Type 1 Diabetes

Summary

• Type 1 diabetes is a disorder of sugar metabolism in which the pancreas is no longer able to produce insulin.
• This is due to destruction of the insulin-producing beta cells of the pancreas by an autoimmune process.
• Type 1 diabetes commonly develops before the age of 40, with a peak incidence around 14. Those with a strong family history of diabetes are at risk of developing the disease.
• The symptoms of diabetes are excessive thirst and urination and weight loss, which can occur abruptly over a few days. Type 1 diabetes can also present as diabetic ketoacidotic coma.
• Type 1 diabetes is treated with insulin and careful attention to diet and lifestyle.
• The long-term complications of type 1 diabetes can be well controlled by using a “tight-control” regime in which blood glucose is measured several times each day and the insulin dose adjusted accordingly.

Alternative names

Insulin-dependent diabetes – now seldom used.

Definition

Diabetes, correctly called diabetes mellitus, is a disorder of carbohydrate metabolism. In type 1 diabetes, the pancreas is no longer able to produce the hormone insulin. Insulin is produced by the beta cells of the pancreas; it is secreted in response to an increased concentration of glucose in the blood, and is vital in controlling blood glucose levels. A person with diabetes cannot control their blood glucose and they become hyperglycaemic – meaning that they have abnormally high levels of glucose in the blood.

Cause

By the time a person with type 1 diabetes experiences symptoms, almost all the beta cells in the pancreas have been destroyed. This destruction is almost certainly as a result of an automimmune process in which the body produces antibodies to its own cells. However, the details of the process are obscure.

It seems that there must initially be a genetic tendency for the disease, which is then triggered by an environmental event such as a viral infection. The third step in the process is an inflammation of the pancreas called insulitis. The fourth step is an alteration in the surface of the beta cell so that it is no longer recognised as “self” – part of the body – but is perceived by the immune system to be a foreign cell or “non-self”. The fifth step is the development of an immune response.

The end result is the destruction of the beta cell and the development of diabetes.

Who gets it?

The percentage of the population with diabetes is highly variable among geographical regions and populations, so estimates are often inaccurate. Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025. Type 1 diabetes probably comprises between 10 and 15% of all cases of diabetes.

Type 1 diabetes usually begins before the age of 40, the peak incidence being around 14.

A strong family history is a definite risk factor for type 1 diabetes, although the way in which the disease is inherited is not clear. There is a strong association between type 1 diabetes and the HLA-D complex on the sixth chromosome.

Symptoms and signs

The characteristic symptoms of diabetes are:

• Excessive thirst
• Weight loss
• Excessive urination
• Tiredness

These symptoms may be abrupt, developing over a period of a few days.

However, the first sign of type 1 diabetes can also be acidote coma, or near coma, as a result of an event called diabetic ketoacidosis in which the levels of glucose in the blood are so high that this life-threatening state occurs. Due to a lack of insulin the glucose in the blood cannot enter the cells where it is desperately needed.

To prevent starvation and cell death, lipids are metabolized to ketones. Ketones can be used as food by the cells, for example cells in the brain, even in the absence of insulin. However, the ketones are not only good. They are acidic in nature and cause an acidosis. The condition is called ketoacidosis and is the result of insulin deficiency in type 1 diabetics. As a consequence of this condition, the blood and the tissues are more acidic than normal and this in turn may lead to malfunctioning of organs such as the heart. Initially, a person with ketoacidosis compensates by breathing deeply (called Kussmual’s breathing), but later this mechanism cannot cope with the acidic load caused by the ketones.

Clinically patients feel unwell and they complain of nausea and vomiting, and no interest in food. There is increased urine production and if the condition is not recognised and treated, the person becomes drowsy and eventually comatose. This is usually in response to an infection, surgery or stress.

The hallmark of diabetic ketoacidosis is the presence of ketones in the urine. Levels of insulin in the blood may be low or unmeasurable.

Diagnosis

Diabetes is diagnosed quite simply by measuring the levels of glucose in the blood. The normal fasting levels are between 3,3 mmol/l and 5,9 mmol/l.

The World Health Organisation defines diabetes mellitus as a condition fulfilling one or more of the following criteria:

• Fasting plasma glucose (plasma glucose measured before breakfast) is over 6.7 mmol/l on two separate occasions and/or
• Random plasma glucose (blood glucose measured at any time) is over 10 mmol/l and /or
• Two-hour blood glucose during glucose tolerance test is over 10 mmol/l
• Corresponding values for plasma glucose are 7.8 mml/L and 11.1 mmol/l

If a person first shows signs of diabetes by developing diabetic ketoacidosis, then the diagnosis may be more difficult since this must be distinguished from other causes of coma and decreased levels of consciousness. The presence of ketones in the blood is characteristic, as are certain other laboratory findings.

