Natural history

Type 1 diabetes has two natural histories, corresponding to the period before and after diagnosis. The first or pre-hyperglycaemic phase is clinically silent, and has only been recognised since about 1980. During this phase, evidence of anti-islet immunity appears and is followed by evidence of deteriorating beta cell function, culminating in frank hyperglycaemia. The second or hyperglycaemic phase represents the traditional 'natural history', i.e. the course and outcome of the condition following diagnosis. This has changed over time, from early death in the pre-insulin era to a progressively longer and healthier life, such that children with access to good quality care now have a life expectancy of 50 years or more. This having been said, children still die for lack of insulin in some of the world's poorest countries, and disabling early complications are still seen in those who do not manage to achieve good control of glucose and other risk factors. This article outlines the natural history of the hyperglycaemic phase of type 1 diabetes.

The pre-insulin era

Childhood onset diabetes was rare – or at least, rarely diagnosed – in the pre-insulin era. Elliot Joslin collected such cases, despaired of by other physicians, and reported in 1917[1] that of 59 who developed diabetes before the age of 10, 38 had died within an average of 1.4 years. Their prognosis had however improved with a low carbohydrate ('Eskimo') diet. Death was from starvation, tuberculosis or diabetic coma.

Lack of access to insulin in the world's poorest countries is still, in 2012, the commonest cause of death in a child with diabetes.[2]

A child on the starvation regime, before and after insulin
A child on the starvation regime, before and after insulin
Joslin himself termed the period from 1898 to 1914 the Naunyn era, after the famous German physician, and the period from 1914 to 1922 the Allen era in honour of the undernutrition treatment which kept children alive, but at a terrible price. The period from 1922 to 1935 was named for Banting and Best, and the period after 1935 for Hagedorn, the Danish physician who introduced the first long-acting insulin. Each saw a steady prolongation of life for young patients on insulin.

The prognosis on insulin

Insulin was like a cure for cancer. Physicians such as Joslin soon learned that diabetic coma, previously fatal, could not only be treated with insulin with great success, but also prevented by appropriate education of families and their physicians. Tuberculosis became much less of a threat once children were properly nourished. Beyond this point, the future of children with diabetes was unknown. Joslin's 1935 medal pictured them as 'Explorers of Unknown Seas'. Sadly, it emerged in the 1930s that they were at risk of the delayed complications of diabetes: kidney disease, eye problems and premature heart disease. As a result, only one person in two who started insulin before the age of 20 would live to see their 55th birthday.[3]

The major cause of premature death was diabetic nephropathy. This irreversible condition is heralded by the appearance of protein in the urine, but its prevalence in early-onset type 1 diabetes fell steadily in the second half of the century. A Swedish study, for example, showed that 30.3% of children diagnosed from 1961 to 1965 developed nephropathy within 25 years, compared with 8.2% in the 1966–1970 cohort, with indications that subsequent cohorts are doing better still.[4] These encouraging results have been replicated in other centres of excellence, but it seems likely that children receiving standard or sub-standard care elsewhere may still be exposed to historical rates of complications.[5]

The observation that between a quarter and a third of children with diabetes developed nephropathy within 20 years or so of diagnosis, whereas the remainder never did,2 prompted the suggestion that the difference was mediated by a nephropathy risk gene or genes, but genes with a sufficiently potent effect have not been identified after intensive search.

The risk of proteinuria in the first 15–25 years of diabetes continues to fall, probably as the result of improved glucose control plus the impact of screening for microalbuminuria and treating those at risk with ACE inhibitors. It is possible that the effect of such treatment may have been to delay rather than prevent kidney disease, but diabetic kidney disease currently seems to be a largely avoidable complication.

Heart disease

One consequence of the diminishing risk of diabetic nephropathy has been the emergence of premature cardiovascular disease in the young diabetic population. This is now the leading cause of excess mortality in those over the age of 30 years.[6] The prevalence of early markers of arterial disease, such as intima–media thickness, is high in children and adolescents with type 1 diabetes, and more intensive screening and intervention for this complication may well be justified.[7]

Factors associated with long-term survival

Although the treatment of diabetes is directed towards ensuring a long and healthy life, relatively little is known about the factors associated with long-term survival. It has always intrigued physicians that some patients develop disabling complications within a few years of onset, whereas others survive with relative health for 70 years or more. In general, long-term survival with diabetes is associated with better-than average glucose control, but psychosocial factors also play an important role. Social disadvantage correlates well with poor glucose control and poor outcomes,[8] for example, whereas long-term survivors are noted for their ability to take control of their own lives.

Another striking feature of long-term survivors is that as a group they are lean, and have low blood pressure, high HDL-cholesterol and relatively low insulin requirements; in other words they present a negative image of the 'metabolic syndrome'.[9] They also tend to have long-lived parents, suggesting a genetic component to their longevity. More detailed studies suggest that their freedom from vascular disease may also be associated with their ability to process advanced products of glycation (AGE).[10]

Looking forwards

The past 90 years have seen a remarkable increase in the life expectancy of young people with type 1 diabetes. Joslin awarded a 10-year medal in 1931, a 25-year medal in 1948 and a 50-year medal in 1970; there are now awards for 70-year survivors. Children starting on insulin today may reasonably expect to live for more than 50 years, yet will also, on average, live 10–20 years less than their non-diabetic contemporaries. Long life with diabetes still has to be fought for and won; it can never be taken for granted.

References

  1. ^ Joslin EP. The Treatment of Diabetes Mellitus, with Observations upon 1300 cases. Lea and Febiger, Philadelphia, 1917

  2. ^ Gale EAM. Dying of diabetes. Lancet 2006;368:1626–7

  3. ^ Deckert T, Poulsen JE, Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty - I. Survival, causes of death, and complications. Diabetologia 1978;14:363–70

  4. ^ Nordwall M et al. Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population with type 1 diabetes—the Linköping Diabetes Complications Study. Diabetologia 2004;14:1266–72

  5. ^ Gale EAM. Type 1 diabetes in the the harvest of sorrow goes on. Diabetologia 2005;48:1435–8

  6. ^ Laing SP et al. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia 2003;46:760–5

  7. ^ Dahl-Jørgensen K et al. Atherosclerosis in childhood and adolescent type 1 diabetes. Early disease, early treatment? Diabetologia 2005;48:1445–53

  8. ^ Muhlhauser I et al. Social status and the quality of care for adult people with type 1 diabetes. Diabetologia 1998;41:1139–50

  9. ^ Gale EAM. How to survive diabetes. Diabetologia 2009;52:559–67

  10. ^ Sun JK et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme the Joslin 50-year medalist study. Diabetes Care 2011;34:968–74

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