What is diabetes?
Diabetes mellitus is a metabolic disorder where the body
cannot control the glucose concentration in the blood. If blood glucose
concentration becomes too high, it can cause serious damage to the body’s
organs. There are several types of diabetes: type 1 diabetes (also known as
insulin-dependent diabetes) occurs when the pancreas does not produce insulin;
type 2 diabetes (insulin-resistant diabetes) occurs when not enough insulin is
produced or the body’s cells do not react to normal insulin levels; gestational
diabetes occurs when pregnant women develop high blood glucose levels (may lead
to type 2 diabetes after pregnancy). Type 1 diabetes is responsible for 10% of
the diabetes cases in the UK and is more likely to affect young people than any
other type of diabetes.
Insulin is a protein hormone produced in the islets of
Langerhans (a type of pancreatic cell). Insulin is synthesized specifically by
ß cells in the islets of Langerhans and is secreted in response to high blood
glucose levels. Insulin causes glucose in the blood to be absorbed by cells in
liver, muscle and fat tissues, where it is stored as glycogen, so reduced blood
glucose concentration. The hormone also prevents lipolysis (breaking down fat
stores for use as an energy source) when blood glucose is high and further
increasing blood glucose levels. Insulin also has a role in controlling how
many amino acids (broken down proteins) are taken up by body cells. If blood
glucose is too low, the pancreas will release the hormone glucagon which causes
glycogen to be converted back to glucose, and because insulin is not produced,
fat stores will be used as an energy source.
In type 1 diabetes the body’s immune system destroys the ß
cells of the pancreas, so prevent insulin synthesis. Type 1 diabetes is said to
be an autoimmune disease, because the immune cells (CD4+ and CD8+ T lymphocytes
and B lymphocytes which produce autoantibodies) mistake pancreatic cells for
harmful/infected cells. There are several causes of this autoimmune
destruction, a genetic trigger, infection or trauma. Genetically, those of European ancestry have a
higher risk of having alleles of the IDDM1 gene on chromosome 6 that code for
decreased histocompatibility and so causing immune cells to see the body cells
as foreign due to the antigens (cell markers) on the cell surface on tissues. In
type 1 diabetes, this is thought to be due to the presence of proinsulin, a
precursor to insulin on the cell surface. However if an identical twin has type
1 diabetes, their twin will only have the condition 30-50% of the time, and
people with no family history of diabetes who migrate to a country with high
prevalence develop the disease, suggesting that genetics only increase
susceptibility and environmental triggers are needed for the expression of
these genes. These triggers could be viral infection of the islets of
Langerhans with rubella or Coxsackie virus causing the cells to be destroyed
alongside the virus; chemicals such as the rodenticide Vacor (no longer in use
in many countries)which destroys pancreatic cells; or drugs such as
streptozotocin, an antibiotic used in chemotherapy for pancreatic cancer. Trauma
such as pancreatitis (inflammation of the pancreas) or tumours can cause
destruction of cells.
What are the symptoms of type 1 diabetes?
Symptoms of type 1 diabetes due to high blood glucose
(hyperglycaemia) include drowsiness (as no glucose is moved into the body cells
for respiration to produce energy), blurred vision (as the lens of the eye
changes shape), polyuria (frequent need to urinate, particularly at night),
extreme thirst and a dry mouth. Hyperglycaemia can lead to diabeteic
ketoacidosis which can be fatal. This occurs when the body breaks down muscle and fat as an
alternative energy source, causing a build up of acid in the blood causing fever,
dry skin and dehydration, rapid deep breathing, unconsciousness, vomiting and
abdominal pain. Additionally, if blood glucose levels get too low (i.e. if too
much insulin injected or a meal is missed) it is known as hypoglycaemia.
Symptoms of hypoglycaemia are hunger, nausea, weakness, sweating, irritability
and potentially slurred speech and unconsciousness.
