**2. Insulin and macronutrient metabolism**

Insulin is the primary hormone responsible for initiating carbohydrate metabolism through phosphorylation of glucose and subsequent formation of glucose-6-phosphate inside the cells [23, 24]. Insulin activates the hexokinase enzymes in non-hepatic tissues and glucokinase (GCK) in β cells and hepatocytes to initiate glucose phosphorylation [25–28]. The insulin hormone acts by binding to the cell surface insulin receptors which are vastly distributed in different tissues of the body [29]. The binding of insulin to its receptors activates adaptor proteins known as insulin receptor substrates (e.g. IRS1, IRS2) [30]. IRS protein converts the tyrosine phosphorylation signal into the lipid kinase by activating phosphoinositide2-kinase enzyme (PI3K). Activated PI3K further recruits ATP molecules which activates AKT (serine and threonine kinase) [31]. The Discovery of insulin's primary role in activating AKT proved a landmark in explaining the conversion of tyrosine phosphorylation into serine/threonine phosphorylation signal. AKT activation also explains the insulin induced regulation of key steps in insulin signaling including (a) glucose uptake by glucose transporter (GLUT4), (b) glycogen synthesis by glycogen synthase kinase 3 (GSK3) inhibition, (c) synthesis of protein and fats via activation of the mechanistic target of rapamycin (mTOR), (d) gene expression regulation at the transcriptional levels by forkhead family box O (FOXO) transcription factor proteins. Insulin enhances GLUT4 activity in muscle and adipose tissue thus increasing the rate of glucose transport, glycolysis and subsequent glycogen synthesis in these tissues [32]. Insulin also prevents hepatic glucose synthesis by inhibiting hepatic glycogenolysis and gluconeogenesis [33–35].

Apart from glucose metabolism, insulin influences lipid and protein metabolism through multiple means. Insulin lowers the plasma fatty acid levels by decreasing adipocyte lipolysis and enhancing the hepatic formation of very low density lipoprotein (VLDL) [36–41]. Insulin increases the protein synthesis in skeletal muscles and the liver by enhancing the amino acid transport inside the cells and reducing protein degradation and urea formation [13, 42–47]. These metabolic

effects of insulin on carbohydrates, lipids and proteins highlight the importance of insulin signaling in maintaining a nutritional consistency at the cellular level and ensuring a balanced physiological interplay between multiple tissues under diverse physiological conditions.
