In 1922 Leonard Thompson, aged 14, became the first patient with diabetes to be treated with insulin therapy. The discovery of insulin was made in 1921 by Banting and Best in Toronto. Prior to this a diagnosis of diabetes was essentially a death sentence. In the 1800s, having observed the improvement in diabetes symptoms which accompanied the food shortages of the Franco-Prussian war, the treatment approach for diabetes was one of severe food restriction and in some unfortunate cases patients died of starvation rather than diabetes. Since 1921, while our understanding of the disease and its subsequent management has been refined, the basis of treatment remains the same: insulin replacement. 

Diabetes is currently categorised according to clinical and antibody presentation, with most patients being diagnosed with either type 1 or type 2 diabetes. Other, rarer, genetic forms are also being increasingly diagnosed.

Type 1 diabetes

Pathogenesis

Type 1 diabetes mellitus (T1DM) is the third most common chronic disease of childhood with an annual incidence of 15 per 100,000 under the age of 18 in the US. T1DM accounts for 99% of children diagnosed with diabetes. Pancreatic ß-cell destruction and subsequent absolute insulin deficiency is the hallmark feature of T1DM.^1-2 Eisenbarth,³ in the 1980s, proposed the current ‘two-hit hypothesis’. The model postulates that we are born with a genetic susceptibility to developing T1DM, largely inherited from the human leukocyte antigen (HLA) DR and DQ genotypes on chromosome 6. The HLA locus confers around 50% of the genetic potential. The ‘second hit’ comes from exposure to one or more environmental triggers, which initiates ß-cell destruction. Proposed triggers include enterovirus, coxsackie⁴ and early exposure to cow’s milk protein, cereals or gluten.^5-7 Vitamin D deficiency in early life has been shown to impair insulin synthesis and therefore may be involved in the pathogenesis of both forms of diabetes, with notably the highest rates of T1DM worldwide seen in northern European countries (with poor sunlight and subsequent low vitamin D as potential theories to explain this).⁸

Epidemiology

The incidence of T1DM is rising at an estimated rate of 3-5% per year.⁸ This rise has been most dramatic in the pre-school age group.^9-10 There is huge geographical variation in incidence, with rates in the UK 30 times higher, and in Finland 100 times higher, than those in China.¹¹ Swedish data collected between 1978-1997 demonstrated a clear shift to a younger age at diagnosis with the steepest yearly increase in annual incidence also occurring in the pre-school group. The peak incidence of diagnosis of T1DM is in adolescence at 10-14 years of age. The prevalence is approx 1:500 adolescents.¹²

Clinical features

In T1DM the classic symptoms of polyuria, polydipsia, nocturia and weight loss are present in 95% of new cases. The rate of diabetic ketoacidosis (DKA) at initial presentation decreases with age. Up to half of infants and toddlers present in DKA, which drops to 12-15% in adolescents.¹³ Younger children tend to have shorter duration of symptoms, a lower HbA1c at diagnosis¹⁴ and higher autoantibody titres, suggesting a more aggressive initial autoimmune insult.¹⁵ Diagnosis is based on the WHO criteria of a fasting plasma glucose ≥ 7.1mmol/l or ≥ 11.1mmol/l unfasted. The ease and availability of blood sugar testing should lead primary care physicians to perform opportunistic testing of patients they may suspect of having diabetes.

Management

The Diabetes Control and Complications Trial (DCCT), followed by the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC), highlighted the importance of tight glycaemic control.^16-17 Improved glycaemic control as reflected by a lower haemoglobin A1c delays the onset or progression of both microvascular and macrovascular complications.^16,17 A reduction in HbA1c of 10% of total (ie. A1c changing from 10 to 9) is associated with a reduction in microvascular risk of 50%. However, there is no HbA1c level below which complications are avoided entirely. In addition, DCCT/EDIC has shown that those patients treated aggressively from diagnosis achieve greater protection from complications than those patients treated with a more conventional approach and has prompted the theory of ‘metabolic memory’. Therefore, intensive management should in ideal circumstances be initiated from diagnosis.¹⁴

The management of diabetes poses difficult problems at the extremes of childhood with toddlers and adolescents often being the most difficult groups to care for. Hypoglycaemia is a great cause of worry for all parents of children with diabetes but especially for parents of infants and toddlers, with severe hypoglycaemia having potentially adverse effects on cognitive function. Toddlers and pre-school children are often very sensitive to small insulin doses while food refusal and the regular childhood infections can impact on management. Hypoglycaemia occurs up to three times more in those patients with tighter glycaemic control (DCCT). Therefore the risk of hypoglycaemia, coupled with unpredictability in food intake in this group, has led some to believe that a higher HbA1c of 7.5-8.5% is acceptable.¹⁹ There is now an increasing focus on insulin pump therapy as being the most physiological and safe method of insulin administration in the young child.

