Type-1 diabetes mellitus: Clinical Review

Type-1 diabetes is a disease of pancreatic islet beta-cell destruction, caused by an autoimmune process in more than 95 per cent of cases.

Hyperglycaemia is present in all cases of diabetes (Photograph: SPL)
Hyperglycaemia is present in all cases of diabetes (Photograph: SPL)

Section 1: Epidemiology and aetiology
The clinical manifestation of type-1 diabetes mellitus is preceded by an asymptomatic prodromal period (months to years) during which time immune destruction progresses.

The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections (mumps, rubella) are the most likely environmental triggers contributing to the aetiopathogenesis.

The diabetes autoimmunity study in the young (DAISY), followed newborns from birth and found no evidence that bovine milk ingestion, enteroviral infection or vaccination contribute to an increased risk of diabetes.

The 'hygiene hypothesis' states that a sterile environment for young infants predisposes to deficiencies in immunoregulation in later life leading to T-helper 2 (Th2) diseases (asthma) and Th1 diseases (type-1 diabetes).1

The HLA on chromosome 6 was the first locus shown to be associated with the disease and contributes to about half of the familial basis of type-1 diabetes.2

Two combinations of HLA genes, which are of particular importance, the DR4-DQ8 and DR3-DQ2, are present in 90 per cent of children with type-1 diabetes. A third haplotype, DR15-DQ6, is found in less than one per cent of children with type-1 diabetes, compared with more than 20 per cent of the general population and is considered to be protective.2

The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the affected family member with type-1 diabetes. If one haplotype is shared, the risk is 6 per cent and if two are shared the risk is 12 to 25 per cent. The highest risk is for identical twins with a concordance rate of 25 to 50 per cent.

Epidemiology
According to Diabetes UK, there are 2.6 million people diagnosed with diabetes in the UK. Among adults, it is estimated that up to 10 per cent of people with diabetes have type-1 diabetes.

The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence of 3 to 4 per cent, with a larger increase in some central and eastern European countries.

The incidence of type-1 diabetes in the UK has doubled every 20 years since 1945.3 Half of patients are diagnosed under the age of 15 and 90 per cent are diagnosed by the age of 30 years. The peak age for diagnosis in the UK is 10-14 years but is becoming younger, with a steep rise in patients diagnosed before the age of five years.

Section 2: Making the diagnosis
The symptoms and signs relate to hyperglycaemia and the effects on fluid and electrolyte imbalance. Typical symptoms of polyuria, polydipsia and weight loss tend to develop insidiously over a period of weeks. In very young children, nocturnal enuresis may signal the onset.

When insulin deficiency is severe and acute, the patient may present with diabetic ketoacidosis (DKA), an acute metabolic complication of type-1 diabetes, where ketone bodies are produced instead of the usual metabolic substrate for energy production.

Symptoms may include abdominal pain, nausea, vomiting and a change in mental status varying from slight drowsiness to profound lethargy and in severe cases, coma.

Investigations
Hyperglycaemia is present in all cases. In autoimmune diabetes the three principal autoantigens for diagnosis are glutamic acid decarboxylase (GAD 65), 43a protein tyrosine phosphatase-like molecule (IA-2A) and insulin (IAA).

About 90 per cent of caucasian children will have at least one of these autoantibodies at diagnosis.4 Tests for these antibodies are often only requested by a specialist when there is uncertainty between a diagnosis of type-1 and type-2 diabetes.

These patients and their first degree relatives are at increased risk of other autoimmune diseases. Detection of two or more autoantibodies in relatives of patients with type-1 diabetes has a positive predictive value of more than 90 per cent.

Guidelines on diagnosis
The following points summarise recommendations from the NICE guidelines on type-1 diabetes (CG15).5

  • If classical symptoms are present, confirm diagnosis by a single laboratory glucose measurement. If classical symptoms are not present then two separate glucose readings are needed.
  • HbA1c measurement may support diagnosis.
  • Where a patient appears to have type-2 diabetes, consider type-1 diabetes if ketonuria is detected, or weight loss is marked, or the patient does not have features of the metabolic syndrome or other contributing illness.
  • Consider the possibility that apparent type-1 diabetes is not type-1 diabetes in younger people with obesity or with a family history of diabetes, especially if of non-white ethnicity.
  • Do not routinely use measurement of specific autoantibodies or C-peptide to confirm the diagnosis of type-1 diabetes - consider their use to discriminate type-1 from type-2 diabetes.

