Endocrine Abstracts

Islet autoantibodies are strong predictors of type 1 diabetes (T1D), as positivity for multiple, i.e.is two or more, autoantibodies is associated with a risk of around 70% of progression to clinical disease over the next 10 years. Autoantibodies do not, however, predict when T1D will present clinically. We have assessed the utility of signs of dysglycemia for the prediction of the time of disease manifestation and observed that an increase in HbA1c of 10% over 3–12 months provides a 50% likelihood of disease presentation within 1.1 year after the observed increase. When the HbA1c value was 5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years. The median time to diagnosis after the detection of impaired glucose tolerance on OGTT was 0.7 years. After the detection of an increased random plasma glucose (≥7.8 mmol/l) the median time to diagnosis was 1.0 years. The omics technologies have raised the issue, whether there is a possibility to identify high risk individuals before the appearance of the first autoantibodies. We have looked at markers generated by transcriptomics. We observed that genes and pathways related to innate immunity functions, such as the type 1 interferon (IFN) response, were active, and IFN response factors were identified as central mediators of the IFN-related transcriptional changes. In a proteomics study we found that when including the total observation time from birth to diagnosis we were able to classify the participants into disease progressors and non-progressors with a success rate of 91%. The classifica-tion was based on the combination of the relative levels of APOC4 (decreased) and afamin (AFAM, increased). Lipidomics and metabolomics analyses showed that individuals who developed T1D had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. Another study focusing on the lipidome/metabolome in cord blood revealed that those children, who progressed quickly to clinical T1D, were characterized by a distinct cord blood lipidomic profile that includes reduced major choline containing phospholipids, including sphingomyelins and phosphatidylcholines. Risk children, who progress to clinical T1D are characterized by a decreased microbial diversity, an increased abundance of potentially pathogenic bacteria and a reduced functional gene content in their intestinal microbiome. These changes, can however, not be seen before seroconversion to autoantibody positivity. To summarize, metabolic markers help in the estimation of time to diagnosis in prediabetic individuals. The potential predictive markers generated by omics technologies have to be validated.