Metabolic Flexibility in Health and Disease

Abstract

Metabolic flexibility is the ability to respond or adapt to conditional changes in metabolic demand. This broad concept has been propagated to explain insulin resistance and mechanisms governing fuel selection between glucose and fatty acids, highlighting the metabolic inflexibility of obesity and type 2 diabetes. In parallel, contemporary exercise physiology research has helped to identify potential mechanisms underlying altered fuel metabolism in obesity and diabetes. Advances in "omics" technologies have further stimulated additional basic and clinical-translational research to further interrogate mechanisms for improved metabolic flexibility in skeletal muscle and adipose tissue with the goal of preventing and treating metabolic disease.

Keywords: adipose tissue; exercise; insulin resistance; metabolic flexibility; obesity; skeletal muscle; type 2 diabetes.

Figure 1. Acute lipid oversupply during hyperinsulinemia reveals metabolic flexibility in trained compared to untrained subjects

During a hyperinsulinemic-euglycemic “glucose” clamp without (light bars) or with (dark bars) co-infusion of intralipid, trained subjects decrease glucose oxidation (green bars), increase fatty acid oxidation (yellow bars) and preserve muscle glycogen storage (red bars) relative to untrained subjects, who exhibit metabolic inflexibility. In other words, untrained subjects do not effectively decrease glucose oxidation or increase fatty acid oxidation, and they have diminished glycogen storage in the face of lipid overload. Data were obtained from (Dube et al., 2014).

Figure 2. Adipose tissue insulin responsiveness is critical for metabolic flexibility of other organs and is blunted in diabetes

(a) Free fatty acids (FFAs) during a during a hyperinsulinemic-euglycemic clamp with a primed-continuous insulin infusion of 80 mU/m²/min for 3–4 hours are related to reduced metabolic flexibility (delta RQ) in a population of 56 healthy young men subdivided into quartiles of metabolic flexibility. (b) People with type 2 diabetes (T2D; n=18) have significantly higher levels of FFAs during an hyperinsulinemic-euglycemic clamp with a primed-continuous insulin infusion of 100 mU/m²/min for 3–4 hours compared with age- and BMI-matched healthy people (ND; n=6) and highly active people (Active; n=8). ANOVA was used to test for differences across quartiles of metabolic flexibility (delta RQ), with post hoc testing by mean equality contrast between different groups using the Tukey–Kramer HSD; alpha = 0.05. Type I error rate was set a priori at p < 0.05. Data are shown as means ± SEM. Levels which do not share the same letter are significantly different. FFAs were measured by high-performance liquid chromatography (HPLC) for (a) and by enzyme assay for (b).

Figure 3. Transcapillary flux of FFAs is reduced with obesity

The release of free fatty acids (FFAs) and the extraction of triglycerides from plasma (nmol/100g/min) in abdominal subcutaneous white adipose tissue (WAT) is significantly lower in the WAT of abdominally obese men (red line) compared with lean men (blue line) (both time x group, p < 0.001) across consumption of three mixed meals over the course of 24 hours. Meal consumption is indicated by a dashed line.

Figure 4. Respiratory quotient (RQ) kinetic during 24 hours in a metabolic chamber

Lines represent individual responses for a type I diabetes mellitus patient (DMT1, red line) and a healthy volunteer (blue line). Arrows indicate different features of metabolic flexibility (exercise, response to a meal and sleeping) as assessed in whole room respiratory chamber.

Figure 5. Summary of fuel metabolism changes within skeletal muscle and adipose tissue during periods of sleeping, fasting, feeding, rest and exercise

Skeletal muscle switches from higher rates of fatty acid oxidation during sleeping/post-absorptive conditions to greater oxidation and storage of glucose after feeding, and reduced fatty acid oxidation. Adipose tissue shifts from higher rates of lipolysis to suppression of lipolysis and fat storage during the fasting to feeding transition. From rest to exercise, skeletal muscle increases rates of both fatty acid and glucose oxidation to support higher energy demands, while lipolysis in adipose tissue is drastically enhanced.