Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease

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 pro-hypertensive, 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.

Keywords: DBCD; diabetes; insulin resistance; metabolic flexibility; microvascular and macrovascular complication; prediabetes.

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.

Figure 2

Overview of macromolecule metabolism for generating ATP.

Figure 3

Regulation of blood glucose via insulin and glucagon feedback.

Figure 4

Mechanism of inhibition of fatty acid oxidation in mitochondria in post-prandial state. Malonyl CoA generated from acetyl CoA derived from utilization of carbohydrates through glycolysis and TCA cycle by acetyl CoA carboxylase, inhibits the entry of long-chain fatty acyl CoA into mitochondria.

Figure 5

Lipid transport and storage.

Figure 6

Metabolism in fasting condition. Inhibition of glucose utilization by fatty acid oxidation mediated by inhibition of pyruvate dehydrogenase and phosphofructokinase.

Figure 7

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