Prevention

There is no known prevention yet but vaccine studies are proceeding, even in South Africa.

Outcome

Meticulous control of blood glucose by attention to lifestyle and treatment with insulin generally leads to a good outcome, although complications usually occur with time in most people with the disease.

Research has shown that very tight control of blood glucose achieved by regular measurements throughout the day, which are then used to determine an exact insulin dose, leads to fewer complications and later onset of any complications which may arise.

When to see your doctor

Consult your doctor if you develop symptoms of:

• Excessive thirst
• Excessive urination
• Weight loss
• Genital itch

If you have a family history of diabetes, you must see your doctor as soon as possible.

If you are already diabetic and you develop these symptoms, then it is an indication that your blood glucose is out of control and you should see your doctor immediately.

Treatment

Different types of insulin

Type 1 diabetes involves a deficiency of insulin production due to an autoimmune destruction of the insulin-producing cells of the pancreas, in other words the beta cells of the islets of Langerhans.

As a result, these cells can't produce insulin in adequate amounts to maintain normal glucose homeostasis. This leads to hyperglycaemia (excess of glucose in the bloodstream) and weight loss, accompanied by ketoacidosis (acid build-up), during which the body breaks down fat into fatty acids and ketones.

Type 1 diabetes usually begins in the teenage years, but may have an earlier or later onset, with the hallmark being the presence of diabetic ketoacidosis either at presentation or in the absence of insulin therapy.

Type 1 diabetics require insulin therapy to maintain normal glucose and lipid metabolism. This is non-negotiable, and there are really no other alternatives in the management of this condition, which can be life-threatening.

a. Human insulin vs. insulin analogues
Insulin was previously harvested from animal pancreas, but this form of insulin included impurities, which lead to allergies in some people. Current insulin preparations are manufactured using recombinant DNA technology and can be broadly classified into two categories:

• Human insulin, which is identical to human insulin in structure.
• Human insulin analogues, in which one or two amino acids of human insulin are changed or substituted.

Contrary to what one would expect, human insulin (Actrapid, Humulin N, Insuman, Humulin 30/70, Actraphane and Insuman 30/70) given subcutaneously (beneath the skin) doesn't act optimally. This is due to delayed or variable absorption, which leads to day-to-day variations in glucose.

This led to the development of the human insulin analogues, which have a more consistent absorption and distribution profile. Examples are Apidra, Humalog, Novorapid, Lantus, Levemir, Novomix 30 and Humalog Mix 25.

b. Duration of action
The next factor in classifying insulin is the duration of action:

Rapid-acting insulins are the insulin analogues such as Apidra, Humalog and Novorapid that have an onset of action of approximately 15 minutes. They peak at approximately 30 to 90 minutes and have a duration of action of 3 to 5 hours. The rapid-acting insulins are used 5 to 10 minutes prior to or at mealtimes and typically cover the post-meal blood-glucose surges, provided that the dose is correct.

The regular short-acting insulins are human insulins that can be used as before-mealtime insulin instead of the above-mentioned rapid-acting insulin. Regular insulin has an onset of action of approximately 30 to 60 minutes, a peak at between 1 and 2 hours, and a duration of action of more or less 3 to 5 hours.

Examples of regular insulins are Insuman, Actrapid and Humulin R. The regular insulin is typically taken 30 minutes prior to a meal.

Both regular and rapid-acting insulins are used in sliding-scale regimens (when the dose of insulin is adjusted in accordance with the results of blood-glucose levels), as well as intravenous infusions for emergencies.

The intermediate-acting insulins (Humulin N , Protophane ) are regular insulins that, when attached to zinc or NPH (Neutral Protamine Hagedorn), have an altered onset, peak and duration.

These insulins are usually taken every 12 hours, always beneath the skin. They have an onset of action of approximately 3 hours, they peak at more or less 8 hours, and they have a duration of action of about 20 hours. Note that these are approximate numbers that may vary.

The long-acting insulin analogues are Lantus and Levemir. Lantus, which has a duration of action of 24 hours without a peak level, is taken once daily. Levemir has a more contentious duration of action that is dose-dependent. This form of insulin is taken once or twice a day, depending on the degree of control that is needed.

Then there are the fixed-dose combinations of rapid or short-acting insulin and intermediate-acting insulin in fixed-dose combinations of 25%:75%, 30%:75% or 50%:50%. The first number of the ratio applies to the percentage of rapid- or short-acting insulin in the mixture.

