Insulin administration through intravenous (IV) route results in an immediate decrease in blood glucose levels. This is because insulin inhibits the production of glucose in the liver by suppressing glycogenolysis and gluconeogenesis. It is important to note that insulin not only affects enzyme activity but also alters gene transcription, leading to changes in enzyme amounts. Insulin also plays a role in lipid metabolism by reducing the release of fatty acids (FA) from adipose tissue. This is achieved by inhibiting the activity of hormone-sensitive lipase, which is responsible for breaking down triglycerides (TAG) in adipocytes. Additionally, insulin increases the transport and metabolism of glucose in adipocytes, providing the necessary substrate for TAG synthesis. It also promotes the expression of the gene for lipoprotein lipase in adipose tissue, allowing for the degradation of TAG in circulating chylomicrons and very-low-density lipoproteins (VLDL) and subsequent esterification of fatty acids to glycerol. Insulin also influences protein synthesis by facilitating the entry of amino acids into cells and promoting translation. Mechanistically, insulin binds to high-affinity receptors located in the cell membrane of various tissues, such as the liver, muscle, and adipose tissue. This binding triggers a series of reactions that ultimately lead to diverse biological actions. The insulin receptor is composed of α and β subunits, which are assembled into a tetramer linked by disulfide bonds. The α subunits contain the insulin-binding site, while the β subunits span the plasma membrane and possess a cytosolic domain with tyrosine kinase activity. Upon insulin binding, conformational changes occur, leading to rapid autophosphorylation of specific tyrosine residues on each β subunit. This autophosphorylation initiates a signaling cascade that includes phosphorylation of insulin receptor substrates (IRS), a family of proteins with similar structures but different tissue distributions. Phosphorylated IRS proteins interact with other signaling molecules through specific domains, activating pathways that influence gene expression, cell metabolism, and growth. The actions of insulin are terminated by dephosphorylation of the receptor.
97) in the cell membrane. Thus, the IV administration of insulin causes an immediate decrease in blood glucose level. In the liver, insulin decreases the production of glucose through the inhibition of glycogenolysis and gluconeogenesis. [Note: The effects of insulin are due not just to changes in enzyme activity but also in enzyme amount insofar as insulin alters gene transcription.] 2. Effects on lipid metabolism: A rise in insulin rapidly causes a significant reduction in the release of FA from adipose tissue by inhibiting the activity of hormone-sensitive lipase, a key enzyme of TAG degradation in adipocytes. Insulin acts by promoting the dephosphorylation and, hence, inactivation of the enzyme (see p. 190). Insulin also increases the transport and metabolism of glucose into adipocytes, providing the glycerol 3-phosphate substrate for TAG synthesis (see p. 188). Expression of the gene for lipoprotein lipase, which degrades TAG in circulating chylomicrons and very-low-density lipoproteins ([VLDL] see p. 229), is increased by insulin in adipose, thereby providing FA for esterification to the glycerol. [Note: Insulin also promotes the conversion of glucose to TAG in the liver. The TAG are secreted in VLDL.] 3. Effects on protein synthesis: In most tissues, insulin stimulates both the entry of amino acids into cells and protein synthesis (translation). [Note: Insulin stimulates protein synthesis through covalent activation of factors required for translation initiation.]
E. Mechanism
Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle, and adipose. This is the first step in a cascade of reactions ultimately leading to a diverse array of biologic actions (Fig. 23.7).
1.
Insulin receptor: The insulin receptor is synthesized as a single polypeptide that is glycosylated and cleaved into α and β subunits, which are then assembled into a tetramer linked by disulfide bonds (see Fig. 23.7). The extracellular α subunits contain the insulin-binding site. A hydrophobic domain in each β subunit spans the plasma membrane. The cytosolic domain of the β subunit is a tyrosine kinase, which is activated by insulin. As a result, the insulin receptor is classified as a tyrosine kinase receptor.
2.
Signal transduction: The binding of insulin to the α subunits of the insulin receptor induces conformational changes that are transmitted to the β subunits. This promotes a rapid autophosphorylation of specific tyrosine residues on each β subunit (see Fig. 23.7). Autophosphorylation initiates a cascade of cell-signaling responses, including phosphorylation of a family of proteins called insulin receptor substrates (IRS). At least four IRS have been identified that show similar structures but different tissue distributions. Phosphorylated IRS proteins interact with other signaling molecules through specific domains (known as SH2), activating a number of pathways that affect gene expression, cell metabolism, and growth. The actions of insulin are terminated by dephosphorylation of the receptor.
3.