Physiologic Effects of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, \"Doesn\'t

it have something to do with blood sugar?\" Indeed, that is correct, but such a response is a bit like

saying \"Mozart? Wasn\'t he some kind of a musician?\"

Insulin is a key player in the control of intermediary metabolism. It has profound effects

on both carbohydrate and lipid metabolism, and significant influences on protein and

mineral metabolism. Consequently, derangements in insulin signalling have widespread and

devastating effects on many organs and tissues.

The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma

membrane. The insulin receptor is composed of two alpha subunits and two beta

subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house

insulin binding domains, while the linked beta chains penetrate through the plasma membrane.

The insulin receptor is a tyrosine kinase. In other

words, it functions as an enzyme that transfers

phosphate groups from ATP to tyrosine residues on

intracellular target proteins. Binding of insulin to the

alpha subunits causes the beta subunits to phosphorylate

themselves (autophosphorylation), thus activating the

catalytic activity of the receptor. The activated receptor

then phosphorylates a number of intracellular proteins,

which in turn alters their activity, thereby generating a

biological response.

Several intracellular proteins have been identified as

phosphorylation substrates for the insulin receptor, the best-studied of which is insulin

receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things

happen. Among other things, IRS-1 serves as a type of docking center for recruitment and

activation of other enzymes that ultimately mediate insulin\'s effects. A more detailed look at

these processes is presented in the section on Insulin Signal Transduction.

Insulin and Carbohydrate Metabolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the

small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in

blood stimulate release of insulin, and insulin acts on cells throughout

the body to

stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose

metabolism vary depending on the target tissue. Two important effects are:

Insulin facilitates entry of glucose into muscle, adipose and several other tissues.

The only mechanism by which cells can take up glucose is by facilitated diffusion through

a family of hexose transporters. In many tissues - muscle being a prime example - the

major transporter used for uptake of glucose (called GLUT4) is made available in the

plasma membrane through the action of insulin.

In the absence

of insulin, GLUT4 glucose

transporters are present in cytoplasmic vesicles,

where they useless for transporting glucose.

Binding of insulin to receptors on such cells

leads rapidly to fusion of those vesicles with the

plasma membrane and insertion of the glucose

transporters, thereby giving the cell an ability to

efficiently take up glucose. When blood levels

of insulin decrease and insulin receptors are no

longer occupied, the glucose transporters are

recycled back into the cytoplasm.

The animation to the right depicts how

insulin signalling leads to translocation of

glucose transporters from the cytoplasm into

the plasma membrane, allowing glucose

(small blue balls) to enter the cell. Click on the \"Add Glucose\" button to start it.

It should be noted here that there are some tissues that do not require insulin for

efficient uptake of glucose: important examples are brain and the liver. This is