Since its discovery in the 1920s, scientists have learned a great deal about insulin. They know a lot about how it works in people without diabetes. And they also know that when insulin is absent or doesn’t do its job, people develop diabetes.

Insulin is a hormone. Hormones are chemical signals made by the body that tell various parts of the body how to do their jobs. Some hormones control how the cells in the body grow. Some control how the body uses food and energy to live. And other hormones help muscles to contract, blood to clot, or the heart to beat.

One of insulin’s most important jobs is to help cells use glucose. Insulin acts like a key to unlock the door that lets glucose into the cell. Cells in the body use glucose as a source of energy that they need to live. Without energy, the cells in the body cannot survive. Insulin also helps the body to store extra fuel as fat.

In people with type 1 diabetes, the body does not make enough insulin. This is because most of the cells of the pancreas that make insulin have been destroyed by the immune system. Eventually, all of the cells that make insulin are destroyed and no insulin is produced. That is why type 1 diabetes is also called an autoimmune disorder. People with type 1 diabetes must take injections of insulin in order to live.

In people with type 2 diabetes, insulin is produced, but the cells do not respond to insulin as they should. Glucose has a hard time getting out of the blood and into cells. For some people with type 2 diabetes, diet, exercise, and oral diabetes medication together can help them keep their blood glucose levels on target without insulin injections. But for many people with type 2 diabetes, diet, exercise, and oral diabetes medication are not enough.

Insulin Type

Insulin is a small protein called a polypeptide. It is made up of a chain of small units, known as amino acids. In the early days, only pork and beef insulins were available. These insulins were made from grinding up the pancreases from pigs and cows and purifying the insulin protein. They acted rapidly to lower blood glucose levels. They also were used up rapidly by the body and had to be injected before each meal and at bedtime. Although long-acting animal insulins later became available, the purity and strength of early insulin preparations were not always reliable.

For many years, purified preparations of animal insulins were widely used. However, human insulin is now used most of the time. There is a ready supply of human insulin. It is not harvested from actual pancreases but is made with the help of genetic engineering. The human insulin gene, which tells cells what sequence of amino acids is needed to make the insulin protein, is put into bacteria that multiply rapidly. The bacteria are “tricked” into making human insulin.

Most people who take insulin today use human insulin. Beef insulin is no longer available in the United States and Canada, although pork insulin is. The big advantages to human insulin are that it is easy to make and it is unlikely to cause an allergic reaction. Some people are allergic to animal insulin, because the body sees it as a foreign substance.

Action Times

Premixed Insulin

Insulin Strength

When insulin was first manufactured, different batches often had different strengths. This made it difficult to know how much insulin was needed to lower blood glucose to the right level. Later, the strength of insulin became standardized, but it was available in several different strengths. This often made it confusing to figure out how much insulin to take.

To get the most life out of your insulin supply, keep open bottles “comfortable,” not too hot or too cold. If you’ll use up a bottle of insulin within a month, keep it at room temperature. If it takes longer than a month to use up, it’s best to keep it refrigerated, but warm up the syringe before you inject. Injecting cold insulin can make the injection uncomfortable. Keep unopened bottles in the refrigerator.

Freezing can cause the insulin ingredients to “unmix.” Because insulin is a protein, it will unfold (denature) at temperatures above 86°F, including those reached inside a locked car in the summer.

Today, if you buy insulin in this country, you don’t have to worry about the strength. Nearly all insulin preparations sold in the United States and Canada today are of the same strength: U-100. This means that they have 100 units of insulin in every cubic centimeter (cc) of fluid. U-40, a more diluted insulin, has been discontinued. U-500, a highly concentrated preparation, is available only by special order for people who have developed insulin resistance and need to take extremely high doses of insulin. Hospitals sometimes use U-500 insulin for emergencies.

Insulin syringes also come in different sizes that match the strength of insulin. If you travel outside the United States, bring along sufficient insulin and matching U-100 syringes. You could end up taking the wrong dose if you don’t match insulin strength with the right syringe. If you are planning a long visit outside the country and can’t bring along all the supplies you need, remember that you will need to buy U-40 syringes to use the U-40 insulin found in Latin America and Europe. Ask your provider to help you adjust your dosage.

Buying and Storing Insulin

Using Insulin

Most people with diabetes use a needle and syringe or an insulin pen to take their insulin. Once you learn how, this will be a quick and relatively painless task. If you have problems with your vision or using your hands, there are injection aids that may help solve the problem.

Using a syringe is just one way to take insulin. Advanced delivery systems such as the insulin pump may work better for some people. Some people use an insulin pen, while others use high pressure jet injectors to pass insulin through the skin. Whatever you choose, the basic purpose is the same: to deliver insulin into the fat that lies just under your skin.

Other ways to deliver insulin may become more widely available in the future. Inhaled insulin and insulin patches are being tested. One exciting prospect is an insulin infusion device that is implanted into the body. With this, you might be able to go 2 months without having to worry about refilling it. And scientists hope that one day they will be able to make a device that measures your blood glucose level and delivers the proper amount of insulin automatically.

Injecting Insulin

Coming Soon: Insulin without Injection

Injection Site Rotation

Insulin Pumps

One Shot a Day

A single shot of insulin can sometimes be enough to bring the blood glucose into the target range. Usually, a long-acting insulin such as glargine or intermediate-acting insulin such as NPH is given at bedtime or in the morning. The insulin is used to provide the basal level of insulin. Long-acting insulins provide a steady level of insulin throughout the day and night. Taking intermediate-acting insulin at bedtime helps lower your fasting glucose level. Taking intermediate-acting insulin in the morning provides some coverage for the food you eat as well as basal insulin.

Graph : Typical changes in glucose and insulin levels over 24 hours in someone without diabetes  shows what happens during the course of the day for people who do not have diabetes. Graph : One shot of long-acting insulin  and Graph : One shot of intermediate-acting insulin show what happens during the course of the day when these insulins are used once a day.

Graph : Typical changes in glucose and insulin levels over 24 hours in someone without diabetes.

As you can see, there isn’t always insulin available from this one injection to provide the bolus of insulin that is needed for meals. Taking one shot a day can also mean that you are more locked into a schedule for your meals. If you take an intermediate-acting insulin, you will need to eat when your insulin is peaking, whether it is convenient or not.

Graph : One shot of long-acting insulin.

Graph : One shot of intermediate-acting insulin.

If you take one shot of long- or intermediate-acting insulin, there are several ways to get the bolus of insulin you need for meals. Some people with type 2 diabetes may be able to make enough insulin to cover the post-meal increase in blood glucose. For these people, providing the basal insulin helps their pancreas to do its job better. Another option is to take oral diabetes medications. These medications can provide the coverage needed for meals. Still another possibility is to take a combination of insulins. You can take a rapid- or short-acting insulin along with your morning shot of NPH insulin. This gives you a bolus of insulin to cover your breakfast meal. You can either use pre-mixed insulins or mix two types of insulin in one injection.