In the long term symptoms such as weight loss and loss of
muscle bulk, skin infections and susceptibility to thrush, blurred vision and
cramps are indicative of type 1 diabetes. Blurred vision develops due to
blocking of the blood vessels in the retina causes changes in shape of the lens
and preventing light from fully passing to the retina. If blood sugar levels
are not controlled, the chance of developing atherosclerosis (fatty deposits in
the endothelial walls of arteries, reducing the size of artery lumen and
causing plaques and potentially blood clotting) increases, so heart disease and
stroke risks increase. High blood glucose levels can cause damage to the
nervous system, this can cause tingling pain in the extremities and limbs or
cause diarrhoea or constipation in the digestive system. The nerve damage and
loss of blood flow to the feet can mean injuries to the feet go unnoticed and
foot ulcers and infection can develop, potentially leading to gangrene and
amputation. Also the small blood vessels in the kidneys may become blocked and
lead to kidney failure.
Female diabetics in pregnancy must carefully control blood
sugar levels in early stages of pregnancy to prevent serious damage to the baby
or miscarriage. Diabetes can also lead to a reduced sex drive, in men, nerve
damage can lead to erection problems, and women can suffer from vaginal dryness
and pain during sex.
People with a type 1 diabetes diagnosis have an
approximately three times higher incidence of depression than non-diabetics,
neurological changes such as the thinning of the pre-frontal cortical are
associated with depression in diabetes and may be caused by long term control
of blood sugar. Parents of young people with diabetes have a higher prevalence
of psychological distress than parents of those without the condition. Due to
fear of hypoglycaemia, some people neglect their self care and physical
activity. Eating disorders are more common in female diabetics than female
non-diabetics, and in studies, some women were seen to manipulate their insulin
dose to promote polyuria and reduce appetite to aid weight loss.
How do we diagnose diabetes?
We can diagnose diabetes with urine and blood tests.
Normally urine does not contain glucose, as glucose is reabsorbed by the
kidneys after blood is filtered, however this does not occur in diabetics, we
can also test for ketones in the urine which may suggest diabetic ketoacidosis.
Fasting blood tests are taken and if glucose levels are high, it suggest
diabetes. If blood glucose is low you may still have diabetes and so need to
have an oral glucose tolerance test, where, after drinking a sugary drink, your
blood is tested every 30 minutes for 2 hours. To identify type 1 diabetes in
particular, blood is tested for autoantibodies targeting islet cells and
insulin.
What treatment is available?
There is no cure for diabetes, but the condition can be kept
under control, so that sufferers can have an improved quality of life and a
life expectancy within 5 to 8 years of non-diabetics. Treatment of type 1
diabetes requires regular review of diet and medication, as well as checks of
the eyes, feet, nerves and kidney function. People with type 1 diabetes should
try to eat a healthy and consistent diet, but do not necessarily need to eat a
special diet. Diabetics should aim to exercise regularly to help maintain blood
glucose levels, but any activities should be discussed as it may affect insulin
dose. Children may need to have a care plan put in place at school so that
insulin injections can be administered. Women trying to conceive will need
support to ensure insulin doses and diet match the needs of both mother and
child. Counselling may be needed to overcome needle-phobias to allow for
injection of insulin. Smoking increases the risk of cardiovascular diseases
such as heart attacks and stoke, so it is advised that diabetics in particular
give up smoking. Additionally, diabetics may need to take statins to reduce
high cholesterol or blood-thinning medication to prevent stroke. Alcohol should
be not drunk in excess or on an empty stomach, as this can lead to either
hyperglycaemia or hypoglycaemia. Diabetics should also be regularly vaccinated
(i.e. against seasonal flu) as people with diabetes have a higher risk of
complications associated with infection due to the increase in blood glucose as
a response to many infections. Some people may experience reactions to
vaccination such as swelling and a slight fever due to mild disruption in blood
glucose.
