‘dysglycaemia’. Both the presence of impaired fasting glucose or glucose intolerance (see Chap 3) following a 75g OGTT and a 20% increase in baseline HbA1c have a positive predictive value (PPV) of 98% for symptomatic type 1 diabetes within 5 years in prospective studies in high risk individuals, and it is known that the first phase insulin response to intravenous glucose declines rapidly 18–6 months before diabetes symptoms. Stage 3 is the development of symptomatic diabetes.
Prevention Trials
This staging has helped in the design of clinical prevention trials. Early studies focused on antigen specific (by early exposure to intravenous or oral insulin), or immunosuppressive approaches. Neither proved to be successful, partly because of the difficulty in recruiting patients at a potentially reversible stage of their disease. The most successful study used an anti‐CD3 antibody which decreased the actions of CD8 T lymphocytes on target β cells. Teplizumab was given for 14 days in a randomised controlled trial to 76 high risk (Stage 2) individuals. The intervention delayed the diagnosis of type 1 diabetes by a median of 24 months and was well tolerated, although there was a significant reactivation of EB virus disease in those with evidence of previous infection. This proof of concept trial will likely lead to further studies of this and other agents, and several are ongoing.
Screening for Type 1 Diabetes
The improvement in assays for islet autoantibodies and the development of genetic prediction models has raised the possibility of population screening for individuals at high type 1 diabetes susceptibility. The problem is that the numbers needed to be screened to identify a single case are prohibitive (Figure 6.10) and the absence of an effective treatment means that conventional criteria for screening are not fully satisfied. The TrialNet and other research programmes aims to recruit first degree relatives of probands with type 1 diabetes and as our understanding of heritability develops, the argument for more widespread but focused screening may become stronger.
Figure 6.9 Stages of Type 1 Diabetes as proposed by the Juvenile Diabetes Research Foundation, Endocrine Society and American Diabetes Association and adopted by TrialNet for preventative studies. Autoantibodies are present many years prior to development of symptomatic diabetes (Stage 3). Prior to this those in Stage 1 have normal glucose tolerance and those in Stage 2 varying levels of hyperglycaemia below the diagnostic thresholds of diabetes. Intervention and prevention studies have largely focused on Stage 2 and 3 patients.
Reproduced from Insel RA et al. Diabetes Care 2015; 38: 1964–74 with permission.
Figure 6.10 Lifetime risk of developing Type 1 diabetes (left axis) compared to prevalence of risk in the overall population (right axis). Individuals in the apex have the highest risk of developing diabetes (>75% within 5y) but represent 0.01% (1 in 10,000) of the overall population.
From Dayan CM et al Lancet 2019 with permission.
CASE HISTORY
A 4‐year‐old boy whose mother has had type 1 diabetes since age 13 years developed thirst, polyuria, hyperphagia, and weight loss shortly after recovering from a head cold. His mother tested his capillary blood glucose with her own meter and found it to be 25.3 mmol/L. His birth weight was 4.1 kg and he was bottle fed with cow’s milk from birth.
Comment: This case illustrates several cardinal features of type 1 diabetes. A positive family history, age of onset <5 years, symptoms beginning after a minor infection, and early exposure to cow’s milk. Birth weight >4 kg is linked to type 2 diabetes in some populations.
LANDMARK STUDY
The Barts–Windsor study was the first prospective family study in type 1 diabetes and was created by the fortuitous collaboration between Andrew Cudworth (then at St Bartholomew’s Hospital) and John Lister who was the diabetologist in Windsor and who kept a file index of all new cases of type 1 diabetes that he had seen in the district. Around 200 families with a proband with type 1 diabetes and an unaffected sibling were identified and serum collected from as many family members as possible. The findings contributed to what Edwin Gale termed a paradigm shift in the thinking around the aetiology of type diabetes (see 2001 reference below for masterful description). The original objective was to detect the viral culprit for type 1 diabetes. Instead, they confirmed the autoimmune basis of the disease; the clinically silent but immunologically active stage in individuals who had islet cell and GAD autoantibodies years before developing diabetes; and the causative links with some HLA antigens and the protective nature of others. Sadly, Andrew died just as the study was producing its most impressive results, but it remains a fine example of how happenchance and clinical diligence can combine to change our thinking about disease in fundamental ways.
KEY WEBSITES
Diabetes Atlas: www.diabetesatlas.org
www.Trialnet.com International network of scientists and clinicians exploring cause and treatment of type 1 diabetes
FURTHER READING
1 Craig ME, Nair S, Stein H et al. Viruses and diabetes: a new look at an old story. Pediatr Diabetes 2013; 14: 149–58.
2 Dayan CM, Korah M, Tatovic D et al. Changing the landscape for type 1 diabetes: the first step to prevention. Lancet 2019; dx.doi.org/10.1016/S0140–6736919032127–0
3 Gale EAM. The discovery of type 1 diabetes. Diabetes 2001; 50:217–226.
4 Gomez–Taurino I, Arif S, Eichmann M, Peakman M. T cells in type 1 diabetes: instructors, regulators and effectors: a comprehensive review. J Autoimmunity 2016; 66: 7–16.
5 Insel RA, Dunne JL, Atkinson MA et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015; 38: 1964–74 doi:10.2337/dc15‐1419
6 International Diabetes Federation. Diabetes Atlas, 9th edn. Brussels: International Diabetes Federation, 2019.
7 Laugsen E, Ostergaard JA, Leslie RDG. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabetic Medicine 2015; 32: 843–52 doi:10.1111/dme.12700
8 Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G and the EURODIAB Study Group. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 2009; 373: 2027–2033.
9 Patterson CC, Harjutsalo V, Rosenbauer J et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study. Diabetologia 2019; 62: 408–17 doi.org/10.1007/s00125‐018‐4763‐3
10 Redondo MJ, Steck AK, Pugliese A. Genetics of type 1 diabetes. Pediatr Diabetes 2018; 19: 346–53.
11 Stiemsa LT, Reynolds LA, Turvey SE, Finlay BB. The hygiene hypothesis: current perspectives and future therapies.