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).