Section 1: Aetiology and epidemiology
Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia, the fundamental defect being a deficiency of insulin action. In the classical, juvenile-onset form of diabetes (now termed type-1 diabetes) there is an absolute lack of insulin. Conventionally the diagnosis of diabetes is based on the results of an oral glucose tolerance test, however, these criteria are of little relevance in type-1 diabetes where the majority of patients present with severe symptoms.
Symptoms include lethargy, polydipsia, polyuria, profound weight loss and, if treatment is delayed, potentially fatal ketoacidosis. In this setting, the diagnosis is confirmed by an elevated random blood glucose and the presence of urinary ketones.
The peak age at onset of type-1 diabetes is 12 years and the incidence appears to be increasing in the UK, where it is now the third most common chronic disease of childhood.
Diabetic retinopathy with new vessels emerging from the optic disk
Type-1 diabetes can be diagnosed at any age and there is increasing recognition that patients previously labelled as having type-2 diabetes have a slowly progressive form of type-1 diabetes, termed latent autoimmune diabetes of adulthood (LADA). The diagnosis can be supported by a positive screen for antibodies to glutamic acid decarboxylase (GAD). LADA patients tend to be younger and slimmer than typical type-2 diabetic patients and have a more rapid progression towards insulin treatment.1
The pathological process culminating in type-1 diabetes (and LADA) involves chronic autoimmune destruction of insulin-producing beta cells within the pancreatic islets of Langerhans. This process appears to be a protracted one, with sensitive measures of beta cell function being abnormal up to seven years before clinical presentation.
Antibodies to different islet cell components (ICA), present in 70-80 per cent of new patients, can also be detected up to 10 years before diagnosis. By the time of clinical presentation of type-1 diabetes 90 per cent of the pancreatic beta cells may have been destroyed.
The typical presentation of type-1 diabetes tends to be short and dramatic. Weight loss can be profound (perhaps 10kg over a few weeks) and patients are dehydrated due to osmotically-driven polyuria and nocturia.
Attempts to combat this, such as drinking huge volumes directly from the tap, ultimately fail and extreme lethargy is typical. Patients may have noticed recurrent infections, such as thrush or boils, leading up to this stage and the acute metabolic decompensation can be a result of current infection.
Although it still occurs, presentation with severe diabetic ketoacidosis needing high dependency care is now unusual and loss of consciousness is rare.
Section 2: Investigations and initial management
Antibodies to ICA, insulin and GAD may be detected; however, they are of little use in a typical case and will not alter management even if the screen is negative.
Likewise, testing for rare genetic causes of diabetes has no place in routine practice and the diagnosis is a clinical one, supported by the finding of elevated blood glucose and ketonuria.
While near-patient testing now allows the detection of blood ketone bodies in this scenario, this is not generally available through biochemistry laboratories.
Initial management of type-1 diabetes depends on the severity of the presentation and local practice. Patients with diabetic ketoacidosis need hospital admission for IV insulin, fluids and electrolyte monitoring while those adults with a less severe metabolic disturbance can be managed at home with frequent contact with the diabetic specialist nurse team.
For children, there is still no consensus as to whether hospital admission is beneficial and local policy will vary; hopefully this question will be resolved by an on-going clinical trial.2
The treatment for all patients with type-1 diabetes is life-long insulin, which currently remains a subcutaneous injection.
A commonly advocated regimen is the so-called 'basal-bolus' regimen, which usually involves four injections per day. Patients inject a long-acting insulin once a day, usually before bedtime, and then three pre-meal injections of short-acting insulin, which are varied according to food intake.
Most modern diabetes units would choose analogue insulins, in which the human insulin molecule has been manipulated to enhance or delay the release of insulin from the injection site.
Although trial evidence that these preparations lead to better diabetic control, as assessed by HbA1c levels, is slender, they do reduce the risk of hypoglycaemia and the need for frequent snacking.
Other less intensive regimens can be offered, such as twice daily injection of mixtures of fast-and slow-acting insulins. These may be preferred for young children where a lunch-time injection at school can be problematic. Likewise, some adult patients prefer the simplicity of twice-daily dosing.
Insulin is usually administered using 'pen' devices with removable fine-bore needles which, in theory (although rarely in practice), are changed for each injection.
The pens differ in subtle ways and so pen preference is one of the major drivers in choosing which brand of insulin to prescribe, emphasising the equivalence of the commercially available insulin preparations.
Section 3: Insulin
Patients need to perform regular blood glucose checks to allow for optimisation of insulin dosing and to detect hypoglycaemia. This requires finger-prick testing, which is a major disincentive to compliance.
HbA1c testing gives an indication of average glycaemic control (usually cited as a three-month average, although the level is more influenced by glycaemia in the two weeks preceding testing); this requires a formal venesection, although near-patient testing is available.
Patients with type-1 diabetes are prone to the long-term complications of hyperglycaemia, which are usually classified into small and large vessel disease. Within the small vessel complications, there are major differences in the risks of diabetic retinopathy, nephropathy and neuropathy.