Examples are:

Novomix 30:
- 30% insulin aspartate, 70% protaminated insulin aspartate
- taken 5 to 10 minutes before a meal

Humalog mix 25:
- 25% insulin lispro, 75% protaminated insulin lispro
- taken 5 to 10 minutes before a meal

Humalog mix 50:
- 50% insulin lispro, 50% protaminated insulin lispro
- taken 5 to 10 minutes before a meal

Actraphane/ humulin30/70:
- 30% short-acting insulin, 70% intermediate-acting insulin
- taken 20 to 30 minutes before a meal

Different insulin regimens

In healthy people, insulin is secreted at a constant, low level over 24 hours. This prevents glucose release by the liver, which may occur via the processes of gluconeogenesis (when glucose is produced from non-carbohydrate sources such as amino acids) and glycogenolysis (when the carbohydrate, glycogen, is broken down into glucose).

Increases in insulin secretion occur during mealtimes when the digestion of food leads to an increase in blood glucose. The insulin helps to keep the blood-glucose levels in a normal range.

In type 1 diabetics, the aim is to mimic normal insulin secretion, which is best done by the so-called "basal bolus regimen".

This means that a long-acting insulin such as Lantus or Levemir is given once a day, at the same time (for example at 21:00). This is to provide a 24-hour basal insulin supply .The aim is to keep the fasting blood glucose between 4 and 7mmol/l.

Rapid-acting or short-acting insulin is then taken before meals to cover meal-time surges in glucose. This usually involves a further three injections during the day.

So, the basal bolus regimen usually involves four injections per day. It gives the diabetic some flexibility, better blood-glucose control and fewer hypoglycaemic episodes (when there's too little glucose in the bloodstream), especially if the insulin analogues are used.

Another regimen is to use a twice-daily premixed insulin at breakfast and supper. However, in some diabetics a third dose may be needed at lunchtime.

Doses are best worked out by the prescribing doctor and sometimes by a diabetic nurse. Note that every diabetic has his or her own appropriate dose. Don't compare your dose to that of another diabetic as his or her circumstances may be very different to yours.

Insulin devices

a. Insulin pens
In type 1 diabetics, insulin is usually administered beneath the skin ("subcutaneously"), using an insulin pen, which may be disposable or reusable.

Most diabetics easily find, or "dial", the prescribed dose of insulin on these user-friendly pens. The added bonus is that the fine bore needles, which are screwed onto these pens, usually don't cause pain.

However, South African state hospitals and clinics frequently supply insulin syringes and insulin vials, which are more difficult to use.

b. Insulin pumps
Insulin pumps are battery-operated pumps that are worn by diabetics and which continuously deliver short- or rapid-acting insulin into the tissue beneath the skin via a narrow gauge tube. This provides a continuous basal supply of insulin at the programmed dose.

At meal times, the diabetic can then dial a bolus of insulin to cover the surge of glucose elevation that's caused by the ingestion of food.

Problems experienced with insulin pumps are:

• Hypoglycaemia (when there's too little glucose in the bloodstream) in the first few months
• Changing of the tubing, which needs to happen every third day
• Cost: these pumps are very expensive.

As a result, insulin pumps are rarely used in South Africa.

c. Inhaled insulin
A novel method of insulin administration – via the inhaled route (similar to asthma pumps) – was taken off the market in 2008 due to safety concerns. Currently there is no inhaled insulin on the market.

Controlling your diabetes

Ideally, type 1 diabetics should maintain their levels of glycosylated hemoglobin (HbA1c) at a value of less than 6.5. This should be balanced against the risk of hypoglycaemia and hence a value of <7 is still widely accepted. The HbA1c reflects the average blood glucose control over the last three months.

Hypoglycaemia (low blood glucose) is a complication of insulin therapy, with the number of attacks increasing with tighter control. The cause of hypoglycaemia should always be investigated and appropriate action should be taken to prevent further episodes.

In diabetics with an increased risk for hypoglycaemia, for example elderly people, people with renal, liver or cardiac failure, alcoholics and people with poor socio-economic status, HbA1c control should be relaxed.

Apart from diabetic control, all other risk factors for vascular disease should be carefully monitored and treated. These risk factors often go hand-in-hand with diabetes, and include dyslipidaemia (abnormal levels of fats in the body) and hypertension (high blood pressure).

Diet and lifestyle

All type 1 diabetics need to see a dietician so that correct and healthy eating patterns can be implemented. Healthy eating implies a high-fibre, low-saturated-fat diet, which limits high-cholesterol foods and snacks, and which includes lean protein from fish, poultry and legumes.

Apart from providing guidelines on what to eat, a dietician can also help to establish the amount of kilojoules required in the diet, and can help teach the diabetic how to do carbohydrate counting.

As smoking can have a dramatic impact on cardiovascular health, diabetics are strongly urged to stop smoking. Doctors can provide guidance in terms of smoking-cessation aids, such as nicotine replacement therapy (patches, inhalers, gum) and/or prescription medication in the form of Zyban.

Alternatively, the National Council Against Smoking's Quit Line (011 720 3145) can provide assistance.

Treatment section reviewed by Dr Suresh Rajpaul (MbChB, FCPsa), May 2009