More than One Shot

You may get better coverage by splitting your one shot of insulin into two shots. These can be given in the morning and in the evening. Usually, the morning shot will be a bigger dose than the evening shot. Graph 4 shows the amount of insulin available if you split your intermediate dose into a morning and evening shot. However, you’ll notice that even with this plan, you may have a period in the early morning, between 3 and 10 a.m., when your insulin level may be low.

Graph : Intermediate-acting insulin split into two shots.

One way to improve your coverage is to also mix rapid-or short-acting insulin with each intermediate dose. The rapid-acting or regular insulin provides the mealtime bolus. If you use rapid-acting, the insulin is taken with meals. Doses with regular insulin are taken about 30 minutes before breakfast and dinner, as shown in Graph : Split and mixed regular and intermediate-acting insulin in two shots. As you can see in these graphs, as the rapid-acting or regular insulin decreases, the intermediate insulin starts to work. Just when the intermediate insulin starts to wear off before dinnertime, another mixed dose is given. Again, the rapid-acting or regular insulin kicks in early, and the intermediate insulin picks up the slack to carry you through the night.

Graph : A combination of intermediate- and rapid-acting insulins.

Graph : Split and mixed regular and intermediate-acting insulin in two shots.

It may take a little experimenting and consulting with your health care team to figure out how to best mix rapid-acting or regular and intermediate-acting insulins. The ratio may change until you are getting the results that best suit you. You may find it convenient to buy a premixed insulin, such as a 70/30 or 75/25 mixture. Or you may prefer to split and mix the doses yourself. This lets you change the amounts of rapid-acting or regular and NPH independently of each other. You may find this helpful when trying to account for activity level and food intake.

If you are using a two-shot plan using split and mixed doses of intermediate-acting and rapid-acting or regular insulin, you will need to keep close tabs on your body’s response. This means that you need to monitor your blood glucose levels before and after meals. You may need to monitor at other times as well. A two-shot program gives you better coverage than a single-shot plan but still keeps you closely tied to a regular meal schedule and a regular pattern of activity. This is because you cannot make short-term adjustments in longer-acting insulins. Only rapid-acting or regular insulin can be adjusted immediately to respond to a blood glucose level or change in schedule.

If you find that your blood glucose level is fine at bedtime but high in the morning, you may want to move your evening insulin shot from dinnertime to bedtime. This will make insulin available a little later during the course of the night to keep your glucose levels in range. Make sure that your glucose levels are on target during the evening hours if you try this adjustment.

You may find that you have low blood glucose in the early morning (around 2 or 3 a.m.) with the two-shot plan. If this is the case, think about a three-shot plan. With this, you would give yourself a mixture of rapid- or short-acting and intermediate-acting insulin at breakfast, a rapid- or short-acting insulin at dinner, and an intermediate-acting insulin at bedtime. The insulin levels throughout the day are shown in Graph : Three shots: split and mixed morning dose, rapid-acting dinner dose, and intermediate-acting evening dose.

Graph : Three shots: split and mixed morning dose, rapid-acting dinner dose, and intermediate-acting evening dose.

ADA COMPLETE GUIDE TO DIABETES

The more often you inject insulin, the more opportunities you have to fine-tune your control. You also have more freedom and flexibility with your schedule and food choices. One such plan uses three or four shots a day. A common example is to take rapid-acting insulin before all meals. The dose is based on the carbohydrates eaten at that meal. A long-acting insulin such as glargine provides the basal dose of insulin. The injections of rapid-acting insulin provide the bolus for the three meals. To make this plan work for you, you need to monitor your blood frequently. Then you can adjust the amounts of rapid-acting or regular insulin given before each meal to

■ cover the carbohydrates in your meal;

■ lower a high blood glucose level not sufficiently lowered by the previous rapid-acting injection;

■ anticipate the rise in blood glucose caused by the next meal.

The goal is to keep your blood glucose levels within your target range.

Timing Your Insulin Injections

Knowing when to give your injection, or take your premeal bolus by pump, can be confusing.

*The intermediate-acting dose can also be given before dinner.

**The long-acting insulin dose can be taken at bedtime or before dinner or split in half, with half taken before breakfast and half before dinner.

Rapid- and short-acting insulins are taken before meals or very big snacks to counteract the increase in blood glucose that will occur as food is absorbed. Rapid-acting insulins begin to work in about 5-15 minutes. You can take your injection just before you eat. Taking your injection more than 15 minutes before meals can result in a hypoglycemic reaction. Regular insulin takes about 15-30 minutes to start working. If regular insulin is taken too close to the start of a meal, the food will cause blood glucose levels to go too high before the insulin has had a chance to be absorbed for use.

How much in advance of your meal you need to take your regular insulin depends on your blood glucose level before the meal. Try checking about 45 minutes before you plan to start eating. If your blood sugar level is high, you need to inject your regular insulin quickly to help counteract your already high blood glucose level before food sends it even higher. You may also want to postpone your meal for a short time. If your blood sugar level is low, you need to wait to inject regular insulin closer to the time you’ll start eating. Inject at the end of the meal if your blood sugar level is 50 mg/dl or lower. If you can’t check your blood glucose, a general guideline is to take regular insulin 30 minutes before your meal.

Intensive Diabetes Management

Intensive insulin therapy is defined as taking three or more injections a day. But it’s more than just taking shots. It also means more blood glucose checks and spending more time thinking about and caring for your diabetes. So why would you do it? Well, more shots and more monitoring give you more flexibility and spontaneity. It can also keep your blood glucose levels more even and on target. You’ll feel better now and lower your risk for future complications. But is it for you? Ask yourself the following:

Am I unhappy with my blood glucose levels?

1. Do my blood glucose checks frequently show unexpected levels, high or low?
2. Are my glucose checks frequently out of range?
3. Do I have any signs of the complications of diabetes?
4. Do I lack the amount of energy I need to participate in all my activities — both day and night?
5. Do I want more flexibility in my lifestyle for timing meals, exercise, and other activities?

If you answer “yes” to any of these questions, you may want to investigate the idea of intensive diabetes management. See site for more information.

■ onset: the length of time it takes for insulin to reach the blood and begin lowering blood glucose levels

■ peak time: the time during which insulin is at its maximal strength in lowering blood glucose levels

■ duration: the length of time in which insulin continues to lower blood glucose

Before you got diabetes, your pancreas made the insulin you needed to keep your blood glucose in the normal range. The pancreas made a small amount of insulin throughout the day and night that was released in a steady stream. This is the basal insulin level. When you ate and your blood glucose level began to rise, the pancreas released a burst, or bolus, of insulin.

Insulin doses are planned to work as much like the body as possible. Rapid- and short-acting insulins are bolus insulins. Intermediate- and long-acting insulins are basal insulins. Most people with diabetes take both a basal and a bolus insulin.

