Assessing Mitochondrial Fitness May Guide Effective Metabolic Rehabilitation

Implications for intransigent obesity may be related first to your patients’ metabolic inflexibility and only secondarily to their diet, and may offer an early warning sign of diabetes. .

With Iñigo San-Millán, PhD

At similar exercise intensities, research has shown that elite athletes develop increased mitochondrial mass, particularly in muscles, as compared to the presence of increased serum lactate levels in people with metabolic syndrome.1,2 In effect, professional athletes demonstrate the capacity to switch between lipid and CHO oxidation with ease based on energy demand and substrate availability, enabling efficient gluconeogeneisis.3

Conversely, patients with metabolic syndrome present with a low mitochondrial oxidative capacity to metabolize lipids and experience an earlier transition from adipose (FATox) to carbohydrate oxidation (CHOox) as exercise output increases.3 Both insulin resistance states (ie, type 2 diabetes, T2D) and metabolic syndrome are characterized by mitochondrial dysfunction.4,5 As such, these patients are overly reliant on CHO-derived energy sources and exhibit a diminished capacity to transition between CHOox and FATox.

Overcoming metabolic inflexibily will promote easier weight loss and improve dietary management.A metabolic rehabilitation progam offers the clearest and most effective means of promoting weight loss.

Since CHO and lipid metabolism depend largely on mitochondrial function and quantity, the root cause of an inability to lose weight may depend on the efficiency of these factors.3

“While carbs have gotten the rap for causing metabolic diseases, dietary carbohydrates are not the enemy, the problem is a condition we have termed, ‘metabolic inflexibility’ that sets up the problem,” said primary author Iñigo San- Millán, PhD, an assistant professor of medicine in the department of physical medicine and rehabilitation at the University of Colorado (US) School of Medicine in Aurora, and director of sport performance at the CU Sports Medicine and Performance Center in Boulder.

In effect, a patient who insists that she has done everything right but still can’t lose weight is recognizing at a superficial level that she has mitochondrial inflexibility.3

Research findings, published in Sports Medicine, may finally offer some validation to the struggles of many patients with metabolic syndrome and provide clinicians with a viable therapeutic approach to assess and manage their patients.3

Devising a Methodology to Measure Metabolic Status

 “In the past, the only way researchers’ have been able to test metabolic health of cells was to do a muscle biopsy,” said Dr. San-Millán. However, by evaluating a patient’s physical activity level and body weight patterns, we have developed a method to estimate the person’s mitochondrial fitness.3 For example, a person with low energy, who has trouble losing weight despite eating less or cutting out the carbs, and presents with an increase in blood glucose are exhibiting signs of an unhealthy metabolic fitness.”

The only way to adjust for poor mitochondrial function is to increase the level of exercise, but it has to be the right intensity—just enough to boost mitochondrial energy output to reverse the CHOox/FATox interplay.3

“The goal is to formulate a mitochondrial rehabilitation program, essentially an exercise plan that is tailored to the individual and is aimed to raise the intensity to 80% of capacity,” Dr. Millán told EndocrineWeb.

As such, it might be enough for a very sedentary person to add 20 minutes of walking daily to begin to see an improvement in their metabolic response. The more metabolically fit a person, the more flexible their dietary choices may become, he said.

Quantifying the Concept of Metabolic Flexibility

By employing indirect calorimetry and measuring serum lactate concentrations (la-) the authors  aimed to demonstrate the differences in metabolic characteristics between professional endurance athletes, and patients with metabolic syndrome (MtS), with moderately active individuals in the middle3

The results demonstrated that FATox was significantly higher in elite athletes (EA) than in patients with metabolic syndrome (p < 0.01), while La- was significantly lower in the performance athletes than those with metabolic syndrome.3 In patients with MtS, their FATox and La- were inversely correlated in all three groups (EA: r = -0.97, (P < 0.01; MA: r = -0.98, P < 0.01; MtS: r = -0.92, P < 0.01). The correlation between FATox and La- for all measures was r = -0.76 (P < 0.01).

“This method of testing the presence of lactate and fatty acids, mitochondrial substrates, during exercise introduces a method for assessing metabolic flexibility and oxidative capacity in a wide range of individuals with different metabolic capabilities,” said Dr. San-Millán and his co-author in summarizing their study findings.3

“This process represents the potential to assess diabetes risk years before it otherwise would be detected by a standard glucose tolerance test,” he said.

The findings focus a spotlight on critical energy function at the level of muscle—on cell (insulin receptors) vs in cell (glucose oxidation) —where exercise promotes oxidation.

“The most effective means of improving mitochondrial function is to boost mitochondrial function with an increased intensity of physical activity,” Dr. San-Millán said, “It is not about telling a sedentary patient to run a marathon, rather its to seek an exercise level that is sufficient to reverse their mitochondrial dysfunction. While their metabolic intensity is the same, just 60 to 90 seconds of higher intensity may be all that is needed.”

Moving to a Clinically Relevant Assessment Process

Having designed metabolic tests to assess metabolic flexibility in the lab,3 Dr. San- Millán is working on a simpler version for in the primary care setting so that patient risk for cardiometabolic disease may be assessed, and an individualized metabolic fitness plan that Dr. San-Millán refers to as “metabolic rehabilitation” may be prescribed.

To conduct the test, a patient would mount either a stationary bike or treadmill while wearing a mask to capture how efficiently fat and CHO are utilized. Periodic blood samples would be taken from the finger to assess how quickly lactate—a metabolic byproduct of glucose utilization involved in muscle fatigue as it accumulates, which also may be involved in the pathogenesis of chronic diseases such as type 2 diabetes, cardiovascular disease, even some forms of cancer— is cleared by mitochondria of cells  according to Dr. San-Millán.

“By increasing the resistance, clinicians would be able to monitor how efficiently the body adapted to using fat versus CHO. The data would generate a report on the status of patient’s mitochondria. The more mitochondria and the larger their size, the more metabolically flexible the person,” he told EndocrineWeb.

"The next step," said Dr. San-Millán, "will be to design a portable smartphone app version of the metabolic assessment that permits consumers to test their metabolic flexibility with one drop of blood."

The author had no financial conflicts of interest pertaining to this study.


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