Section 3: Managing the condition
Management should be individualised and regular review of the patient's individual care plan should be performed and modified according to changes in circumstances and medical findings.

The following recommendations for a structured care plan are based on the NICE guidelines (CG15).5

Provide patients with diabetes education, including advice on nutrition, physical activity and smoking. Teach self monitoring and set targets, aiming where possible for preprandial glucose levels of 4-7mmol/L and postprandial levels of <9mmol/L, and an HbA1c of less than 7.5%.

Arterial risk factors
Where significant arterial risk exists, aim for an HbA1c of less than 6.5% do not use arterial risk tables equations or engines for factor surveillance and management.

Assess urine albumin excretion. If the result is abnormal (>2.5mg/mmol for men, >3.5mg/mmol for women) confirm the result at a subsequent visit.

In all patients with confirmed kidney damage (including those with microalbuminuria alone), start ACE inhibitors and titrate to full dose.

Check the patient's lipid profile, aiming for total cholesterol of <4mmol/L and LDL <2mmol/L. Use statins as first-line therapy. If triglyceride levels are still raised despite optimal glucose control, consider fibrates. Intervention is required if BP is above 135/85mmHg, or above 130/80mmHg with abnormal albumin excretion rate or another feature of the metabolic syndrome.

Complications
Assess annually for neuropathy, retinopathy and nephropathy. Give advice regarding foot care and assess for complications.

Give advice regarding foot care and assess for complications (Photograph: SPL)

Structured education programmes
Two major studies, the diabetes prevention trial (DPT)6 and the European nicotinamide diabetes intervention trial (ENDIT)7 have shown that strategies to prevent type-1 diabetes have not been successful.

Thus, for individuals with type-1 diabetes, life-long insulin replacement and monitoring of blood glucose levels are required.

Structured education programmes like 'dose adjustment for normal eating' (DAFNE)8 and the 'Dusseldorf diabetes treatment and teaching programme'9 have demonstrated substantial benefits in improving glycaemic control and quality of life while saving costs, without increasing the risk of severe hypoglycaemia.

These two structured education programmes emphasise the importance of carbohydrate counting and insulin dose adjustment according to the carbohydrate meal content and glucose levels.

Section 4: Prognosis
When an optimal glucose level is achieved and maintained in patients with type-1 diabetes, the risk of new eye disease is reduced by 76 per cent, worsening of existing eye disease by 54 per cent, early kidney disease by 54 per cent, more serious kidney problems by 39 per cent and development of neuropathy by 60 per cent.10

Retina damage from diabetes (Photograph: SPL)

Cardiovascular risk
The diabetes control and complications trial (DCCT) showed there was no glucose threshold for the development of microvascular complications.

When the DCCT ended in 1993, researchers continued to study more than 90 per cent of participants over the next 10 years.

The follow-up study, called epidemiology of diabetes interventions and complications10 reported that the risk of any heart disease was reduced by 42 per cent in patients who had been in the intensive treatment group.

Patients in the intensive treatment group also cut their risk of non-fatal heart attack, stroke, or death from cardiovascular causes by 57 per cent.

According to the National service framework for diabetes standards document published in 2001, life expectancy is reduced on average by more than 20 years in patients with type-1 diabetes and up to 10 years in type-2 diabetes.

Mortality rates are up to five times higher for patients with diabetes.

Section 5: Case study
A 37-year-old female was admitted to hospital with sore throat and general malaise. She was diagnosed with type-1 diabetes 18 years ago. She had a significant history of poor attendance to specialist clinics and had not seen her family doctor for three years.

There was no record of any previous diabetes-related hospital admissions. She had attended the eye clinic in the past for extensive laser treatment to both her eyes.

Kidney function
She was on a basal bolus regimen and on admission she was not in DKA. Her HbA1c was 11 per cent and her creatinine was 849micromol/L with an eGFR value of 5ml/min.

