3.1 Ameliorating metabolic abnormality
Insulin is a major regulator of carbohydrate, fat and protein metabolism. Lipid overflow hypothesis suggests that systematic IR and T2DM are mainly caused by abnormal increased lipid levels. The impaired storage capacity in adipose tissues could cause lipid overflow, that lipid would enter into the circulation and accumulated ectopically in other tissues such as skeletal muscle, liver and heart. Microscopically, ectopic lipid accumulation is caused by lipid intermediates, such as diacylglycerols, long chain fatty acyl- coenzyme A (CoAs) and acylcarnitines (Bosma, Kersten, Hesselink & Schrauwen, 2012). The mechanisms by which lipid intermediates affect insulin sensitivity include regulating phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway, protein phosphatase-2A (PP2A), fatty acid transporter CD36 and nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome (Petersen & Shulman, 2017; Tsatsoulis, Mantzaris, Bellou & Andrikoula, 2013). Generally, lipid accumulation in local organs leads to partial IR, or worse, secondary systemic IR (Kojta, Chacinska & Blachnio-Zabielska, 2020). For illustration, ectopic lipid accumulation in skeletal muscle and liver might inhibit the insulin signal transduction, leading to impaired muscle glucose uptake and hepatic glycogen synthesis. IR caused by ectopic lipid accumulation occurs earlier in muscle than that in liver, which contributes to glucose transference from muscle to liver and hepatic adipogenesis. Subsequently, macrophages infiltrate into white adipose tissue (WAT), which ultimately aggravates inflammation, hyperlipidemia and postprandial hyperglycemia (Samuel & Shulman, 2016). Also, excess lipid accumulation inhibits the capacity of mitochondria in catabolizing fatty acid substrate, leads to incomplete β-oxidation, thereby causing oxidized lipid byproducts accumulation and IR (Johnson, Milner & Makowski, 2012).