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Diabetes - Insulin Dependent


Insulin-dependent diabetes (also known as type 1 diabetes) is an auto-immune condition characterised by lack of insulin production. It is due to an autoimmune reaction whereby ß-cells of the Islets of Langerhans in the pancreas, are destroyed by autoantibodies resulting in the patient losing the ability to produce the hormone insulin. 


It is related to other autoimmune conditions such as Addison's disease, pernicious anaemia, coeliac disease and autoimmune thyroid disease.



Type 1 diabetes may present at any age, with peak age of-onset around 12-years. It accounts for approximately 15% of all cases of diabetes. Studies have shown it to be most common in people from northern Europe, for example Scandinavia; possibly due to the genetic component of its pathogenesis.




The exact pathogenesis of type 1 diabetes is not known . Current evidence suggests that it is the result of interplay between genetic and environmental factors.



 The Human Leucocyte Antigen (HLA) system plays a role in regulating the body's immune response. Multiple genes have been linked with type 1 diabetes, but genes in the HLA system are the biggest predisposing factor to the development of the disease. Around 90% of those affected have HLA-DR3 or HLA-DR4.


However, studies in twins show that identical twins only have a 30-50% concordance rate indicating that genetics is not the only cause of the disease.



 Currently, there is no evidence showing a definite role of specific environmental factors in the development of type 1 diabetes. Current hypotheses surround the involvement of infection with enteroviruses e.g. Coxsackie virus. It is suggested that infection with a virus triggers an autoimmune response against beta-cells in the pancreas leading to their destruction. Other current hypotheses involve diet, and the 'hygiene hypothesis' (a very hygienic environment leads to lack of antigen stimulation and therefore increased susceptibility to certain diseases).


Signs and Symptoms


People with type 1 diabetes mellitus will present with hyperglycaemia (glucose >7mmol/l). The table below shows common symptoms that can be present at first presentation of the disease.

    • Polyuria
    • Polydipsia
    • Weight loss
    • Fatigue
    • Recurrent infections e.g. Candida
    • Blurred vision
    • Slow healing

    The left hand column of the table above shows the classical triad of symptoms. Polyuria (increased urination) occurs because glucose levels in the blood exceed the kidney's ability for glucose reabsorption. Therefore, glucose is lost in the urine. Water follows glucose, therefore water is also lost in the urine in greater amounts than usual, producing osmotic diuresis. Polydipsia (increased thirst) also occurs due to excess loss of water from the body.


    Weight loss typically occurs because lack of insulin prevents body tissue from accessing the supply of glucose in the blood. This stimulates the breakdown of other stores of energy in the body, such as fats and proteins, to try to increase the supply of energy to body tissue.


    Some people will present for the first time with ketoacidosis. This is a diabetic emergency and requires urgent treatment.




    This is a very serious complication of type 1 diabetes and requires urgent treatment with insulin. It can occur as the first presentation of type 1 diabetes. It also commonly occurs when people do not adhere to their insulin therapy correctly or when insulin therapy isn't adjusted during intercurrent illness.


    In the absence of insulin, glucose remains in the bloodstream and is unable to be taken up into cells. This stimulates the breakdown of other substrates such a fats (lipolysis). The resultant fatty acids are then metabolised to produce glucose, and ketone bodies are produced. These ketone bodies are acidic and produce a metabolic acidosis.


    Severe hyperglycaemia can exacerbate the classical triad of symptoms and at presentation these patients are severely dehydrated.


    Signs and Symptoms of Ketoacidosis


    • Decreased consciousness leading to coma
    • Dehydration: low blood pressure, increased heart rate, thirst, dehydration
    • Ketones: ketotic fetor ("pear drop" like smelling breath), high rate and depth of breathing (Kussmaul breathing), ketonuria
    • Vomiting, abdominal pain


    • Urine dipstick: Ketones +++, glucose +++
    • BM: very high glucose


    The management of this emergency is to replace the fluid deficit and to administer insulin as soon as possible. Initially, a bolus of insulin will be given as it is required urgently. After this has been given, an insulin infusion will be set up to give the correct amount of insulin according to the patient's glucose levels.