She had raised urine protein excretion of 8.49g per day. Vasculitic screen and ultrasound of kidneys were unremarkable.

With fluid resuscitation over a period of one week her kidney function improved slightly (creatinine 514micromol/L and eGFR 8ml/min) and her urine output improved.

She was transferred to a regional kidney unit for renal replacement therapy.

Need for routine review
This case highlights the debilitating and relentless nature of poorly controlled diabetes. A strong commitment to routine review by both the patient and the healthcare team should lead to prevention or delay of complications in many patients.

This case highlights NICE's recommendation to establish diabetes registers to support recall systems for surveillance of complications and vascular risk.

Section 6: Evidence base
Clinical trials

A Cochrane review in 2008 analysed 23 RCTs where two insulin regimens were used for a period ranging from three months to one year.11

The weighted mean difference for the level of glycosylated haemoglobin was -0.08 (95 per cent confidence interval (CI) -0.12 to -0.04) in favour of the long acting insulin arm, but the observed difference was of doubtful clinical significance.

Longer acting insulins were superior mostly in their nocturnal effect, which resulted in a lower level of fasting glucose levels and fewer episodes of nocturnal hypoglycaemia.

Insulin replacement therapy (Photograph: SPL)

A meta-analysis of 12 trials found that glycaemic control was better with CSII compared with multiple daily injections in patients who had severe hypoglycaemia, with a difference in HbA1c of 0.51 per cent.12

The study also reported a threefold reduction in severe hypoglycaemia with CSII compared with multiple daily injections.

Another systematic review and meta-analysis of 20 studies reported that achieved HbA1c was significantly superior in the CSII group, the mean difference was -0.3 per cent (95 per cent CI -0.4 to -0.1, p=0.001) with significant reduction in the incidence of severe hypoglycemia.13 Thus, CSII is likely to be a clinically useful alternative for those patients in whom there is concern about severe hypoglycaemia.

Guidelines

NICE. Type-1 diabetes: diagnosis and management of type-1 diabetes in children, young people and adults. CG15. London, NICE, 2004.

Online

This website provides useful links for both patients and healthcare professionals in the UK.

Visit our GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum.

 

  • Contributed by Dr Anita Pillai, specialist registrar, and Dr Iskandar Idris, consultant, Sherwood Forest Hospitals Foundation Trust, and honorary senior lecturer, University of Sheffield.

Reflect on this article and add notes to your CPD Organiser on MIMS Learning

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Hold a diabetes 'roadshow' for your local community. Screen for diabetes and hypertension, and talk about the risk factors for diabetes as well as complications and treatment.
  • Hold a practice meeting to decide how to manage poorly attending patients with diabetes.
  • Remind your team how to manage diabetic emergencies and ensure your doctor's bag has all the necessary equipment.

References
1. Gale E A. A missing link in the hygiene hypothesis? Diabetologia 2002; 45: 588-94.

2. Gillespie K. Type 1 Diabetes: Pathogenesis and Prevention. CMAJ 2006; 175(2).

3. Barnett T. The insulin treatment of Diabetes: A practical guide. EMAP Healthcare 1998.

4. Atkinson M A, Eisenbarth GS. Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet 2001; 358: 221-9.

5. NICE. Type 1 diabetes in children, young people and adults. CG15, London, NICE, 2010.

6. Diabetes prevention trial-type 1 diabetes study group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346(22): 1,685-9.

7. ENDIT. Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial. Diabetologia 2003; 46(3): 339-46.

8. DAFNE. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes. BMJ 2002; 325: 746.

9. Aschner P, Horton E, Leiter L A, et al. Practical steps to improving the management of type 1 diabetes. Int J Clin Pract 2010; 64(3): 305-15.

10. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med 2005; 353: 2,643-53.

11. Vardi M, Jacobson E, Nini A, et al. Intermediate acting versus long acting insulin for type 1 diabetes mellitus. Cochrane Database Syst Rev 2008; 3. CD006297.

12. Pickup J C, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002; 324: 705.

13. Misso M L, Egberts K J, Page M, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database Syst Rev 2010, Issue 1. CD005103.

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