Metabolic Inflexibility: More Than 'Energy In, Energy Out'

When breaking a fast, if a meal is consumed that contains carbohydrates, plasma glucose increases, and insulin is released to promote glucose utilization. This change in substrate availability from fasted to fed should lead to oxidation of the available carbohydrates. When such conditions are simulated experimentally, multiple studies have revealed blunted response to the available carbohydrate as a pathophysiologic hallmark of obesity and type 2 diabetes. This aberrant phenotype is one key component of metabolic health.

Metabolic Inflexibility and Health

Karen D. Corbin, PhD, RD

Energy balance and its relationship to weight management — calorie intake and expenditure — are the primary components of the "energy in, energy out" equation, but there are certain aspects of metabolism related to the way energy is used. Although not direct contributors to energy balance, they are key components of metabolic health. One such component is metabolic flexibility.

Metabolic flexibility represents the body's ability to adjust to changes in availability of energy substrates. This is particularly evident in the transition from fasting to fed states. In the fasting condition, the lack of dietary fuels should lead to oxidation of stored fats.

The response to the fed state depends on the primary fuel consumed during the meal, with a "flexible" state defined as a switch to oxidizing the predominant fuel in the meal (carbohydrates vs fat). Metabolic flexibility is a complex physiologic construct that occurs at the cellular, tissue, and whole-body level and is modulated by a complex web of biological and behavioral factors.

This physiologic adaptation to fuel demands is aberrant in metabolic diseases such as obesity and type 2 diabetes, and is termed metabolic inflexibility. Metabolic inflexibility is often associated with insulin resistance involving skeletal muscle, liver, and adipose tissue via mechanisms relating to mitochondrial function and accumulation of lipids.

Although there is some debate about whether metabolic inflexibility per se, after accounting for impaired cellular glucose uptake, is a causal mechanism in insulin resistance, it is clear that the inability to appropriately respond to fuel demands is a pathophysiologic feature that contributes to the insulin-resistant state common in obesity and type 2 diabetes.

Measuring Metabolic Inflexibility

Given the importance of metabolic flexibility, how is it measured? There are two key approaches: hyperinsulinemic-euglycemic clamps — currently considered the gold standard — and whole-room indirect calorimetry. Both methods center on substrate challenges to evaluate transition from fasting to fed state (single substrate, such as an oral glucose tolerance test, or mixed meals).

With hyperinsulinemic-euglycemic clamps, plasma insulin is infused to achieve an a priori determined state of hyperinsulinemia, followed by infusing a variable amount of glucose to maintain euglycemia. The assessment of the respiratory exchange ratio measured by indirect calorimetry (respiratory exchange ratio [RER], the ratio of carbon dioxide production to oxygen consumption) yields information on how well an individual switches from fat oxidation in the fasting state to glucose oxidation in the hyperinsulinemic state.

With whole-room indirect calorimetry, the traditional approach evaluates the change in RER from fasting to fed stimulated conditions, similar to the indirect calorimetry performed during clamps. But the meal challenge is more physiologic than the glucose infusion during a clamp, and the precision of whole-room calorimeters for evaluating RER leads to a more reliable assessment of substrate oxidation.

More contemporary approaches have evaluated the kinetics of RER from fasted to fed states at various times of the day using 24-hour whole-room indirect calorimetry to reveal the comprehensive dynamics of metabolic flexibility. Currently, there are no reliable clinically accessible diagnostics for metabolic inflexibility, although there are commercial products and programs that purport the ability to test and treat metabolic flexibility.

Strategies for Correcting Metabolic Inflexibility

What can be done clinically to improve metabolic flexibility in patients who are likely to be inflexible, such as those with obesity or type 2 diabetes? The same lifestyle interventions that improve insulin sensitivity also improve fuel utilization and, thus, metabolic flexibility. These include exercise and caloric restriction (either continuous or intermittent).

In addition, under active investigation are potential pharmaceutical approaches to improve metabolic flexibility by targeting key players in metabolism such as AMP-activated protein kinase(AMPK), sirtuins, mammalian target of rapamycin (mTOR), and peroxisome proliferator–activated receptors (PPARs).

Viewing energy metabolism as a linear energy-in/energy-out paradigm excludes the journey that energy takes within the body as it is used. Although the efficiency and appropriateness of this journey may not affect body weight directly, it is an important consideration for metabolic health. Metabolic inflexibility is one component of energy utilization that could have an impact on the health of your patients and can be targeted within usual care paradigms for managing weight and insulin sensitivity.

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Cite this: Metabolic Inflexibility: More Than 'Energy In, Energy Out' - Medscape - Aug 30, 2023.