Metabolic flexibility and its impact on health and disease

[madman]

Abstract: Metabolic flexibility is the ability to efficiently adapt metabolism based on nutrient availability and requirement that is essential to maintain homeostasis in times of either caloric excess or restriction and during the energy-demanding state. This regulation is orchestrated in multiple organ systems by the alliance of numerous metabolic pathways under the master control of the insulin-glucagon-sympathetic neuro-endocrine axis. This, in turn, regulates key metabolic enzymes and transcription factors, many of which interact closely with and culminate in the mitochondrial energy generation machinery. Metabolic flexibility is compromised due to the continuous mismatch between availability and intake of calorie-dense foods and reduced metabolic demand due to sedentary lifestyle and age-related metabolic slowdown. The resultant nutrient overload leads to mitochondrial trafficking of substrates manifesting as mitochondrial dysfunction characterized by ineffective substrate switching and incomplete substrate utilization. At the systemic level, the manifestation of metabolic inflexibility comprises reduced skeletal muscle glucose disposal rate, impaired suppression of hepatic gluconeogenesis, and adipose tissue lipolysis manifesting as insulin resistance. This is compounded by impaired β-cell function and progressively reduced β-cell mass. A consequence of insulin resistance is the upregulation of the mitogen-activated protein kinase pathway leading to a prohypertensive, atherogenic, and thrombogenic environment. This is further aggravated by oxidative stress, advanced glycation end products, and inflammation, which potentiates the risk of micro-and macro-vascular complications. This review aims to elucidate underlying mechanisms mediating the onset of metabolic inflexibility operating at the main target organs and to understand the progression of metabolic diseases. This could potentially translate into a pharmacological tool that can manage multiple interlinked conditions of dysglycemia, hypertension, and dyslipidemia by restoring metabolic flexibility. We discuss the breadth and depth of metabolic flexibility and its impact on health and disease.




Introduction

There is an alarming surge in the prevalence of diabetes globally, and it has become a significant public and economic health burden. According to the 2019 International Diabetes Federation (IDF) estimates, the global prevalence of Type 2 diabetes mellitus (T2DM) is 463 million (9.3%) and is projected to reach 578 million (10.2%) by 2030.1 Among these, the second-highest number of people with diabetes after China is in India (69.2 million), and it is estimated to increase to 123.5 million by 2040. In the latest report of the Indian Council of Medical Research (ICMR), the estimated prevalence of diabetes and prediabetes was 7.3% and 10.3%, respectively, indicating a large pool of individuals at the risk of T2DM.2




Metabolic Flexibility and Its Physiological Relevance in Maintaining Energy Homeostasis

*Metabolism in Post-Prandial Condition

*Metabolism in Fasting Conditions

*Metabolism in Caloric Restriction or Prolonged Fasting




Hormones Involved in Maintaining Energy Homeostasis

*Insulin
*Glucagon
*Renin-Angiotensin-Aldosterone System (RAAS)

*Other Factors Regulating Metabolic Flexibility

*Epigenetic Regulation of Energy Homeostasis

*Sex Difference in Metabolic Flexibility




Metabolic Inflexibility: Cellular and Metabolic Pathways

*Calorie Excess and Reduced Physical Activity Causing Metabolic Inflexibility

*Pancreatic Beta-Cell Dysfunction




Metabolic Inflexibility Associated with DBCD and the Spectrum of Micro- and Macro-Vascular Complications

Unmet Need for Therapy Addressing Metabolic Inflexibility




Conclusion

Insulin and other glucoregulatory hormones provide an integrated set of signals to maintain metabolic flexibility. Sex-based differences arising from genetics, epigenetics, and hormones influence metabolic flexibility. Disruption in metabolic flexibility is most commonly caused by excess food intake and sedentary lifestyle, contributing to mitochondrial dysfunction characterized by inefficient nutrient sensing and ineffective substrate switching deemed as “Metabolic inflexibility.” This condition alters metabolic and non-metabolic pathways leading to the development of IR and β-cell dysfunction. All these effects induce cellular events, including increase oxidative stress and inflammation, endothelial dysfunction, production and accumulation of advanced glycation end products, ectopic fat accumulation resulting in dyslipidemia, hypertension, and micro-and macro-vascular complications. These complications can be addressed through traditional lifestyle measures such as caloric restriction and exercise that are vital components for tackling metabolic inflexibility. However, these traditional lifestyle measures are challenging over the long-term in the modern era of nutrient excess. Therefore, pharmacological interventions, in addition to lifestyle changes, can play a major role in the management of dysglycemia, dyslipidemia, and hypertension collectively, by addressing the underlying defect and help prevent progression to vascular and, consequently, end-organ damage. Targeting pathways that address mitochondrial dysfunction would exert a beneficial effect on metabolic inflexibility that may correct IR, β cell dysfunction, and endothelial dysfunction and, as a consequence, would be therapeutically effective across the entire continuum of DBCD.

 

[madman]

Figure 1 Key features of dysglycemia-based chronic disease and the insulin resistance-prediabetes-type 2 diabetes spectrum. Insulin resistance is the driving factor leading to prediabetes, diabetes, micro-and macro-vascular complications.

 

[madman]

Figure 2 Overview of macromolecule metabolism for generating ATP. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; TCA, tricarboxylic acid cycle

 

[madman]

Figure 3 Regulation of blood glucose via insulin and glucagon feedback.

 

[madman]

Figure 4 Mechanism of inhibition of fatty acid oxidation in mitochondria in post-prandial state. Malonyl CoA generated from acetyl CoA derived from the utilization of carbohydrates through glycolysis and TCA cycle by acetyl CoA carboxylase inhibits the entry of long-chain fatty acyl CoA into mitochondria. Abbreviations: ATP, adenosine triphosphate; ACC, acetyl CoA carboxylase; CPT, carnitine palmitoyltransferase; FAS, fatty acyl synthase; LDH, lactate dehydrogenase; TCA, tricarboxylic acid cycle; PDH, pyruvate dehydrogenase.

 

[madman]

Figure 5 Lipid transport and storage.

 

[madman]

Figure 6 Metabolism in a fasting condition. Inhibition of glucose utilization by fatty acid oxidation mediated by inhibition of pyruvate dehydrogenase and phosphofructokinase. Abbreviations: ATP, adenosine triphosphate; ACC, acetyl CoA carboxylase; Cyt C, cytochrome C; CoQ, coenzyme Q; CPT, carnitine palmitoyltransferase; FAS, fatty acyl synthase; DHAP, dihydroxyacetone phosphate; LDH, lactate dehydrogenase; NAD/NADH, nicotinamide adenine dinucleotide; PFK, phosphofructokinase; PEPCK, phosphoenolpyruvate carboxykinase; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid cycle.

 

[madman]

Figure 7 Metabolic perturbation in different organ system due to mitochondrial dysfunction leading to metabolic inflexibility.

 

[madman]

*Disruption in metabolic flexibility is most commonly caused by excess food intake and sedentary lifestyle, contributing to mitochondrial dysfunction characterized by inefficient nutrient sensing and ineffective substrate switching deemed as “Metabolic inflexibility.” This condition alters metabolic and non-metabolic pathways leading to the development of IR and β-cell dysfunction. All these effects induce cellular events, including increase oxidative stress and inflammation, endothelial dysfunction, production and accumulation of advanced glycation end products, ectopic fat accumulation resulting in dyslipidemia, hypertension, and micro-and macro-vascular complications.