The first type of insulin that was made available is known as regular insulin. Regular insulin is short acting and must be injected several times throughout the day. Regular insulin begins working rapidly and is used up fairly quickly by the body. As shown in the table on insulin action times, regular insulin begins to act within an hour. Rapid-acting insulin, lispro insulin and insulin aspart, go to work within minutes. An intermediate-acting insulin, NPH (neutral protamine Hagedorn), contains a molecule known as a protamine, which slows down how fast the body absorbs insulin. Because the insulin reaches the blood more slowly, the onset, peak, and duration times are longer. By using a slower-acting insulin, you can get by with fewer injections each day. For example, a mixture of NPH and regular insulin injected at breakfast can last until dinnertime. You may not need an injection at lunchtime.

People who are allergic to the prota-mine in NPH can consider using lente, another intermediate-acting insulin. An even longer-acting insulin, ultralente, provides a continuous level of insulin with a less pronounced peak. In some people, human ultralente insulin may really act more like an intermediate insulin. Insulin glargine is the newest long-acting insulin. It has no peak and works well with rapid-acting insulin taken before meals. Whenever you change insulins, you need to figure out how quickly the new insulin works in your body.

All insulins used for injections have added ingredients. These prevent bacteria and molds from growing and help keep insulin from spoiling. Intermediate- and long-acting insulins also contain ingredients that prolong their action times. If you think you may be experiencing an allergic reaction to your insulin preparation, talk to your provider.

Signs of a local allergic reaction to insulin:

► dents under the skin at injection sites

► redness at injection sites, either persistent or temporary

► groups of small bumps, similar to hives

► swelling at injection sites

Rapid- or short-acting insulins can both be used for bolus doses of insulins. But many people find rapid-acting insulins more convenient.

Rapid-acting insulins can be used by people with either type 1 or type 2 diabetes. The faster action of these insulins makes it easier to time insulin with food. In other words, you can match the rise in blood glucose from food absorption to the rise in insulin in your blood from the rapid-acting insulin.

Rapid-acting insulins are in a form that the body can absorb right away without having to break it down. With regular insulin, the body needs to reduce the insulin protein chain to a smaller size before it can be absorbed and go to work. It can take over 30 minutes from the time regular insulin is injected until it starts working on cells. With rapid-acting insulins, this time is cut in half, so there’s less room for error. It goes to work almost as fast as naturally produced insulin does.

This rapid-acting insulin may give you a lot more flexibility. You can count the carbohydrates in your meal and take insulin to cover that amount. If you eat an extra helping at a meal, you can take care of the carbohydrates with a booster shot right away. You may even be able to wait until you know how much carbohydrate you’ve eaten to inject these insulins. Also, because rapid-acting insulins don’t remain in the body as long as regular insulin does, you may experience fewer episodes of hypoglycemia. Ask your provider whether you could benefit from using a rapid-acting insulin.

Crossing time zones can confuse your insulin schedule. You may need to make a new plan for timing your insulin injections. You may also need to adjust your total daily insulin dose. When traveling east, you get a shorter day and need less insulin. When traveling west, you get more hours in a day and need more insulin. Keep your watch on your home time until the first morning after you arrive in a new time zone. Check your blood glucose level more often than usual. For more on insulin and traveling.

70 percent NPH. Preparations containing intermediate- and rapid-acting insulins are also available. Premixed insulins can also be useful for people with eyesight or dexterity problems that make drawing different amounts of insulin from two different bottles difficult. You may want to discuss assistive devices for people with impaired sight with your doctor or diabetes educator.

Even though you can buy mixtures of insulin or can mix them yourself, make sure to talk to members of your health care team before you make any changes in the insulin you take. Never mix types of insulin without the okay from your provider. Mixing insulin with lente or ultra-lente insulin can be more complicated than mixing with NPH. These longer-acting insulins can interfere with rapid-and short-acting insulins and lead to unpredictable results. Rapid-acting and regular insulins are not always readily absorbed by the body when mixed with slower insulins. If your injection schedule calls for taking both regular and lente insulin at the same time, try to inject them immediately after mixing. Glargine cannot be mixed in the same syringe with other insulins. If you have any questions or notice that you don’t get the response you expect from the bolus insulin, talk to your provider. You may need to increase the amount of regular insulin in the mixture or switch to a rapid-acting insulin.

Before you leave your diabetes care provider’s office, be sure you understand the following:

■ what type of insulin you will be taking and the name of the insulin

■ the symptoms of high and low blood glucose that could indicate a problem with your insulin doses

■ where you should inject it

■ whether you need to prepare any mixtures

■ how often to give yourself injections

■ the best times of the day to take your insulin

■ how to store your insulin

Don’t be afraid to take notes or ask questions about anything that’s not clear. Even if you have taken insulin before, you might want to review your insulin schedule on a return visit, especially if you are experiencing any difficulties. You might also want to go over any changes in your schedule that were recommended. Make sure you understand how to time injections with mealtimes. Go step-by-step through a typical day. Also talk about how to adjust for an unusual day. What happens if you oversleep, get sick, travel across time zones, or plan to be unusually active?

In choosing a pharmacy, convenience may be just as important as cost. You may want a pharmacy that is close by or one that delivers your insulin to you. This can be convenient, especially if you are very busy, ill, or housebound. Also think about the pharmacist. Is the pharmacist easy to talk to? Does he or she seem willing to answer your questions?

Once you find a pharmacy that you like, try to develop a relationship with the pharmacist. Don’t just ask for NPH insulin. Ask questions. Check to make sure you have the desired brand and type. You may want to bring along an empty bottle to make sure you get exactly the same thing each time. Before you pay, double-check to see that you have what you want. If something doesn’t look quite right, or if you are uncertain, be sure to ask your pharmacist.

Storing Insulin

Unopened bottles and unused insulin pens or cartridges

I

Stored in the refrigerator

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Discard after expiration  date on bottle

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Opened bottles

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Kept at room

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Discard after 1 month temperature

You don’t have to worry about storing the bottle of insulin you are using in the refrigerator in between injections. Store unopened bottles of insulin in the refrigerator. The expiration date on a bottle of insulin applies to bottles that have not been opened and have been stored in the refrigerator. If an open vial of insulin is kept at room temperature for more than a month, the insulin may lose some of its strength. Throw away bottles that have been opened for a month and kept at room temperature. If you go through bottles slowly, write the date you first open a bottle on the label so you know when to toss it. Storage guidelines vary from 10 to 28 days for different types of insulin cartridges and prefilled pens. Read the label or package insert or ask your pharmacist or nurse educator if special storage is needed.

One good reason to store the insulin you’re using at room temperature is that injecting cold insulin can make the injection feel more uncomfortable. If your insulin is cold, draw it up into the syringe, then warm it up by gently rolling it back and forth in your hands.

If you are traveling and keep your insulin stored in a cooler, make sure the insulin doesn’t freeze or come in contact with ice.

