Insulin
Action
Clinical scenario
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.
Insulin effects
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.