    Insulin drives potassium into cells which can result in hypokalaemia. Therefore, electrolytes will need to be monitored throughout the treatment and potassium replacement added to the I.V. fluids accordingly.


    Along with the initial management, it is also important to investigate the cause of ketoacidosis. If an underlying medical condition is found, this can be treated. If the cause is poor adherance to the insulin therapy, patient education is important to ensure it does not happen again.




    A diagnosis of diabetes mellitus is made by measuring glucose levels. Fasting blood glucose is the primary investigation in symptomatic patients. An oral glucose tolerance test (OGTT) is used in asymptomatic patients or those in which the diagnosis is in doubt. An OGTT invovles the patient drinking 75g of glucose (usually lucozade) and then measuring the blood glucose 2 hours later.

    Fasting glucose test

    • Diabetes: glucose >7mmol/l
    • Impaired tolerance: glucose 6-7mmol/l
    • Normal: glucose <6mmol/l

    Oral Glucose Tolerance Test

    • Diabetes: glucose >11.1mmol/l
    • Impaired tolerance: glucose 7.8-11.1mmol/l
    • Normal: glucose <7.8mmol/l

    These tests make a diagnosis of diabetes mellitus but do not differentiate between the two types.


    There are some features of the presentation that point to a specific type of diabetes, e.g. an older, overweight person is most likely to have type 2, and a younger, thin person most likely to have type 1. However, this is not always the case. In general, ketonuria, significant weight loss and the lack of features of the metabolic syndrome (high blood pressure, high lipids, central obesity) point to a diagnosis of type 1. A urine dipstick looking for ketones should always be done. This is important as ketonuria will be present before ketoacidosis develops in type 1 diabetics.


    Specific autoantibodies can be measured if the diagnosis is in doubt. If a diagnosis of type 2 diabetes does not respond to oral hypoglycaemics, a diagnosis of type 1 diabetes should be considered.




    The treatment of type 1 diabetes mellitus is to replace the body's deficit of insulin with injections of a synthetic insulin. Normally, the body has a background level of insulin, with peaks of increased concentrations of insulin at meal times. Insulin injections need to be administered by the patient themselves numerous times a day, therefore patient education about treatment is vital.


    There are a range of different insulin preparations that last differing lengths of time in the body. This allows for different treatment regimes that closely mimic the body's natural insulin levels and increase treatment flexibility.


    Different types of insulin are grouped according to duration of action:


    • Rapid-acting Insulin e.g. Novorapid: This works within 15 minutes, so can be given after a meal. The dose can be adjusted according to the carbohydrate content of what was eaten
    • Long-acting Insulin e.g. Levemir, Lantus: These mimic the normal background basal dose of insulin.
    • Short-acting Insulin e.g. Actrapid: This takes longer to work so has to be injected 30 minutes before a meal.
    • Intermediate acting Insulin e.g. Humulin I: This acts similarly to the long acting insulin to provide a basal dose.


    In addition to the above groups of insulin, there are also formulations of insulin that are premixed; containing both intermediate acting and short acting preparations e.g. Novomix 30. Different premixed formulations containing different concentrations of the two insulins exist. These formulations are used in a basic treatment regimen, where only two injections are required per day.


      Premixed Insulin Regimens

      The above regime is good because it is simple and only requires two injections per day. However, it does not allow much flexibility in the diet and mealtimes have to be regular. With this regime diet must be adjusted according to the insulin dose, which can have a negative impact on quality of life.

      An example of a much more flexible insulin regime is the basal bolus regime. This allows for the insulin dose to be tailored around food intake. This results in insulin levels which are much closer to the bodies normal pattern of insulin release. The disadvantages of this regime are that it requires more injections per day. It also requires effective patient education to allow them to take control of their insulin therapy safely.  This can be achieved through patient courses such as the DAFNE course (Dose Adjusted For Normal Eating).


