Type 1 diabetes: clinical review

Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Further resources

Section 1: Epidemiology and aetiology

Type 1 diabetes (T1DM) affects around 1 in 300 people in the UK. It is the most common endocrine disorder of childhood and accounts for around 5% of patients with diabetes. There is an increasing incidence in all populations, especially in younger children. T1DM can develop at any point during childhood, with a peak at puberty, and most patients present before the age of 40.

Note that there are some forms of T1DM, particularly in people of African or Asian origin, where patients have insulin deficiency and are prone to ketoacidosis but have no evidence of beta-cell autoimmunity. Older patients can also develop T1DM.

Most patients presenting in primary care have type 2 diabetes (T2DM) but it is important to note that the remaining patients do not, by default, have T1DM (see box 1).

Latent autoimmune diabetes in adults (LADA) occurs in around 10% of diabetes cases and can easily be diagnosed with a positive anti-GAD antibody test. This is often misdiagnosed as T2DM, resulting in long periods of poor glycaemic control on oral therapies when patients should be on insulin, thereby increasing their risk of complications.¹

Monogenic diabetes includes neonatal diabetes (onset less than 6 months of age) and maturity onset diabetes of the young (MODY, around 2%). Neonatal diabetes can either be transient or permanent.²

MODY is significantly underdiagnosed. In a leading diabetes centre in the US, only 1 in 22 patients fulfilling all the criteria for MODY, who were subsequently diagnosed by genetic testing, had actually been previously diagnosed.³ 

The alternative diagnosis of T1DM leads to a lifetime of unnecessary insulin, because patients with MODY can be extremely responsive to low dose sulphonylurea treatment.⁴ A diagnosis of monogenic diabetes should be considered if:

• Diabetes was diagnosed within the first six months of life.
• There is a strong family history of diabetes but without typical features of type 2 diabetes i.e. non-obese, low-risk ethnic group.
• There is mild fasting hyperglycemia (5.5-8.5 mmol/L]) and the individual is young and non-obese.
• There are negative diabetes associated autoantibodies.

Pathogenesis

T1DM has an autoimmune basis and is characterised by destruction of the pancreatic beta cells. Genetic and environmental factors play a part and HLA-DR/DQ genes can either predispose to, or confer protection from, T1DM.

Environmental factors include exposure to the coxsackie or rubella virus and cow's milk protein, although the exact mechanisms and temporal relationship with exposure are not confirmed.⁵

Vitamin D deficiency has been implicated via a modulation of the autoimmune response leading to T1DM.⁶

In keeping with an autoimmune aetiology, a number of antibodies directed against antigens on the beta cells can be detected before or at the onset of diabetes and include islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65-kDa isoform of glutamic acid decarboxylase (GAD) and autoantibodies targeting the tyrosine phosphatases IA-2, IA-2β and ZnT8.

Section 2: Making the diagnosis

Patients may present with a variety of symptoms, including polyuria, polydipsia, weight loss, fatigue and blurring of vision. In the presence of ketonuria and weight loss T1DM must be excluded, particularly in a young child — urgent plasma glucose testing is warranted. A glucose level of >11.1mmol/L will confirm the diagnosis.

Subcutaneous insulin should be started immediately in patients with T1DM. Delay may lead to diabetic ketoacidosis, which is a medical emergency.

For patients with T2DM without overt symptoms, a diagnosis can be confirmed with two fasting plasma glucose measurements >7mmol/L or HbA1c >6.5% on two different days. An oral glucose tolerance test using a 75g glucose load confirms the diagnosis if plasma glucose is >11.1mmol/L after two hours.

When patients are diagnosed with T1DM, coexisting autoimmune diseases should be considered. Urea and electrolytes, BP and TFTs should be checked to exclude Addison's disease or hypo/hyperthyroidism, and younger patients should have a coeliac screen.

Section 3: Managing the condition

The aim in managing T1DM is to achieve a HbA1c of <6.5% to prevent micro- and macrovascular complications and reduce mortality.⁷ However, targets should be tailored to the individual and it is vital to ensure patients do not have increased episodes of hypoglycaemia or gain excessive weight.

The mainstay of treatment is insulin, which is conventionally delivered subcutaneously. There are several formulations of insulin, each of which attempt to simulate the normal release of endogenous insulin.

The multiple daily injection regimen requires patients to have at least four injections, based on three meals a day. This provides the most flexibility and is the preferred choice in younger patients.

Biphasic insulin, which contains a combination of short- and long-acting/intermediate insulin analogues, may be used as a twice-daily regimen, but provides less flexibility with meal times. Patients have to eat at set times because the insulin has already been administered, so there is an increased risk of hypoglycaemia if a meal is missed or delayed.

Continuous subcutaneous insulin infusion provides rapid-acting insulin at an adjustable rate and is NICE approved for children >12 years and adults, but markedly underused in the UK.