Diabetic retinopathy appears to be a predominantly glucose-related complication, so that all patients with type-1 diabetes will eventually develop evidence of eye involvement. Eye screening strategies (usually based on digital imaging, see figure in section 1) facilitate life-long annual examinations.
In contrast, diabetic kidney involvement affects a minority of patients (40 per cent at most), irrespective of the level of hyperglycaemia, implying an inherited predisposition to this complication.
Those patients who develop diabetic nephropathy are at increased risk of other small vessel complications but also experience foot ulceration and typically succumb to cardiovascular death. This highlights the arbitrary division of complications of diabetes and should focus our therapeutic efforts on those type-1 patients with microalbuminuria and hypertension.
Neuropathic foot ulcer in a patient with long-standing type-1 diabetes
There is evidence that the incidence and progression of diabetic complications can be reduced by tight glycaemic control, assessed by HbA1c levels, and this forms the basis for targets in clinical practice.
For many patients with type-1 diabetes these targets are not achievable due to the amount of lifestyle modification required and the attendant danger of hypoglycaemia. For these reasons, we strongly advocate individualised HbA1c targets, which should be negotiated with patients based on their value judgments and modified by their individual risk.
Section 4: New developments
The principal advantages of continuous administration of insulin are less variability in insulin levels and ease of variation of insulin dose. These translate into a substantial reduction in severe hypoglycaemia, although the benefits in HbA1c levels are less dramatic, especially in those with reasonable control on multiple injections.3 Although currently available devices are robust, compact and relatively easy to use, they are not suitable for all patients.
The hardware and consumables currently cost approximately £2,700 and £700 per annum respectively. There is also the need for detailed knowledge of carbohydrate values and frequent self-monitoring.
The latter issue may be resolved by so-called 'closed loop' insulin delivery systems, where insulin dose is automatically adjusted according to blood glucose levels. The FDA has recently approved such an application.
Had this review been written 12 months ago, inhaled insulin would have been a major topic. Studies had demonstrated that pre-meal injections could be replaced by inhalation of insulin and the first of a new class, 'Exubera', was launched in the UK in January 2006.
A further two formulations were in phase III clinical trials. Then in October 2007, Exubera was voluntarily withdrawn by its manufacturers and earlier this year trials involving similar products were halted.
In April 2008 came the news that six patients treated with Exubera (all ex-smokers) had been diagnosed with lung cancer. The focus has now turned to oral preparations.
Oral insulin delivery has so far failed because gastric acidity renders insulin inactive. However, a number of companies claim to have created delivery systems that protect the insulin molecule from enzymatic digestion and facilitate its absorption across the intestinal mucosa. Abstracts have been presented to support efficacy but, as yet, there is little in the peer-reviewed literature to allow an adequate scrutiny.
Islet cell transplantation
The replacement of the body's capacity to produce insulin has been a goal of research for many years. Initially, the focus was on whole-organ pancreas transplantation and these programmes continue to run with a target population of type-1 diabetics who require a donor kidney, on the basis that they will need to be on immunosupression anyway.
However, in 2000, a group in Canada published a groundbreaking study describing seven consecutive patients who had been rendered insulin independent by the transplantation of pancreatic islets.4
A schematic representation of an islet cell transplant
The advantages of such a technique were immediately obvious, with minimal surgical intervention (islets are infused overnight into the liver circulation) and no need to deal with the exocrine function of the whole organ.
The advances the group had made related to successful extraction of islet tissue from cadaver pancreata and a relatively non-toxic immunosuppressive regime.
Quite how widespread islet-cell transplantation can be is a subject of debate, as suitability for the treatment is limited. There also remains the difficult issue of suitable donor organs.
Nevertheless, in February 2008, the NHS in England decided to fund islet cell transplantation in six centres, with a target of 80 procedures per year.
An advance that most patients with type-1 diabetes would happily adopt would be an efficient way of blood glucose monitoring without the need for painful testing.
Early versions of this technology have passed the proof-of-principal test and are even commercially available in the UK (the Glucowatch device). However, there are still issues around cost, reliability and adverse effects; for example Glucowatch tended to fail on moist, cool skin (as might be expected during a hypo) and caused long-lasting skin irritation in many patients.
The area of non-invasive testing is a rapidly expanding one and a recent review highlighted 14 different technologies under development with over a dozen instruments approaching approval.5
1. Brophy S, Davies H, Bain S et al. Randomized, controlled, parallel-group prospective study to investigate the clinical effectiveness of early insulin treatment in patients with latent autoimmune diabetes in adults. BMC Endocr Disord 2008; 8: 8.
3. The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008; 359: 1,464-76.
4. Shapiro AM, Lakey JR, Ryan EA et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230-8.
5. Tura A, Maran A, Pacini G. Non-invasive glucose monitoring: assessment of technologies and devices according to quantitative criteria. Diabetes Res Clin Pract 2007; 77: 16-40.
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