Introduction

• Type I diabetes is a disorder that results from the destruction of the beta cells of the pancreas, which produce insulin
• It occurs in genetically susceptible individuals with environmental trigger factors, although the exact aetiology is not well understood
• The development of the disease probably occurs over months or years, during which time the patient is asymptomatic
• It can cause the acute presentation diabetic ketoacidosis (DKA) which is life-threatening if untreated, although with the correct treatment, it often improves rapidly
• Patients require life-long insulin therapy
• The pathology differs from type II diabetes, where decreased insulin production, and increase insulin resistance in the peripheral tissues are the main factors
   

Aetiology

• It is not strictly genetically determined, but a given individual may have an increased risk due to their genetic make-up. Monozygous twins show a concordance rate of 30-50%.
• The risk is highest in those with a close family member with type 1 diabetes
• Certain human leucocyte antigen (HLA) variants are correlated with the disease
• Having a father with type 1 puts you at greater risk (3-8%) than having a mother with type 1 diabetes (1-4%)
• It is often associated with other autoimmune diseases, particularly auto-immune thyroid disease, celiac disease and pernicious anaemia.
• Proposed environmental triggers include viral infection, and early exposure to cow's milk in childhood. Particularly suspected are enteroviruses such as coxsackie, Epstein-Barr, rubella, mumps. It is thought that this risk is greatest if an individual was exposed wither very early in life, or before they were born, via the mother (in utero).
• Also suspected but not proven is a ‘clean environment’ during childhood. This means less exposure to pathogens, and thus the immune system is not stimulated as much as normal in a child. This is known as the hygiene hypothesis and it is a hypothesis for all autoimmune diseases.
• Bovine serum albumin (BSA) has also been implicated. This is found in cow’s milk. This link has been proposed because type 1 diabetes is more common in those who were not breast fed. BSA can cross the neonatal gut and enter the blood stream. Its structure is similar to a heat-shock protein that is expressed on the surface of beta cells, and thus the child may develop antibodies to BSA, which it is then suggested may cause an immune reaction against beta-cells.
• Nitrousamides – these are found in smoked and cured meats and some have also suggested these may be implicated.
• Islet cell autoantibodies (ICAs) have been identified in up to 85% of individuals with type I diabetes, although it is likely there are several antibodies involved, including anti-insulin antibodies

Epidemiology

• It is a disease that usually shows itself in childhood. There are two incidence peaks, one around age six, and one around the time of puberty (age 10-14).
• Incidence shows strong geographical variation. In the USA, in white children, the incidence is about 15 per 100,000, and lower in children of other racial backgrounds
• The incidence of type-1 diabetes is on the increase, particularly in children under 5. The annual increase in Europe is about 3-4%.
• There is no gender difference in incidence, despite the fact that autoimmune diseases are usually more common in women

Pathology

• It is a T-cell mediated autoimmune disease that results in destruction of beta cells of the pancreas. It is quite slowly progressing. It can be caused by other pathologies, and so technically speaking the type caused by T-cell mediated autoimmunity is type 1A, however, the other causes are very rare.
• High glucose levels lead to high osmolality of blood, and thus the patient become ‘dehydrated’ and has to drink lots. They will also secrete lots of aldosterone.
• Age of onset is typically around puberty.
• Investigations have shown that the first islet antibodies appear in the blood during the first few years of life. This shows that the disease is very slow to progress, and also opens up the possibility of screening and prevention programs. However, there has yet to be a preventative method that has proven effective.
• In the short term, cyclosporin as an immunosuppressive agent has been shown to reduce beta cell degeneration.

Clinical presentation

• These people will usually have a normal BMI
• Patients will present when beta-cell destruction is such that the remaining beta-cells can no longer secrete enough insulin. High glucose levels may actually induce beta-cell death, thus speeding up the progression of the disease in later stages.
• Weight loss is a major symptom, and this will fail to correct itself when diet is altered. There will also be ketonurea, hyperglycemia, and the presence of autoimmune products. Note that these are only present in 90% of newly presenting patients.
• The majority of patients present with the classical presentation of hyperglycaemia, without ketoacidosis. They have symptoms such as polyuria, polydipsia and weight loss. The mean duration of symptoms before presentation is about 10 days.
• Diabetic Ketoacidosis (DKA)– is an acute life-threatening medical presentation, less common but more serious than the classical presentation. It is a result of lack of insulin. In normal function, the liver produces keto acids from deamination of amino acids (this is how the liver gets most of its energy). Keto acids are also produced through metabolism of fatty acids. In diabetes, there is a massive perceived lack of glucose by the body (because little or no glucose can be taken up by cells), and so the body resorts to metabolism of fatty acids, and thus production of ketone bodies as its main source of energy. The body produces two ketoacids in this process, one of which is called acetoacetic acid. This spontaneously breaks down to form acetone which is the smell (of nail polish / varnish) that can be smelt on a person’s breath who is suffering from type one diabetes
• Ketoacidosis can also occur in alcoholism. Alcohol blocks the first step in gluconeogenesis, and thus the body has to break down fatty acids to get its energy.
• Ketoacidosis is also significant because it causes a generalised acidosis.
• It principally occurs in those with type 1 diabetes, because most people with type two can still utilise enough glucose to prevent this from occurring.
• It is a medical emergency and a major cause of morbidity. Many type 1 patients present in this state, but it can also occur in those that have been diagnosed and are undergoing treatment.
• In established diabetes there will usually be a precipitating event for DKA (although one isn’t always found). This is commonly illness, most usually infection. It occurs because during this episode, patients will lose their appetite, and thus reduce their levels of insulin in a mistaken belief that they no longer need it.
• During illness, patients need up to 25% extra insulin to help them fight the infection – the immune system’s effectiveness is reduced as a result of diabetes!
• The mortality rate from ketoacidosis is 5-10% in developed countries. This increases with age.
• It is estimated that 25% of cases of this could be prevented through better communication to the patient- they should be instructed never to stop taking their insulin!
• The three key features of DKA are:
  • Hyperglycaemia – this has a profound effect on osmosis, and causes osmotic diuresis, leading to dehydration and electrolyte loss.  However, the level of hyperglycaemia is not necessarily related to the level of ketoacidosis. In some cases, only a small hyperglycaemia can cause ketoacidosis, whilst in other patients, there may be massive hyperglycaemia but little or no ketoacidosis.
  • Hyperketonaemia – this occurs as a result of very little circulating insulin. The effect is exaggerated by stress proteins, such as those present during illness. This results in the utilization (by the liver via ketogenesis) of loads of free fatty acids for metabolism. The mitochondira of cells will then utilise these for metabolism, producing excess ketones as a result. This results in metabolic acidosis.
  • Metabolic acidosis- When the number of free ketones in the blood exceeds those that can be metabolised, ketoacidosis occurs. This will then force H+ into cells, where it will replace potassium. The potassium will go into the blood, where it may induce vomiting. Otherwise, the potassium ions are lost in the urine. (Thus two possible signs and symptoms of ketoacidosis are high potassium levels in the urine, and vomiting (also containing large amounts of potassium).
  • Only a slight elevation in insulin level is enough to prevent ketogenesis in the liver, and thus reverse or prevent this state.
  • The real danger in this condition is reduced perfusion of the kidneys as a result of fluid and electrolyte depletion. This will result in an inability to excrete the excess hydrogen and ketones, and the patient will die.