Chapter 2 - Cellular and molecular mechanisms involved in metabolic disorders

Abstract

Metabolic disorders are conditions that originate due to metabolic dysfunction or disruption of normal metabolism. They can be broadly classified as inherited or acquired. Inherited metabolic disorders are also known as an inborn metabolic disorders in which there is a genetic variation or mutation that disrupts metabolic homeostasis. Obesity contributes to the pathogenesis of type 2 diabetes by increasing insulin resistance that further ultimately increases the risk of cardiovascular problems such as atherosclerotic cardiovascular disease, myocardial infarction, etc. Leptin is a hormone secreted by adipocytes that regulate insulin sensitivity. Reduced level of leptin or leptin deficiency often results in a predisposition to as well as worsens insulin resistance. Clinical and preclinical evidence document an alteration in transcriptional factor single-minded protein 1 (SIM-1) in obesity. Any variation in SIM-1 may lead to impaired food intake and fat storage. Moreover, osteocalcin deficiency also contributes to type 2 diabetes due to the disruption of insulin homeostasis. Furthermore, JAK/STAT pathway plays a pathological role in insulin resistance. Inhibition of the overactivated JAK-STAT pathway improves insulin sensitivity and reduces hyperglycemia and body weight. In the JAK-STAT signaling cascade, a divergence from the normal functioning of the growth hormone/IGF-1 axis often results in hepatic steatosis. Hepatic steatosis is a key feature of obesity and worsens type 2 diabetes. Besides this, AMP-activated protein kinases also play a pivotal role in synchronizing lipid and glucose metabolism. Various mediators such as adiponectin, resistin, and proinflammatory cytokines are responsible for the downregulation of AMPK activity. Overall, this chapter discusses the correlation of various mediators such as SIM-1, JAK-STAT, AMPK, and osteocalcin with obesity, type 2 diabetes, and cardiovascular problems.