For people with type 1 diabetes, insulin treatment is needed to keep blood glucose at stable levels. We can produce insulin by genetically engineering bacteria by inserting a gene for human insulin production. Insulin cannot be taken orally as would be digested by the stomach, so is taken by a subcutaneous (into the fat/muscle layer just below the skin) injection, so uses a smaller needle than those used for taking blood. Alternatively, insulin pens can be used so that the correct dose is injected (rather that drawing up dose into syringe), or auto-injectors to surround the injector pen to automatically inject the needle. It is important to relax the area or perhaps numbing it with ice before injection, the site into which you inject should be alternated regularly. the sites for insulin injection are shown above. Insulin must be stored below room temperature (i.e. in a fridge) and not kept for more than 28 days out of the fridge. There are many different types of insulin: rapid-acting analogues can be injected around the time that food is eaten and work for 2 to 5 hours, with peaks at 0 and 3 hours; long-acting analogues provide background insulin and are injected once a day, lasting 24 hours; short-acting insulin is injected half an hour before a meal, it lasts 8 hours, and has peak action between 2 and 6 hours; medium/long-acting insulin again provides background insulin for up to 30 hours. Often a combination of insulin is used, with around 2 to 4 injections a day. Insulin pumps have also been developed, which can be worn for 24 hours, they involve a small device (about the size of a mobile phone) which contains insulin and a piece of tubing and cannula which is inserted under the skin, allowing insulin to flow into the bloodstream, regular monitoring of blood glucose levels using a finger prick test are needed. Insulin pumps can be removed for up to a hour if needed, e.g when taking part in contact sports.
We can control hyperglycaemia by adjusting diet or insulin
dose, however if it leads to diabetic ketoacidosis, hospital admittance is
needed for intravenous insulin treatment and fluids given by drip to restore
normal blood composition. We can treat hypoglycaemia by taking pure glucose
tablets, or having a glucagon injection to increase blood glucose, however,
often a high sugar food may be all that is needed. Another treatment is islet
transplant, where cells are extracted from the pancreas of a dead donor and
implanted into the patient. Islet transplant is a minor procedure requiring only
local anaesthetic. Islet transplants are offered to people who have had several
incidences severe hypoglycaemia. However the treatment is not suitable for
those with poor kidney function, the medication to prevent islet cell rejection
has some side effects and there is a risk of infection. The transplants lead to improved awareness and responsiveness of the body when blood glucose is low (especially in people who have used insulin therapy for many years and have become unresponsive), less variation in blood glucose levels and so an improved quality of life.
What are the conclusions of current research into the treatment of type 1 diabetes?
Recent research has shown that some pancreatic cells in mice (specifically glucagon producing α cells) can be converted into insulin producing ß cells. It was also found that pancreatic duct cells can be made into α and therefore ß cells, by forcing the activation of a gene called Pax4. This means that the pancreas has an almost endless supply of ß cells to replace those destroyed in type 1 diabetes. This research provides an avenue for the development of new treatments for type 1 diabetes.
Attempts to prevent the autoimmune destruction in type 1 diabetes using immunosuppressant medication has not yielded very promising results, as the drugs prevent the body from fighting infection. This week however, there have been results from the clinical trial of a new vaccine to treat type 1 diabetes. the aim of the vaccine was to suppress the CD8+ lymphocytes which destroy ß islet cells leading to type 1 diabetes. Normally vaccines stimulate an immune response by exposing lymphocytes to foreign antigens (proteins) so that cells which display these proteins can be destroyed. In treating an autoimmune disease, we need to prevent the destruction of cells showing proteins which the immune system does not recognise, such as proinsulin. This was achieved by modifying the gene that codes for proinsulin so that the cells to which the vaccine was delivered could send an anti-inflammatory signal to the CD8+ cells, preventing an immune response. In those trialled, levels of insulin production were either maintained or increased, implying that the ongoing destruction of ß cells was halted by the vaccine. A DNA vaccine has never before been approved for human use, this vaccine could be the first, and similar principles could be used in treating other autoimmune conditions. However, this particular vaccine still requires more attention, as after the 12 week course of the trial, the beneficial effects of the vaccine began to wear off, but as no side effects were observed, this vaccine gives a lot of hope for the future treatment of this condition.