On the Go with Insulin

Wear a medical ID bracelet or necklace that says you have diabetes.

Don’t get separated from your supplies. Carry your insulin, syringes and/or insulin pump and infusion sets, lancets, glucose meter, blood and ketone test strips, glucagon kit, glucose gel or tablets, and snacks with you. Check with the airlines to meet security requirements.

Some states require a prescription only for lispro, glargine, and aspart. Other insulins are available over the counter, as are syringes. In other states, you need a prescription for all insulins and the syringes. If you are traveling and your insulin is lost or destroyed, ask a pharmacist for help.

Take twice as much insulin and blood testing equipment as you think you’ll need. Getting extra diabetes supplies when you’re away from home can be difficult.

Keep insulin out of direct sunlight and protect it from very hot or very cold temperatures. If flying, keep your insulin supply with you instead of packing it in bags that might get too hot or too cold (such as in an airplane baggage compartment).

Storing insulin at temperatures colder than 36°F can cause it to lose potency and clump. Also avoid getting insulin too hot or leaving it in direct sunlight for too long. Insulin can spoil if it gets hotter than 86°F. The general rule of thumb is, if the temperature is comfortable for you, your insulin will be okay, too. Never use insulin if it looks abnormal. Regular, lispro, aspart, and glargine insulins are clear. If you use clear insulin, always check for any floating particles, cloudiness, or change in color. This could be a sign that your insulin is contaminated or has lost its strength.

Other types of insulin come as suspensions. This means that the material is not completely dissolved, and you might be able to see solid material floating in liquid. However, it should look uniformly cloudy. If you are using NPH or lente, check that your insulin is free of any large clumps of material. Do not use any insulin if you see chunks of material floating around. These changes could mean that crystals or aggregates are forming and the insulin is spoiled or denatured. This can be caused by too much shaking of the insulin bottle or storing insulin at temperatures that are either too hot or too cold.

If you have been instructed to dilute your insulin, use only the diluent recommended by the manufacturer. Properly diluted insulin is good for 2 to 6 weeks stored in the refrigerator.

If you find anything wrong with your insulin right after you buy it, return it immediately. If the condition develops later, try to figure out whether you have handled or stored the insulin the wrong way. If not, talk to your pharmacist about a refund or exchange.

Syringes. Today’s smaller gauge needles are slimmer, have sharper points, and are specially coated to slide into the skin smoothly. If you are already using these needles and your injections are still uncomfortable, talk to your diabetes care provider or educator. It often helps to go over your injection technique with them. Trying to relax before injections can help. Tense muscles can make the injection hurt.

Keeping your injection site clean will reduce the risk of developing an infection. But you don’t have to use alcohol to clean your skin before injecting the needle. Soap and water works fine. If you use alcohol before injections, make sure the alcohol dries before you inject, or it could cause stinging. See the Appendix for more tips on injections.

Buying syringes. The syringe consists of a needle, barrel, and plunger. Syringes come in different sizes. It is important to match the size of the syringe to the dose you’ll take with it. You want a syringe that will hold your entire dose of insulin. For example, if you need to take 45 units of insulin, you would want to use a 50-unit syringe to hold all your dose. A 30-unit syringe (the next smallest size) is handy for giving yourself injections of 30 units or less. Likewise, if you need to inject very small doses of insulin, 1/2 unit for example, use syringes that have 1/2 unit marks to keep doses accurate.

Also, check to see whether you can read the markings on your syringe. A 100-unit syringe holds 100 units of insulin in a volume of 1 cc (or 1 ml). Each line marks 2 units of insulin. A 50-unit syringe holds 50 units of insulin in 0.5 cc of liquid, and each line marks 1 unit. A 30-unit syringe holds 30 units of insulin in 0.3 cc, and each line marks 1 unit. You will need to measure out each dose in units. So, if you can’t see the lines marked on the syringe, you will have problems getting an accurate dose. There are devices you can buy to make it easier to read the markings on the syringe. Your pharmacist or diabetes educator can tell you what supplies are available to help you. Another good source of information is the American Diabetes Association Resource Guide published yearly by Diabetes Forecast, the members’ magazine of the American Diabetes Association. The Resource Guide is also available online at www.diabetes.org/diabetes-forecast.jsp and in single copies from the American Diabetes Association.

If you are planning to travel or will be away from home, take along a prescription for syringes. Also ask your provider to write a letter stating that you have diabetes and indicating what type of insulin you use. Some states require a prescription to purchase supplies. If you have problems getting supplies while traveling, try a hospital emergency room.

Reusing syringes. There is no right or wrong answer to the question of whether you should use your insulin syringes over again. It’s really up to you. Reusing syringes can save money.

And it creates less medical waste to litter the environment. There is no evidence that you are more likely to become infected if you reuse a syringe — as long as you follow some safety guidelines. If you choose to reuse syringes, the American Diabetes Association offers guidelines for maintaining them properly.

Most manufacturers of disposable syringes recommend that they be used only once. This is because syringes cannot be guaranteed to be sterile if they are reused. If you have poor personal hygiene, are ill, have open wounds on your hands, or have a low resistance to infection for any reason, you should not reuse syringes. Needles also can become chipped or dull after use. Most needles can be used several times before the tip becomes dull. A dull tip is more painful than a new, sharp needle.

The most important advice about syringe reuse is this: never let anyone use a syringe you’ve already used, and don’t use anyone else’s syringe — ever.

Syringe disposal. How you get rid of your syringe can affect anyone who might come in contact with your trash. This includes the members of your family, neighbors, your trash collector, and people using beaches and other public areas. So it’s important that you do it safely. Never toss a used syringe directly into a trash can. Syringes and lancets and any other material that touches human blood is considered medical waste and must be handled carefully. Before deciding what you will do, you might want to check with your local health department. Some towns and counties have special laws or rules for getting rid of medical waste and may offer safe alternatives. When traveling, if possible, bring your unused syringes home. Pack them in a heavy-duty container, such as a hard plastic pencil box.

Injection Devices. Talk to your doctor or your diabetes educator if you are having problems with any aspects of insulin injection. There are alternatives to injecting by syringe, such as an insulin pen or jet injector. And there are products available that make giving an injection easier. Ask your educator if you can try out some of the insulin-injection aids before you buy anything. This way you can see if any new product is right for you before you invest your money. Be sure to let them know as well if the injections are causing you a great deal of stress or anxiety.

Insulin pens. An insulin pen looks like an ink pen. Instead of a writing tip, it has a disposable needle, and instead of an ink cartridge, there is an insulin cartridge. These pens are popular because they are convenient and accurate in dose. You don’t have to worry about filling syringes or carrying them with you when you are away from home. There are two types of pens. You can buy a pre-filled pen that you throw away once the insulin cartridge is empty. Or you can buy a pen that uses disposable cartridges. A variety of insulins are available in pens and cartridges. You decide the number of units you want, set the injector for that dose, stick the needle in your skin, and inject the insulin. This makes them useful for multiple dose schedules. Pen injectors are conveniently portable because you don’t have to carry around a bottle of insulin. Some are designed to make it easier for people with visual or dexterity problems to give injections.

