or fat. They are overweight, fatigued and inflamed from this excess that does not fuel their body.

Someone who has become metabolically inflexible cannot easily mobilize fat from storage. Instead they become dependent on frequent meal spacing to stay fueled with carbohydrates. This is driven by neuropenia, a shortage of glucose in the brain, usually due to transient low blood sugar. It becomes increasingly difficult to eat exactly the number of calories needed for energy each day and nearly impossible to sustain a sub-caloric diet to achieve weight loss and re-establish metabolic flexibility. What was an advantageous metabolism for a world where food security was uncertain, has become a curse in a society where abundant food is driving metabolic disease.

Metabolic Syndrome

As stated earlier, MetIF is associated with Metabolic Syndrome (MetS); the clinical presentation of a person on the verge of chronic disease. Diseases associated with this condition include diabetes, obesity, heart disease, Alzheimer’s and non-alcoholic liver disease.

MetS is defined as elevated blood pressure, weight gain in the mid-line, high fasting glucose, high fasting triglycerides and low HDL cholesterol. More recently, elevated liver enzymes, in particular alanine aminotransferase (ALT) and gamma-glutamyl transference (GGT) have been added to the list of biomarkers associated with MetS.

Looking beyond the clinical definition, metabolically ill people experience the all-too-common symptoms of weight gain, fatigue and inflammation throughout their body. According to the National Health and Nutrition Examination Survey (NHANES), the incidence of MetS increased by 35% between 1998-2012 and is a common presentation in a large percentage of patients seeking medical care today.

Where Modern Life “Messed It Up” and How to Get Back on Track

In industrial countries where MetS is prevalent, most people are exposed to calorie-dense nutrient-poor food on a daily basis, while rarely facing food shortage. This shifts metabolism toward fuel storage that will not needed at a future date. This one-way path leads to excess of glucose, cholesterol and triglycerides in the bloodstream as well as ever increasing fat stores, particularly belly fat. Metabolically, this is driven by inappropriate insulin activity and response.

It has long been recognized that the lifestyle modifications of diet, exercise and circadian rhythms is key to reversing metabolically driven chronic disease. While diabetes, overweight and obesity are common features of metabolic illness, caloric restriction and weight loss alone often does not heal the underlying disorder. This has been demonstrated repeatedly both clinically and scientifically. Blood sugar, triglycerides and cholesterol profiles do improve with weight loss achieved through caloric restriction, however the metabolically dysregulated profile returns as soon as a regular diet is resumed. To achieve lasting health benefits, metabolism must return to the flexible state.

There is considerable disagreement regarding the best time for eating, sleeping and exercise to achieve positive and permanent results. Likewise, there are conflicting arguments pitting a low-fat diet against a low-carb diet. Clinically there is always a balance of what science demonstrates and what an individual experiences.

This is where the art of medicine dictates intelligent experimentation and individualization. To heal metabolism, it is important to address an individual’s cultural norms, personal preferences and work requirements. The next step is to introduce a nutrient-dense minimally processed and low-pesticide diet. This is followed by sleep optimization and a manageable physical activity schedule. Additionally, exposure to toxic chemicals that cause weight gain should be assessed and remediated. Assess and adapted your plan on a regular basis as your health improves and when life brings unexpected challenges. Once metabolic flexibility is reinstated, a supported plan to maintain MetF is often essential to create lasting health.

Sources

Zhang, S., Hulver, M.W., McMillan, R.P. et al. The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab (Lond) 11, 10 (2014).

Smith RL, Soeters MR, Wüst RCI, Houtkooper RH. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocr Rev. 2018;39(4):489-517. doi:10.1210/er.2017-00211

Freese J, Klement RJ, Ruiz-Núñez B, Schwarz S, Lötzerich H. The sedentary (r)evolution: Have we lost our metabolic flexibility?. F1000Res. 2017;6:1787. Published 2017 Oct 2. doi:10.12688/f1000research.12724.2