Prediction of Type 1A Diabetes:
The Natural History of the Prediabetic Period
George S. Eisenbarth
Predictive Factors in Relatives
Prediction in the General Population
Prediction/Diagnosis in Adults
Stage in Life Initiation
Are there Abnormalities that Precede Autoantibodies?
Are Beta Cells Destroyed in a Progressive/Linear Fashion?
The importance of understanding the natural history of immune mediated pre-diabetes1-3 lies in the development of prevention strategies4-6. Several initial randomized clinical intervention trials have concluded and the next generation of such trials will rely upon improved and simplified identification of individuals7 who are at high risk of progression to diabetes8. This is essential to ensure that trials will have sufficient statistical power to detect a given effect of the intervention (if it exists) within the time available for the study. Such understanding is also needed to avoid exposing those who will not develop diabetes to the risk of adverse effects of the intervention. In addition, it is likely that many interventions will be more effective if given early, with more extant beta cells. In addition there is accumulating evidence that at the onset of type 1A diabetes, and in a subset of patients years after the onset of diabetes (Figure 11.1) there remains islet beta cells9, and preservation of even low levels of insulin secretion has multiple benefits in terms of improved glycemic control and prevention of complications10-14.
The amount of beta cell destruction at the onset of diabetes remains an open question15-20 with one estimate that a 40% reduction in beta cell mass is sufficient for diabetes of a 20 year old while 80-90% loss may be required for children presenting with diabetes less than age 521. Given individual differences in rates of progression to diabetes and insulin resistance (as well as potential function per beta cell), it is likely that the variance of beta cell loss will be large at any age. It is of interest that the slope of loss of c-peptide after diabetes onset decreased modestly from the immediate prediabetic phase22. This may reflect “synchronization” with greater rate of loss associated with presentation with diabetes. With long-term type 1 diabetes the mean beta cell loss is dramatic(Figure 10.1).
Figure 11.1. Area of insulin containing cells in long-term patients with diabetes 23.
First-degree relatives of individuals with type 1A diabetes have an approximate 5% risk of developing the disease (independent of country 24) while children without a relative with diabetes in the United States have a risk of 1/300 while in Japan the risk is less than 1/3,000. Longitudinal studies of autoantibody-positive relatives and more recently general populations25, 26 have provided a wealth of information on the natural history of autoimmunity during the pre-hyperglycemic phase of the disease (prediabetes). These studies have established the predictive value of age27, islet cell antibodies (ICAs)28, multiple “biochemical” autoantibodies 29-32 first phase insulin release (FPIR)33, impaired glucose tolerance, C-peptide secretion (Prediction”Scores”) 34, and human leukocyte (HLA) haplotypes35. Increasingly, combinations of markers are being used to better define the risk of diabetes 36-40 Prediction is not absolute, but can be expressed as the percentage of individuals developing diabetes within a given time period. In addition the age at which islet autoantibodies first appear and levels of insulin autoantibodies (not antibodies reacting with GAD, IA-2 or ZnT8) predict approximate age of onset of type 1 diabetes25, 26. This chapter will review predictive factors currently in use and discuss some of the unanswered questions on the natural history of Type 1A (immune mediated) prediabetes.
Predictive Factors in Relatives
The first large
scale studies of the prediction of type 1A diabetes relied upon the detection
of cytoplasmic islet cell autoantibodies (
coworkers reported on the
Bart's-Windsor family study, conducted in
Data from the Joslin Diabetes Center family study indicate that impaired FPIR (First Phase Insulin Release, usually analyzed as the sum of insulin at 1 and 3 minutes following a bolus of intravenous glucose) is an additional risk factor33. Thirty-five first-degree relatives with high-titer ICAs (> 40 JDF units) underwent serial intravenous glucose tolerance testing (IVGTT). The age of the subjects ranged from 2.6 to 66 years, the mean follow-up was 3.6 years from the first test, and 18 progressed to overt diabetes. The FPIR was calculated as the sum of the 1- and 3-minute insulin levels after a standard bolus of intravenous glucose (0.5 g per kg body weight, infused as a 20%-25% solution over 2 to 4 minutes). Percentiles for the FPIR were determined in 225 healthy, non-obese, control subjects. Even in control subjects the FPIR showed wide within-subject variation (discussed in detail below). Nevertheless, relatives with an initial FPIR below the first percentile (48 mU/l) had significantly reduced diabetes-free survival. Importantly, the presence of FPIR below the first percentile did not signify that diabetes was already present47-50. For most of the relatives, oral glucose tolerance tests (OGTT) were also performed during follow-up to detect asymptomatic diabetes. For the survival analysis the onset of diabetes was defined by a diabetic OGTT or the occurrence of symptomatic hyperglycemia, or whichever came first. A number of recent studies are analyzing impaired fasting glucose, impaired glucose tolerance (2 hour glucose on oral glucose tolerance testing)51, c-peptide secretion52 and potential correlates of insulin resistance (e.g. HOMA-R) and there is evidence of abnormalities preceding diabetes even in the subset of individuals with relatively normal first phase insulin secretion53, 54. The average time from the discovery FPIR below the first percentile to the onset of diabetes was 1.8 years. Sosenko and coworkers for DPT and Trialnet data have developed risk scores that primarily depend on quantitation of glucose tolerance testing. Though there is variability between subsequent tests, in general, as glucose increases risk increases especially in children53, 54.