Each fall, the American Diabetes Association publishes the Resource Guide, a supplement to Diabetes Forecast. You can also buy the guide separately or view it online at diabetes-forecast.jsp. The Resource Guide lists the latest offerings of diabetes tools from manufacturers.

Insertion aids. An automatic injector shoots a needle into your skin. Some automatically release the insulin when the needle hits your skin. With others, you have to press the plunger on the syringe. An automatic injector can be useful if you have arthritis or other problems that make it difficult to hold a syringe steadily. If you cringe at the thought of injecting yourself or don’t like the sight of needles, an automatic injector may be for you.

Jet injectors. Jet injectors push the insulin out so fast that it acts like a liquid needle, passing insulin directly through the skin. If you fear needles or take several injections each day, a jet injector may be a possibility.

The downside is that jet injectors are expensive and may not accurately deliver the insulin dose. Check with your insurer about whether it will cover the cost of this device. Although you will save on the cost of needles and syringes, there may be a hefty initial cost. Ask to test a jet injector before buying. Bruising can be a problem, especially in thin people, children, and the elderly, all of whom have less fat under the skin. Jet injectors also need to be cleaned on a regular basis. Ask your doctor, diabetes educator, and others you know who have used them what they think of jet injectors before deciding.

Aids for the visually impaired. Several products are available that make it easier for people who are visually impaired. These include

■ dose gauges to help you measure your insulin accurately — even mixed doses. Some click with every 1 or 2 units of insulin you measure, and others have Braille or raised numbers.

■ needle guides and vial stabilizers to help you insert the needle into the insulin vial correctly. Some of these will also let you set a desired dosage level.

■ syringe magnifiers that can enlarge the measure marks on a syringe barrel. One model combines a magnifier with the needle guide and vial stabilizer. Another clips around the syringe and magnifies the scale.

Some of these aids only fit certain brands of syringes. Make sure that any aids you purchase will fit the equipment you already have. Some of these aids can be used along with some of the devices discussed above. In addition to injection aids, you can also buy blood glucose meters for the visually impaired.

Artificial Pancreas. A device that serves as an artificial pancreas continues to be tested and has been shown to be effective in treating patients with type 1 diabetes. The device consists of a glucose sensor implanted in the abdominal cavity connected to an insulin reservoir. When the sensor detects a rise in blood glucose levels, it triggers a release of insulin from the reservoir, thus functioning much like a healthy pancreas. Preliminary results show that the artificial pancreas is more effective in controlling blood glucose levels than insulin injections alone. The device requires further testing and government approval before making it to the marketplace.

Insulin Pills. Oral insulins are currently being tested in human clinical trials. Because insulin is a protein, it gets degraded in the stomach. But new ways of linking the insulin molecule to polymers allow it to escape digestion and become absorbed into the bloodstream. Preliminary studies are promising. The pills appear to have no adverse side effects and can be taken 15 minutes before a meal.

Insulin Patch. Insulin is normally too big to be absorbed directly through the skin. But a special battery-operated skin patch is being developed that creates microscopic openings in the skin to allow insulin to pass through and into the bloodstream. The patch uses a two-step process to deliver insulin. First, an electronic patch vaporizes cells on the skin surface. A second patch containing a reservoir of insulin is then applied, and the insulin molecules can be absorbed into the bloodstream over a 12-hour period. The delivery system will require government approval before making it to the marketplace. Potentially, the insulin pill and skin patch could be combined to deliver both basal and bolus doses of insulin.

Oral Spray. A new device called Rapid Mist is currently being tested that could deliver an aerosolized version of insulin through the mucus membranes of the cheeks, tongue, and throat. Early results indicate that Rapid Mist, which resembles an inhaler used by people with asthma, is identical to an insulin injection in its ability to lower blood glucose levels.

Inhaled Insulin. Several companies are working on liquid or powdered forms of insulin that are inhaled through the mouth and delivered to the lungs. The insulin then enters the bloodstream as a rapid-acting insulin. The products are being tested for safety and efficacy before making it to the marketplace.

Typical Injection Sites. Insulin works best when injected into a layer of fat under the skin, above the muscle tissue. Several areas of the body have enough fat tissue under the skin for insulin injection. The abdomen, except for a 2-inch circle around the navel, is used most commonly. Another suitable area is the top and outer thighs. This is best used when you are in a sitting position. The backs of the upper arms, the hips, and the buttocks also work well. Some people, especially those with a large body size, have other options. For example, the lower back can also be a good injection site, as long as there is enough fat under the skin. Wherever you choose to inject, keep these basics in mind:

■ Divide the body area into injection sites about the size of a quarter. Try to make each new injection at least a finger-width away from your last shot. You may need to devise a way to remember where that last site was. For example, you might inject all of your morning shots on the right side and all of your evening shots on the left. When injecting into the arm, use the outer back area of the upper arm, where there is fatty tissue. Avoid the deltoid muscle, the large triangular muscle that covers the shoulder joint. Don’t inject into muscle tissue anywhere in the body. Inject anywhere there is fat on the abdomen except for the 2-inch space around the navel. This has tough tissue that causes erratic insulin absorption.

Avoid injecting too close to moles or scar tissue anywhere on the body.

When injecting in the thighs, shoot for the top and outside areas. If you inject the inner thighs, rubbing between the legs may make the injection site sore. Also avoid the bony area above the knees where there isn’t much fat.

Differences in Insulin Absorption. Most insulins are absorbed most quickly (and at the most consistent speed) when injected into the abdomen, more slowly when injected into the arms, and slower still when injected into the thighs and buttocks.

After you have been injecting insulin into your abdomen for several weeks, you probably know how long it will take for the insulin to take effect. This predictability can help you better manage your blood glucose.

If you were to suddenly switch to injecting insulin into your thigh, you might experience a different response. You might find that it takes longer for your insulin to take effect. Then it would be more difficult to meet your target blood glucose levels without adjusting what time you inject.

Other factors, such as body temperature, diet, exercise, and level of stress, affect your body’s response to insulin. In general, anything that increases the blood flow to an area increases insulin absorption. Your response to insulin could even be the opposite of what you might expect, based on where you inject. For example, playing soccer for 2 hours may cause your insulin to be absorbed more quickly than usual so that your blood glucose level isn’t where you expect it to be. So what can you do? Routinely check your blood glucose level. It is the only way to make sure you are having the response you had planned. Then you’ll know if your site rotation plan is working for you.