There has been considerable interest in the artificial pancreas and there are some promising data, although it is likely the delivery of insulin and glucagon will be required to achieve optimal blood glucose control.⁸

Simultaneous pancreas and kidney transplantation remains the procedure of choice for beta-cell replacement in uremic patients. Islet cell transplantation (ICT) should be considered in non-uremic patients with a low BMI and low insulin requirements, patients lacking the cardiovascular reserve to undergo open abdominal surgery.⁹ 

ICT is NICE approved and National Commissioning Group funded for patients with severe recurrent hypoglycaemic episodes. The main criteria for ICT is severe unawareness of hypoglycaemia. ICT achieves modest insulin independence rates of 20-25% at five years, but the main benefit is a significant reduction in the incidence of severe hypoglycaemia.

Patient education in T1DM is important and there are national education programmes, such as Dose Adjustment For Normal Eating (DAFNE), which enable patients to adjust their diet to their insulin therapy. However, this approach provides only modest improvements in HbA1c so its cost-effectiveness is debatable.¹⁰

Section 4: Prognosis

A recent analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study found that mortality in the intensive therapy group was non-significantly lower than in the general US population (standardised mortality ratios = 0.88).

Mortality in the conventional therapy group was significantly higher (standardised mortality ratios = 1.31) than that in the general US population.⁷ This emphasises the importance of optimal early glycaemic control, aiming for a HbA1c of around 6.5%.

Additional benefits included: 76% reduction in retinopathy, 50% reduction in nephropathy, 60% reduction in neuropathy, 42% risk reduction in cardiovascular disease and a 57% reduction in nonfatal heart attack, stroke, or death from cardiovascular causes.

However, the achievement of optimal glycaemic control in the study required:

• Testing blood glucose levels four or more times a day.
• Injecting insulin at least three times daily or using an insulin pump.
• Adjusting insulin doses according to food intake and exercise.
• Monthly visits to a health care team (physician, nurse educator, dietitian, and behavioral therapist).

Other potentially modifiable risk factors should be assessed and treated including smoking cessation, weight reduction and optimal control of BP and lipids.¹¹

All patients should undergo screening for the diabetic triopathy from 15 years of age, or 5 years after the diagnosis of T1DM.¹² 

Painful diabetic neuropathy and erectile dysfunction often go undiagnosed — screening for neuropathy is limited to a rudimentary inspection of the feet and monofilament examination, which only identify advanced neuropathy and have not been shown to reduce amputation.¹³ 

Earlier diagnosis of small fibre neuropathy is essential to prevent its progression.¹⁴ The ophthalmic technique of corneal confocal microscopy¹⁵ is a rapid non-invasive early diagnostic test for neuropathy which could be implemented in a one-stop diabetes complication screening model, alongside retinal screening.¹⁶ Pregabalin, duloxetine and tramadol may be beneficial in painful diabetic neuropathy.

Section 5: Case study

A 42-year-old woman presents with a two-month history of fatigue. She smokes 10 cigarettes a day and drinks eight units of alcohol a week. She is generally well, with a history of hypertension, for which she takes olmesartan 20mg. Her mother developed T2DM in her late fifties.

The patient has a BMI of 22.5 and examination was unremarkable. Random blood glucose was found to be 12mmol/L. FBC, U&Es and TFTs were normal. Urine glucose was high, with ketones +.

Lifestyle advice

The patient was given lifestyle and diet advice and commenced on metformin 500mg twice a day, which was then titrated to 1g twice a day after two weeks. She was reviewed five months later and although her HbA1c had improved from 9.8% to 8.1%, it was still suboptimal.

Given that she was not overweight, gliclazide 80mg twice a day was added. At her review four months later, her HbA1c had improved minimally to 7.8%, so the gliclazide was titrated to 160mg twice a day.

A year later, her HbA1c was 8.3%, despite good compliance with her medication. Although she was reluctant to commence insulin because of her 'fear of injections' she agreed to commence once-daily basal insulin.

At a subsequent review, her HbA1c had dropped to 7.4%.

In view of the quick progression to insulin, it is important to reconsider the type of diabetes this patient has. She initially presented with some osmotic symptoms and her BMI was normal. Although she had a family history, she was lean and did not respond well to oral therapy.

Antibody testing was carried out and she was found to be positive for GAD antibodies. The diagnosis is LADA, which is why her HbA1c improved quickly with the introduction of insulin.

Section 6: Further resources

Online

American Diabetes Association. Standards of Medical Care in Diabetes - 2016. Diabetes Care.http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

Autologous pancreatic islet cell transplantation for improved glycaemic control after pancreatectomy. NICE. IPG274. Sept 2008. https://www.nice.org.uk/guidance/ipg274

• Professor Rayaz A Malik, Professor of medicine, Weill Cornell Medicine, Qatar, Honorary professor of medicine, Institute of Cardiovascular Medicine, Manchester Royal Infirmary and University of Manchester
• Dr Shazli Azmi, University of Manchester and Central Manchester University, Hospitals Trus
• Dr Uazman Alam, University of Manchester and Central Manchester University, Hospitals Trust

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