Updated data from the Joslin family study, with longer follow-up and larger numbers of relatives, have confirmed these findings. Among 79 relatives with high titer ICAs (> 40 JDF units), those with FPIR below the first percentile on the first test had 3-year diabetes-free survival of 13% (95% confidence interval: 0%-30%) compared with a 78% (95% confidence interval: 63%-93%) for the group with higher FPIR55. Studies at the Barbara Davis Center have confirmed the predictive value of FPIR measurements as has studies from the Melbourne family study, studies from Finland 56, and the DPT-1 (Diabetes Prevention Trial) North American study 57 and analysis of the combined ICARUS database58.
Data from the
Joslin study also suggest that IAA add to the prediction of type 1 diabetes,
but with a weaker effect than
identifying ICA subtypes improves the predictive value of ICA can now be put in
the general context of the rule that multiple biochemical autoantibodies are
associated with high risk36. The restricted ICA subtype (reacting with
human and rat islets but not mouse [mouse islets express little or no GAD65]
and with antibody staining restricted to beta cells of rat islets), defined
according to the pattern of sustaining on pancreatic sections, confers a
significantly lower risk of progression to diabetes than a non-restricted
subtype60. Preabsorption of sera with glutamate
decarboxylase (GAD) blocks the ICA staining of restricted ICA-positive sera61 and reduces the ICA staining
of most non-restricted ICA-positive sera62. This suggests that restricted
The ICA assay
is difficult to standardize, is labor intensive, and requires human pancreas36. At the Barbara Davis Center, we utilize a
combination of four assays employing recombinant antigens (insulin
autoantibodies, anti-GAD, anti-ICA512(IA-2) and anti-ZnT8 63) and no longer determine
cytoplasmic ICA. For children the
can also be considered in assessing diabetes risk64-68. Deschamps and coworkers examined the
predictive value of HLA typing in a study of 536 siblings of diabetic probands
in France69. The risk of type 1 diabetes after 8 years,
estimated by life table analysis, was 10% for siblings who were HLA identical
with the probands, 3%-4% for siblings with either DR3 or DR4, and 16% for those
with DR3/DR4. This compares with 56% for
Aly et al Extreme genetic risk for type 1A diabetes67
Figure 11.3 Highest risk siblings in the DAISY study with DR3/4-DQ2/8 genotype progressing to expression of islet autoantibodies (left panel) and diabetes (right panel).
In other studies, molecular typing has revealed that the HLA haplotype DQA1*0102 DQB1*0602 confers strong protection from type 1 diabetes, in a dominant fashion (Chapter 7). In our experience, autoantibody-positive relatives with this haplotype have a very low risk of progression to diabetes71 and usually express only a single autoantibody, namely anti-GAD, although a few also express IAA. Such protection is however not absolute, and approximately 1% of children developing type 1A diabetes72 (versus 20% of the general U.S. population) and 3% of adults with type 1 diabetes have DQB1*0602 (DQB1*0602 is usually part of the haplotype DRB1*1501, DQA1*0102, DQB1*0602). Approximately 5% of older individuals developing type 1 diabetes are reported to have the protective HLA allele DQB1*060273.
In addition to HLA more than 50 loci contribute to risk of type 1 diabetes74. Each locus has a small effect but a report by Winkler and coworkers suggests that combining loci can impact prediction68. We have followed a set of identical triplets and now all three triplets have progressed to diabetes including the last triplet who was non-diabetic in 1983 (Figure 11.4).
Prediction in the General Population
It is likely
that genetic typing will have an even greater impact on assessing diabetes risk
in the general population25, 68, 75, 76. Most studies of prediabetic subjects have
involved the screening of first-degree relatives of diabetic probands, rather
than the general population. However,
less than 10% of new cases of type 1 diabetes have an affected relative, so the
general population will need to be screened eventually if an effective
intervention is to have a major impact.
Screening the general population is likely to be more difficult than
screening relatives. Bayes' theorem
states that a screening test will have a lower positive predictive value in the
general population than in a selected group with a higher prevalence of
disease, such as first-degree relatives.
One approach toward solving this problem is to screen the general
population with markers of genetic susceptibility first, followed by
autoantibody testing of susceptible individuals. For example, among the general
studies performed in Florida suggest that ICA have a predictive value in the
general population similar to that in relatives77. In contrast, studies in
Figure 11.4: Development of autoantibodies and loss of first phase insulin secretion in identical triplets of a patient with type 1A diabetes.
have now been initiated where children are followed from birth for the
development of anti-islet autoantibodies.
The three studies with the longest follow-up are the BabyDiab study from