Exercise and Injection Sites. Strenuous exercise of muscles near an injection site can make the insulin act more rapidly than normal. This is because there is an increased flow of blood to exercising muscles. That doesn’t necessarily mean that you should stop injecting insulin in the areas of your body you use during exercise. But if you notice that your insulin is peaking faster than you would expect when you exercise, you might want to think about the absorption rate. In general, it’s a good idea to avoid strenuous exercise during the peak action times of your insulin. Insulin plus exercise can lead to a low blood sugar (hypoglycemia).

When you exercise, you have to decide whether to eat more or take less insulin. That’s because exercise and insulin both decrease the amount of glucose in the blood. And you don’t want your blood glucose levels to get too low. Frequent blood glucose monitoring will help you figure out these ups and downs in blood glucose and how to keep things in balance.

Skin Problems and Injection Sites. Two main skin problems can occur at insulin injection sites: lipoatrophy and hypertrophy. With lipoatrophy, fatty tissue under the skin disappears, causing dents in the skin at the injection site. Hypertrophy is the overgrowth of cells, usually fat cells, that makes the skin look lumpy. It can look similar to scar tissue. By rotating the injection site, you can avoid some of these problems. There is also the possibility that some of the problems are caused by the type of insulin you are using.

Lipoatrophy is probably caused by an immune reaction, although its exact cause is not known. Your body is responding to insulin as an injected “foreign” substance. This problem is not common with human insulin. Make sure you are using highly purified insulin, preferably human.

Hypertrophy is not an immune reaction, so you don’t have to change your insulin if you are having this problem. But you do need to change injection sites to avoid this. When the same sites are used over and over again, fat deposits can accumulate in the area. This is also called lipobypertropby. You may be reluctant to change because injections seem less painful in these areas. This can be true because the hypertrophy can numb the area. On the other hand, injections can sometimes be more painful in these areas. The abnormal cell growth can limit the absorption of your insulin. Do not inject into the lumps. Insulin action can be restricted by not being able to move through the tissue. Inject away from the lumps and remember to rotate the sites. Ask a member of your health care team to check your injection sites periodically.

If you use insulin frequently, you have probably thought about getting an insulin pump from time to time. But maybe it seemed too costly or inconvenient. Maybe you didn’t like the idea of being hooked to a machine or changing your diabetes care routine so abruptly. Pumps today weigh less than 4 ounces, so they are easy to wear. You can remove the pump for an hour or two for special occasions and still keep your glucose where you want it. The cost of a pump is high. But with a prescription, and persistence on your part, most insurance companies will pay for all or part of it.

Paying for the Pump. Insulin pumps can cost up to $6,000. Monthly maintenance can run $300 or more, including insulin, infusion sets, and blood testing supplies. If your insurance company will cover them, you’re all set. But some insurance companies won’t pay the start-up or maintenance costs of the pump. What to do?

■ Keep asking! Keep in mind that it took many years, much research, and lots of people asking to convince insurance companies to pay for other therapeutic measures, such as prescription footwear, that have long-term health benefits. Your provider should be your most convincing advocate. He or she may have to write several letters and make several calls to your insurance company with details of your need for the improved glucose levels that are possible on the pump.

■ Ask your diabetes educator to write to your insurance company as well.

■ Work on writing effective, informative letters. All letters should stress how lower glucose levels can mean fewer and less severe diabetes complications in the long run — which is also less expensive for the insurance company in the long run.

How Pumps Work. The pump is a marvel of technology:

■ It beeps if clogged.

■ It lets you know when the batteries run low.

■ It has dosage limits to stop an accidental overdose.

■ You can program it to change the amount of insulin pumped to match your metabolism.

However, insulin pumps are not foolproof. Although they will alert you when a clog stops the flow of insulin, they will not identify a slow flow. Even if you are using an insulin pump, you will still need to monitor your blood glucose frequently.

Pumps use rapid-acting or regular insulin. The insulin is pumped from a filled syringe or cartridge inside the pump through thin plastic tubing to a needle or catheter inserted under the skin. Depending on your insulin needs, the pump can hold a 1- or 2-day supply of insulin. The tubing comes in different lengths, but it is long enough to allow plenty of slack for normal body movement. The insulin pump sends a continuous flow of insulin that trickles through the tube into the injection site at a slow, steady (basal) rate, day and night. The basal rate for pumps can be adjusted from 0.1 to 10 units per hour, depending on your metabolism. Before you eat, you push a button to deliver an extra portion of insulin, called a bolus. You can program, or adjust, the size of the bolus, depending on how much carbohydrate you will be eating in your meal. Delivering a bolus of insulin is just like injecting your premeal shot of insulin when you take multiple injections — without the shot! Usually, you won’t have to take an extra bolus when you eat between meals, unless the snack is large.

Your diabetes care provider or educator will help you calculate your basal and bolus insulin doses. The total basal dose over a day is some percentage of the total daily insulin dose that you’ve been injecting, perhaps 40 to 50 percent. The other 50 to 60 percent of your daily insulin dose is divided into the before-meal bolus doses, most of it at breakfast and dinner, and the remainder at lunch and bedtime. You will need to know how these doses were chosen, so you can learn to adjust them for fine-tuning.

A big advantage to using a pump is that you will have flexible insulin coverage for meals and snacks. You will have to spend a lot of time at the beginning to find the best basal rates, to find out when you need to adjust the basal rate, and to figure out how big a bolus you will need for each meal. You’ll probably want to learn how to estimate the number of grams of carbohydrate in your meals so you can take the needed number of insulin units. This will help you even out your after-meal blood glucose levels. You’ll avoid having big changes in blood glucose levels throughout the day. Eventually, this will lead to a more flexible eating schedule. Pumps still cannot automatically sense your body’s need for insulin. It doesn’t adjust by itself. You still need to take blood glucose readings throughout the day.

Unexplained High Blood Glucose Levels on the Insulin Pump

Have you considered these possibilities?

► The insulin: Is it expired? Has it been exposed to extreme heat or cold? Does it look clumped or filled with particles? Is the vial nearly empty? Have you used it for more than 1 month?

► The insertion site: Have you placed the needle in or near a scar or mole? Near your beltline or other area where there’s friction from clothing? Does the site hurt? Is it red or swollen?

► The infusion set: Did the needle come out? Is insulin leaking around the infusion site? Is there blood or air in the infusion line? Is there a kink in the line? Did the line come loose from the pump? Has the infusion set been in place for more than 2 days? Think about changing the infusion line. The insulin pump: Is the basal rate set correctly? Has the battery run down? Was the cartridge of insulin placed correctly? Is it empty? Was the pump primed with insulin when a fresh cartridge was put in? Is the pump working correctly?

Where will you attach the needle for the insulin pump? Most people choose the abdomen for insulin delivery. This area is convenient to use and gives a reliable, uniform absorption of insulin. How you insert the insulin needle will be different for different brands of infusion sets. With some infusion sets, you use a needle to insert a catheter and then remove the needle, leaving the soft catheter under your skin. With other sets, you insert a short needle. Pumps are easy to remove temporarily because, after clamping the tubing, you can leave the infusion set (the needle and tubing or the soft Teflon catheter) in place. You reattach only the pump. Some infusion sets even have a quick-release feature.