      Basal Bolus Insulin Regimen

      With treatment for type 1 diabetes, patient education is just as important as insulin therapy. Self-management education programmes are very important, as people with type 1 diabetes are at the forefront of their own treatment. They need to understand how to monitor their blood glucose with blood glucose meters, and how to adjust insulin treatment accordingly. Education classes can address issues such as; how to manage diabetes during illness, driving restrictions, monitoring for ketonuria and nutrition and exercise. They can also provide psychological support.


      Diabetic control can also be assessed by measuring HbA1c or glycosylated haemoglobin. Glycosylated haemoglobin forms during a reaction between haemoglobin and plasma glucose. Diabetics with poor control have higher levels of plasma glucose and therefore higher HbA1c levels. Red blood cells live for 90-120 days before they are replaced, therefore HbA1c is a good indication of glucose control over the preceeding 3 months.


      The aim for most people with type 1 diabetes is a target HbA1c of around 7%. However the units for this measurement are changing to mmol/mol. The equivalent target using the new units is 53mmol/mol. This change will occur in May 2011.


      There are also complications related directly to the treatment with insulin.


      If too much insulin is given, there is a risk of developing hypoglycaemia (glucose <4mmol/l). The blood glucose level at which symptoms of hypoglycaemia occur depends on the normal glucose concentrations of the individual. For those who have poor control of their diabetes and continually high blood glucose, symptoms will occur at a higher level than those who have good control. Hypoglycaemia is described in more detail in a separate article.


      Complications can also occur due to the physical effect of the injections. If the injections are too shallow, painful, red areas will develop. Also, if the same injection site is used too frequently, fatty lumps known as lipohypertrophy occur. Lipohypertrophy decreases the amount of insulin that is taken into the blood stream.


      There may also be a problem of insulin resistance, which means that some people will require very large insulin doses. This problem increases with obesity. Insulin therapy compounds this problem as it causes weight gain.




      Patients with type 1 diabetes will need insulin therapy for life. Once the diagnosis has been made, it will never be cured. Patient education is vital so that they understand how important it is to maintain glucose levels as normal as possible. The probability of micro- and macrovascular complications increases with poor control and constantly high glucose levels. Type 1 diabetes is associated with a high morbidity and mortality due to complications.




      Diabetics are at an increased risk of numerous complications. These can be divided up into micro- and macrovascular complications. These are discussed further in a separate article and are only briefly mentioned here.


      It is very important that people with diabetes try and decrease their risk of cardiovascular disease by addressing risk factors such as smoking, high cholesterol, high blood pressure and being overweight.


      Microvascular complications result from damage to small vessels. In the retina, vessels become leaky, fibrose and new fragile vessels form. This results in retinopathy and may lead to blindness if not treated. In order to prevent such damage, a regular screening programme is in place to detect early changes.


      Small vessels in the kidney are also affected, albeit at a later stage than the retinal vessels, producing nephropathy. This starts with a stage of hyperfiltration leading to an increased glomerular filtration rate (GFR). The GFR then decreases as the damage to the vessels increases. Also, the amount of protein in the urine increases as the GFR decreases. This can lead to end stage renal failure. This is monitored initially by detecting how much albumin is present in urine.


      Neuropathy occurs when the small vessels supplying the nerves are affected or when there is an abnormal accumulation of sugars in the nervous tissue. There are four main types of neuropathy; peripheral neuropathy, autonomic neuropathy, amytrophy and mononeuropathy.


      Macrovascular complications occur due to the increased risk of developing atherosclerosis. This leads to complications such as myocardial infarction, stroke and peripheral vascular disease.


      References and Further Reading

      Gale EAM, Anderson JV. Kumar & Clark Clinical Medicine 6th ed; Pg 1103-1131, Elsevier Saunders 2005

      Holt T, Kumar S. ABC of Diabetes 6th ed, BMJ Books. Wiley Blackwell 2010.

      Davey P. Medicine at a Glance, 3rd ed; Pg 298-302. Wiley Blackwell 2010.

      Longmore M, Wilkinson IB, Davidson EH, Foulkes A, Mafi AR. Oxford Handbook of Clinical Medicine 8th ed. Oxford University Press 2010.



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