Insulin is the key hormone involved in the regulation of cellular energy supply and macronutrient balance derived from food and may be considered as the hormone that signals the post- meal fed state. Insulin secretion is influenced by many factors (Table 1), but food ingestion is the most important. After a meal, once glucose concentrations rise above 5 mmol/l, insulin is secreted in a coordinated pulsatile fashion into the portal vein in a characteristic biphasic pattern; first there is an acute rapid first- phase release of insulin, lasting for a few minutes, followed by a less intense but more sustained second phase. Insulin is also produced during the fasting state; although at a low level, this background secretion accounts for ~50% of total daily insulin production.
Table1. Factors regulating insulin release from the β cells of the pancreatic islets.
Insulin exerts its biological actions by binding to the insulin receptor, which is a heterotetrameric transmembrane protein comprising two α- and two β- glycoprotein subunits linked by disulfide bonds. Following binding to the α subunits, insulin induces a conformational change in the β subunits, resulting in activation of tyrosine kinase and initiation of a cascade response involving a host of other intracellular substrates. The insulin- receptor complex is then internalized by the cell, insulin is degraded, and the receptor is recycled to the cell surface.
Effect on glucose metabolism
Insulin is involved in the regulation of carbohydrate metabolism at many steps (Table 2), but predominantly acts to increase the uptake and storage of glucose in liver, adipose tissue, and skeletal muscle. Cell membranes are not inherently permeable to glucose and require a family of specialized glucose- transporter (GLUT) proteins to carry glucose through the membrane into cells. The function of GLUT 1 to 3 is insulin independent, but insulin stimulates glucose uptake into muscle and adipose tissue through GLUT 4. GLUT 4 is normally present in the cytoplasm, but after insulin binds to its receptor, GLUT 4 moves to the cell surface where it creates a pore for glucose entry.
Table2. Insulin actions on carbohydrate metabolism.
Effect on lipid metabolism
Insulin promotes fat storage within adipose tissue and the liver by increasing the rate of lipogenesis and controlling the formation and storage of triglyceride. The critical step in lipogenesis is the activation of the insulin- sensitive lipoprotein lipase in the capillaries. This enzyme acts to release fatty acids from circulating chylomicrons or very low- density lipoproteins, which are taken up into the adipose tissue. Lipogenesis is also facilitated by glucose uptake, because its metabolism by the pentose phosphate pathway provides nicotinamide adenine dinucleotide phosphate (NADPH), which is needed for fatty acid synthesis.
Insulin increases triglyceride synthesis by activating acetyl co- enzyme A (CoA) carboxylase, while at the same time suppressing fat oxidation through the inhibition of carnitine acyltransferase (Table 3). Insulin also stimulates triglyceride synthesis through the esterification of glycerol phosphate. By contrast, triglyceride break down is suppressed by insulin by inhibiting hormone- sensitive lipase. Within the liver, insulin reduces ketogenesis. Cholesterol synthesis is increased by insulin through activation and dephosphorylation of hydroxymethylglutaryl co- enzyme A (HMGCoA) reductase, while cholesterol ester breakdown appears to be inhibited by dephosphorylation of cholesterol esterase.
Table3. Insulin actions on fatty acid metabolism.
Effect on protein metabolism
Insulin stimulates amino acid uptake into cells and promotes protein synthesis in a range of tissues by increasing transcription of specific mRNA and translation into proteins on the ribosomes. Examples of enhanced mRNA transcription include glucokinase and fatty acid synthase. By contrast, insulin decreases mRNA- encoding liver enzymes such as carbamoyl phosphate synthetase, which is a key enzyme in the urea cycle. However, the major action of insulin on protein metabolism is to inhibit protein breakdown. In this way, it acts synergistically with growth hormone and insulin- like growth factor I (IGF- I) to increase protein anabolism.