You don’t have to worry that it will hurt when you exercise or if someone bumps into your pump or infusion area. The needle or catheter should be comfortable at all times. If you see any redness or swelling at the infusion site, remove the needle or catheter right away and find a new infusion site. Discuss persistent problems (lasting longer than 24 hours) with your health care team.

Every 1 to 3 days, you’ll need to replace the infusion set and move to a new insertion site. This helps you avoid infection at the insertion site or a clog in the infusion set. Place the new insertion site at least 1 inch away from the last insertion site on the abdomen. Just like with syringes, you need to avoid inserting the needle in scar tissue or moles and use a site rotation schedule.

Using the same insertion site too often or for too long can cause the same skin problems that develop when you don’t rotate your syringe injection sites. Scarring can occur. Check your injection site every day to make sure no insulin is leaking out.

You’ll need to wear the pump almost all the time. If you take the pump off, you’ll need to resume a schedule of insulin injections. However, it is possible for you to take off the pump temporarily, but not for more than 1 to 2 hours. Your blood glucose levels will get high again quickly because you don’t have any insulin. You may want to unhook during lovemaking or other physical activities that can lower blood glucose level. How long you can keep the pump off without an injection depends on how active you are when the pump is off. A dancer might be able to keep it off during an entire performance because exercise lowers blood glucose levels. Through experience and testing, you will figure out how long you can keep the pump off before you need to put it back on or take an insulin injection.

Like all things worthwhile, using a pump successfully takes practice. You will most likely have problems here and there. Perhaps the most common problem is mysterious high blood glucose levels. This occurs quickly when clogged or kinked tubing stops the flow of insulin and pressure builds up in the infusion line. Your pump will sound an alarm if this happens. This is not the only reason for high blood glucose levels. For instance, an infection or inflammation at the insertion site can develop and delay the absorption of insulin. See the box on page 124 for other things to consider when you have unexplained hyperglycemia on the pump.

Should You Use a Pump? Maybe you’re already having trouble sticking to your current testing and injection routine. Then a more intense schedule, such as multiple daily injections or an insulin pump, may not be for you. However, the possible benefits may help you find a new level of commitment.

A major advantage of a pump is that you don’t have to stop what you’re doing to fill a syringe. Your insulin is delivered at the push of a button. You can do this anywhere and at any time. Pumps are also precise. You can set them to pump out as little as one-tenth of a unit (0.1 unit) of insulin per hour.

What are some other reasons for choosing a pump? Maybe you’re planning a pregnancy and want the tightest control possible. Maybe you have to work odd hours at your job and it’s hard enough to balance work, family, and meals during the week without having to adjust to a new injection schedule every weekend. Maybe you have had unwanted swings in blood glucose when injecting intermediate- or long-acting glucose, and you’d like to keep your blood glucose in check. People who want an insulin plan that adapts to day-to-day changes in their lifestyle might like an insulin pump. Making a list of personal advantages and disadvantages may help you decide. One of the most important factors is your level of commitment to this therapy. It does take work — especially at first. But many people find that the added flexibility and improved control are worth it.

Choosing a Pump. There are several insulin pumps on the market today. Your doctor or diabetes educator may prefer one brand over the other. Ask for his or her thoughts on each model. Your best bet may be to talk to other people who use pumps. Find out what they like and what they don’t like about each model. Here are a few things you might want to know:

■ Is it waterproof? Some models are waterproof and can be submerged for up to 30 minutes. Other models are splash proof or water resistant. Check to see whether you can shower, swim, or dive into a pool with the model you want.

■ Can you adjust the basal rate for different times of day? Your pump can alter the rate up to 48 times a day. For example, your basal rate is likely to be greater from

3 a.m. to 7 a.m. than during the rest of the day. All pump manufacturers offer a 24-hour toll-free number. You will want to talk to service people about problems when you suspect the pump isn’t working correctly.

■ What kind of warranty does the manufacturer offer? How often do you have to change the batteries? How easy are the batteries to find, and how expensive are they? Batteries usually last 2 to 4 months.

■ Do you want a pump that will help you calculate doses based on your blood glucose level and carbohydrate intake?

Insulin Plans

How often should you inject insulin? There is no answer that is right for all people at all times. Different plans suit different people, depending on how easily managed your blood glucose levels are and how well you understand the way different foods and physical activity, and even stress, affect your blood glucose levels.

With type 1 diabetes, the pancreas no longer secretes insulin. The goal of insulin therapy is to mimic a normal pancreas as closely as possible. This often requires multiple daily injections of insulin or the use of an insulin pump and frequent blood glucose monitoring.

Type 2 diabetes can cause two different problems. In some people, not enough insulin is produced in relation to how much is needed by the body. Insulin is often needed along with meal planning and exercise. In addition, the cells in the body resist the action of the insulin that is produced. Diet and exercise and oral diabetes medications alone or with insulin may be needed. Therapies for type 2 diabetes may have to take into account both lack of insulin and resistance to insulin. Because their bodies make and release natural insulin, people with type 2 diabetes may be able to manage blood glucose by changing their eating and exercise habits. Others will need oral diabetes medication and still others will need insulin in addition to diet and exercise.

Some women with gestational diabetes manage the high blood glucose levels caused by insulin resistance without insulin therapy. Others need the help of insulin.

Insulin plans can use one, two, or three types of insulin. This means using rapid-acting or regular (short-acting) insulin and, for some people, also using a longer-acting insulin. When deciding on an insulin plan, you and your diabetes care provider will consider how to match your personal goals and needs, both medical and practical, to a combination of insulin type, dose, and schedule. You also need to know when the different injections of insulin are likely to have an effect on your blood glucose levels.

Most insulin plans try to mimic the effects a normal pancreas could produce. A pancreas puts out a steady stream of insulin (a basal or baseline dose) day and night. It also secretes an extra dose of insulin (a bolus) in response to meals. This is the way insulin pumps are usually set up. If insulin injections are preferred, a longer-acting insulin is used to mimic the basal insulin secretion. To substitute for the bolus of insulin, a dose of rapid-acting or regular insulin is usually given before each meal. Which combination of short- and long-acting insulins you use is up to you and your provider. Together, work out a plan that will suit your life and schedule. If your plan is not working out for you, talk to your provider. There are usually many other plans you can try.



There are approximately 1 million islets of Langerhans in a normal adult pancreas and these constitute 1-2% of the gland’s mass. There are four main cell types in the islets: the predominant B or β cells (producing insulin); A or α cells (glucagon), D or δ cells (somatostatin) and PP cells (pancreatic polypeptide). The principal physiological stimulus for insulin release is the blood glucose concentration, although numerous other metabolites, hormones and neural factors also modulate this process. Glucose concentrations of > 5 mmol/l stimulate insulin release and β cells are exquisitely sensitive to small changes in extracellular glucose concentrations within a narrow physiological range.

