Mrs PC, a 45-year-old woman, was referred to her GP having been found to have a raised random blood glucose measurement at an insurance medical examination. On questioning she admit- ted to feeling increasingly tired recently and her weight had increased over the preceding year. She smoked 15 cigarettes a day. Her mother and maternal grandfather had Type 2 diabetes. On examination she was obese (body mass index 34 kg/m2). Blood pressure was 160/90 and there was an absent posterior tibial pulse at the right ankle. The rest of the examination was normal. Subsequent investigations revealed a fasting blood glucose of12.2 mmol/L, HbA1c 9.2%, cholesterol 7.4 mmol/L, normal renal function, glycosuria of 3+ on dipstix urine testing. She was strongly advised to stop smoking and treatment was commenced with antihypertensives and lipid-lowering agents. She was seen by the specialist nurse and dietician and advised about monitoring her blood glucose and about diet and exercise. Initially, her progress was slow but she eventually started to lose weight after the introduction of the drug metformin. This was accompanied by improved glycaemic control.
Mechanism of action of insulin
The insulin receptor belongs to a superfamily of transmembrane receptor tyrosine kinases. Other members of this receptor superfamily include the receptors for insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The insulin receptor consists of subunits: two alpha subunits and two beta subunits, which are linked covalently to each other by disulphide bridges (Fig. 39a). The alpha subunits are extracellular and contain the insulin-binding sites. The beta subunits span the membrane and transduce the binding of insulin to the alpha subunits into an intracellular signal by the following mechanism. When insulin binds to the receptor site, this interaction is transmitted to the intracellular domain of the beta subunit. This subunit becomes autophosphorylated, which in turn activates its own protein kinases, resulting in an intracellular cascade of phosphorylation and dephosphorylation reactions through which the actions of insulin are expressed.
A link between the insulin receptor and the rest of the phosphorylation cascade may be a family of proteins called insulin receptor substrate (IRS). Two IRS proteins, IRS-1 and IRS-2, are essential for the complete expression of the action of insulin. Autophosphorylation of the insulin receptor results in the tyrosine phosphorylation of the IRS proteins. This confers on IRS proteins the ability to bind other sets of signalling proteins that contain signalling domains and this docking process leads, ultimately, to the various effects of insulin on glucose transport, glycogen synthesis, protein synthesis and mitogenesis (Fig. 39b). Insulin converts glucose into glycogen, and this reaction is controlled by glycogen synthetase, which is inactive in the phosphorylated state, and activated by dephosphorylation. Hepatic phosphorylase, on the other hand, is activated by phosphorylation. Hepatic phosphorylase activates glycogenolysis. It has been suggested that insulin exerts its action on glycogen metabolism through its inhibition of phosphorylation of both these enzymes, possibly through the mechanism involving SH2 domains.
Glucose transporters. Insulin stimulates the cellular uptake of glucose, a major physiological action of insulin. Glucose is taken into the cell by glucose transporters, through a process of facilitated diffusion. The transporters can transfer glucose and other sugars across the cell membrane down a chemical concentration gradient (Fig. 39c). Glucose transporters vary in structure and ionic requirements from tissue to tissue.
Receptor internalization. After the receptor binds insulin, the hormone–receptor complex leaves the membrane through a process of endocytosis and enters the cell. After binding to the receptor, the complex becomes encapsulated in a coated pit, formed by invagination and fusion of the cell surface. Once inside the cell, the pit becomes progressively uncoated to form what is called an endosome. The endosome releases the receptor and insulin, the former being mainly recycled to the membrane, and insulin being degraded. The process of receptor internalization may provide a means of regulating the effects of insulin by limiting the numbers of receptors available for binding to the hormone. This mechanism effectively down regulates the insulin receptor.
After a meal, insulin removes glucose from the circulation and promotes its conversion to glycogen and lipids (Fig. 39d). Insulin promotes the conversion of fatty acids to lipids, and the uptake of amino acids into liver and skeletal muscle, where they are elaborated into protein. Insulin is thus an anabolic hormone.
Liver. The liver is the major site of gluconeogenesis and ketogenesis. Lipid and protein production also take place in the liver. Insulin stimulates a number of enzymes involved in glycogen production, including glycogen synthetase, which catalyses the formation of glycogen. Glycogen is also stored in smaller amounts in skeletal muscle and other cells which need to mobilize energy stores rapidly. Within the cell, glucose is also converted into glucose-6-phosphate, which is unable to leave the cell, since the plasma membrane is impermeable to phosphoric acid esters. This creates a concentration gradient, and more glucose moves into the cell.
Fat. Approximately 90% of stored glucose is as lipids. The adipocyte is therefore an important site of insulin action. Insulin is required for the activation of the enzyme lipoprotein lipase. If insulin is absent, lipoproteins accumulate in the circulation. Insulin also opposes the action of glucagon (see Chapter 42), a hormone which promotes the production of ketone bodies. The ketone bodies, acetone, acetoacetic acid and β-hydroxybutyric acid, are an energy source for muscle and brain, especially during prolonged fasting. They are derived from lipids, and are produced in conditions of insulin lack. The ketone bodies inhibit glucose and fatty acid oxidation, which results in the preferential use of the ketone bodies as a source of energy. When their rate of production exceeds their rate of utilization, ketoacidosis will result.
Muscle. Insulin stimulates amino acid uptake into skeletal muscle, and increases the incorporation of amino acids into proteins. These two actions are independent of insulin’s action on glucose transport into the cell.