Adolescence often heralds a deterioration in HbA1c. This deterioration is caused by a combination of physical and psychological factors. Puberty results in a doubling in the daily insulin requirement. Then, usually by the early 20s, insulin requirements fall again, often to prepubertal levels.²⁰ The shift from parental dependence to independence is frequently studded with conflict and risk-taking behaviour. Some reports suggest that up to half of teenagers can go through a period of non-compliance with their diabetes management ranging from not checking their blood sugar to omitting insulin to achieve weight loss.²¹ Furthermore, depression and eating disorders are more prevalent in teenagers with T1DM. Ideally, the adolescent with diabetes should be managed in a separate adolescent clinic where problems specific to their needs can be addressed.²² Transition clinics run by a paediatrician with an adult physician should be then provided to achieve a smooth transition to the adult services.

A potential cure for diabetes remains the ideal. Novel technologies such as islet stem cell transplantation are still in their infancy, with 80% of recipients showing a return to insulin dependence within five years of transplantation. Insulin pump therapy currently provides the most physiological method of insulin administration with numerous studies demonstrating the benefits of this approach in terms of both better glycaemic control and quality of life. The ‘closed loop’, where an insulin pump communicates directly with an in-dwelling continuous glucose sensor, is still in its evolution and being applied currently in research centres but is a promising potential advance in diabetes care.

Type 2 diabetes 

Prevalence increasing

Type 2 diabetes mellitus (T2DM) is characterised by hyperglycaemia, insulin resistance and relative impairment in insulin secretion. It is recognised as a global epidemic by the WHO. T2DM, in contrast to childhood diabetes, is 10 times more prevalent than T1DM in adults and is associated with the obesity epidemic. Today, it is estimated that at least 140,000 adults in the Republic of Ireland (4.7%) have diabetes and this is predicted to rise to at least 190,000 or 5.6 % of the population by 2015.²³ This increase will have a cost implication in both personal and societal terms. It is estimated that around 10% of healthcare spending in Ireland is on diabetes care. That figure is projected to rise to almost 25% by 2040. Life expectancy is reduced by up to seven years in adults with T2DM and they are five times more likely to require hospital admission than non-diabetic patients, with the significantly raised morbidity and mortality statistics particularly relating to cardiovascular disease, but other complications include retinopathy, kidney failure and peripheral vascular disease.²³ From a paediatric perspective, figures emerging from the US show that 20% of newly diagnosed diabetic teenagers are type 2 and that figure is set to rise to over half by 2020.²⁴

Management

The management of T2DM differs from T1DM in the first instance with exercise and dietary approaches being initially instituted. Oral hypoglycaemic agents are the next line with metformin, sulphonylureas and thiazolidinediones being considered. Newer therapies include GLP-1 agonists, which act to increase insulin secretion from the pancreas. Insulin therapy evidently remains an option for those patients whose metabolic control remains sub-optimal with the initial measures.

Other considerations in relation to screening for T2DM (who, when and how?) as well as prevention of T2DM (how?) are questions to be addressed at a national and international medico-political level  

Other rarer forms of diabetes include maturity onset diabetes of the young (MODY) which accounts for 15% of non-type 1 diabetes.²⁷ This diagnosis should be considered in non-obese patients with diabetes developing before the age of 25 with a strong history of diabetes on one side of the family.²⁶

Rarer still is diabetes associated with disorders such as cystic fibrosis or syndromes like Wolfram syndrome or Bardet-Biedl syndrome. Iatrogenic diabetes as a result of prolonged use of high-dose steroids, after bone marrow transplantation or repeated transfusions in conditions such as thalassaemia, should be remembered if managing this cohort of patients.

Conclusion

Prevalence of both T1DM and T2DM is rising. Although T1DM is not preventable, the slow year-on-year rise must be considered when planning for future healthcare services. T2DM and obesity, on the other hand, should be viewed as a preventable epidemic and urgent action to tackle this needs to be taken at all levels of society. 

References

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