Figure 2. Glucose-stimulated insulin secretion from the β cell.

Other factors affecting insulin secretion

• Glucagon is a powerful potentiator of insulin secretion when glucose levels are appropriately raised. It is also a major counter-regulatory hormone, being released in response to hypoglycaemia, and stimulates hepatic glucose production through enhanced gluconeogenesis and glycogenolysis. These counter-regulatory effects underlie its use in the treatment of severe hypoglycaemia.

• Somatostatin, secreted from islet D cells, inhibits the secretion of insulin as well as growth hormone and glucagon.

• GLP-1, formed by alternative processing from the same precursor (preproglucagon) as glucagon, is released from the small intestine in response to eating. It potentiates insulin secretion, and its possible use in the treatment of type 2 diabetes is currently being explored.

• Amino acids, such as arginine, stimulate insulin secretion (through uncertain mechanisms).

• Parasympathetic nerves releasing acetylcholine stimulate insulin release from islet cells. Parasympathetic nerves are activated during eating.

• Sympathetic nerves releasing noradrenaline inhibit insulin secretion. Sympathetic nerve activation switches off insulin secretion during stress such as exercise and trauma, and especially during hypoglycaemia.

Insulin actions

Carbohydrate metabolism

The liver is the principal organ of glucose homeostasis: 200 g of glucose is produced and utilized each day; 90% comes from glycogen breakdown and hepatic gluconeogenesis. Insulin:

• Switches off hepatic glucose production even at low levels;

• Stimulates the uptake of glucose by muscle and fat.

The energy requirements of these tissues are met by fatty acid oxidation in the absence of insulin. By contrast, the brain is not dependent on insulin for glucose uptake. If glucose levels fall it can use alternative fuels such as ketone bodies.

Lipid metabolism

Triglyceride lipase breaks down triglyceride in adipose tissue to release non-esterified fatty acids (NEFA). NEFA can be oxidized as fuel by many tissues and their partial oxidation in the liver leads to the production of ketone bodies (ketogenesis). Insulin (even at very low levels):

• Inhibits triglyceride lipase;

• Turns off lipolysis and thus ketogenesis.

Profound insulin deficiency is required to develop diabetic ketoacidosis, which is why this is rare in type 2 diabetes. It can, however, occur in this condition when severe physical stress (such as myocardial infarction or infection) markedly increases counter-regulatory hormone secretion.

Insulin also stimulates lipoprotein lipase, which breaks down triglycerides stored in chylomicrons absorbed from the gut into the circulation. The non-esterified fatty acids generated are taken up by the fat cells under insulin stimulation and stored as fat. Decreased lipoprotein lipase activity is partly responsible for the hypertriglyceridaemia/chylomicronaemia associated with diabetes.

Protein metabolism

Insulin stimulates the uptake of amino acids into muscle and stimulates protein synthesis whilst inhibiting protein breakdown.

Summary

Following a meal:

• Blood glucose levels rise and stimulate insulin secretion;

• Insulin secretion is enhanced by the release of glucagon and GLP-1 and by increased parasympathetic nerve activity;

• The rise in insulin secretion stimulates glucose uptake and the metabolism and storage of ingested fats and protein.

In the fasting state:

• Insulin secretion falls, enabling maintenance of blood glucose levels by a combination of hepatic glycogenolysis and gluconeogenesis;

• Decreased insulin levels and increased counter-regulatory hormones lead to lipolysis and the release of NEFA;

• NEFA can be used as fuel or be oxidized to ketone bodies (another fuel substrate).

Figure 3. Insulin actions on glucose metabolism.

During stress/hypoglycaemia:

• Sympathetic nerve activity is increased, stimulating the release of counter-regulatory hormones (particularly glucagon and catecholamines);

• Lipolysis is enhanced;

• Glucose production is increased through increased glycogenolysis and gluconeogenesis;

• Catecholamines suppress insulin secretion, further potentiating a rise in blood glucose levels;

• In insulin deficiency this leads to uncontrolled hyperglycaemia and unrestrained lipolysis, with the production of ketone bodies and development of keto-acidosis.

In the ovaries of normal women, progesterone is converted within the theca cells to 17alpha-hydroxyprogesterone, then to androstenedione, and finally to testosterone. Testosterone, in turn, is converted to estradiol in the granulosa cells. In women with polycystic ovaries, there is an increase in the enzyme cytochrome P450c17alpha that converts progesterone to androstenedione. Since androstenedione is rapidly converted into testosterone, the result is increased testosterone production. Some of the excess testosterone causes premature follicular atresia and anovulation, some of the excess reaches the circulation.

What causes the increase in ovarian enzyme activity? It appears that the culprit is insulin, or more to the point, insulin resistance with compensatory hyperinsulinemia. Insulin increases testosterone production by stimulating ovarian function, specifically, by stimulating the activity of cytochrome P450c17alpha. Insulin also decreases serum sex hormone-binding globulin by decreasing the hepatic production of the binding protein; with less binding capacity, there is more free testosterone in the serum. Finally, it appears that insulin increases LH production. Дuteinizing hormone (LH) contributes to POS by stimulating theca-cell growth and thus enhancing testosterone production.

Recently Nestler and Jakubowicz published a report in the New England Journal of Medicine describing the results of their study of an oral hypoglycemic agent – metformin (Glucophage/Bristol Myers Squibb) – on glucose tolerance and serum steroid concentrations in 24 obese women with polycystic ovary syndrome (POS). Metformin is a biguanide that reduces insulin resistance and secondarily inhibits insulin secretion. The subjects were given either placebo or metformin (500 mg three times daily) for 4-8 weeks. Compared with placebo, metformin reduced insulin secretion by about 50% and caused a reduction of approximately 50% in levels of basal and peak serum 17alpha- hydroxyprogesterone and serum free testosterone. Metformin also reduced serum LH about 75% and increased serum sex- binding globulin concentration about 75%. These values remained basically the same in the placebo group.

In some of the study participants, metformin actually induced ovulation. The fact that the reduction in insulin secretion caused a prompt drop in serum basal and stimulated-peak 17alpha-hydroxyprogesterone levels indicates that insulin has a direct effect on cytochrome P450c17alpha, enhancing the production of the hydroxyprogesterone. The effects of insulin on this enzyme are probably heritable, since not all women with insulin resistance and hyperinsulinemia have POS.

In an accompanying editorial in the New England Journal of Medicine, Robert Utiger said that POS is currently treated with weight loss and oral contraceptives and/or an antiandrogen such as spironolactone of cyproterone. The infertility is treated with clomiphene or assisted- reproduction procedures. However, if metformin can reduce androgen production, restore cyclic pituitary-gonadal function, and improve fertility, “it could represent a substantial advance in treatment for women with polycystic ovary syndrome.”