Contribution of Retrotransposons to the Pathogenesis of Type 1 Diabetes and Challenges in Analysis Methods.

Type 1 diabetes (T1D) is one of the most common chronic diseases of the endocrine system, associated with several life-threatening comorbidities. While the etiopathogenesis of T1D remains elusive, a combination of genetic susceptibility and environmental factors, such as microbial infections, are thought to be involved in the development of the disease. The prime model for studying the genetic component of T1D predisposition encompasses polymorphisms within the HLA (human leukocyte antigen) region responsible for the specificity of antigen presentation to lymphocytes. Apart from polymorphisms, genomic reorganization caused by repeat elements and endogenous viral elements (EVEs) might be involved in T1D predisposition. Such elements are human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, including long and short interspersed nuclear elements (LINEs and SINEs). In line with their parasitic origin and selfish behaviour, retrotransposon-imposed gene regulation is a major source of genetic variation and instability in the human genome, and may represent the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. Autoreactive immune cell subtypes with differentially expressed retrotransposons can be identified with single-cell transcriptomics, and personalized assembled genomes can be constructed, which can then serve as a reference for predicting retrotransposon integration/restriction sites. Here we review what is known to date about retrotransposons, we discuss the involvement of viruses and retrotransposons in T1D predisposition, and finally we consider challenges in retrotransposons analysis methods.

Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries.

BACKGROUND: An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic. METHODS: For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker. FINDINGS: 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27·3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1·6% (95% CI 1·3 to 1·9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39·4% (95% CI 34·0 to 45·6) in 2020 and 38·9% (33·6 to 45·0) in 2021, significantly higher than the predicted prevalence of 32·5% (27·8 to 37·9) for 2020 and 33·0% (28·3 to 38·5) for 2021 (p<0·0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1·037 (95% CI 1·024 to 1·051; p<0·0001) per ten-unit increase in the Stringency Index for 2020 and 1·028 (1·009 to 1·047; p=0·0033) for 2021, but was not significantly associated with excess all-cause mortality. INTERPRETATION: During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents. FUNDING: German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.

Telemedicine and COVID-19 pandemic: The perfect storm to mark a change in diabetes care. Results from a world-wide cross-sectional web-based survey.

BACKGROUND: Telemedicine for routine care of people with diabetes (PwD) during the COVID-19 pandemic rapidly increased in many countries, helping to address the several barriers usually seen. OBJECTIVE: This study aimed to describe healthcare professionals' (HCPs) experience on telemedicine use in diabetes care and investigate the changes and challenges associated with its implementation. METHODS: A cross-sectional electronic survey was distributed through the global network of JENIOUS members of ISPAD. Respondents' professional and practice profiles, clinic sizes, their country of practice, and data regarding local telemedicine practices during COVID-19 pandemic were investigated. RESULTS: Answers from 209 HCPs from 33 countries were analyzed. During the pandemic, the proportion of PwD receiving telemedicine visits increased from <10% (65.1% of responders) to >50% (66.5%). There was an increase in specific privacy requirements for remote visits (37.3% to 75.6%), data protection policies (42.6% to 74.2%) and reimbursement for remote care (from 41.1% to 76.6%). Overall, 83.3% HCPs reported to be satisfied with the use of telemedicine. Some concerns (17.5%) about the complexity and heterogeneity of the digital platforms to be managed in everyday practice remain, feeding the need for unifying and making interoperable the tools for remote care. Also, 45.5% of professionals reported to feel stressed by the need for extra-time for telemedicine consultations. CONCLUSIONS: Telemedicine was rapidly and broadly adopted during the pandemic globally. Some issues related to its use were promptly addressed by local institutions. Challenges with the use of different platforms and for the need of extra-time still remain to be solved.

A Worldwide Perspective on COVID-19 and Diabetes Management in 22,820 Children from the SWEET Project: Diabetic Ketoacidosis Rates Increase and Glycemic Control Is Maintained.

Aims: To investigate the short-term effects of the first wave of COVID-19 on clinical parameters in children with type 1 diabetes (T1D) from 82 worldwide centers participating in the Better Control in Pediatric and Adolescent DiabeteS: Working to CrEate CEnTers of Reference (SWEET) registry. Materials and Methods: Aggregated data per person with T1D ≤21 years of age were compared between May/June 2020 (first wave), August/September 2020 (after wave), and the same periods in 2019. Hierarchic linear and logistic regression models were applied. Models were adjusted for gender, age-, and diabetes duration-groups. To distinguish the added burden of the COVID-19 pandemic, the centers were divided into quartiles of first wave COVID-19-associated mortality in their country. Results: In May/June 2019 and 2020, respectively, there were 16,735 versus 12,157 persons, 52% versus 52% male, median age 13.4 (Q1; Q3: 10.1; 16.2) versus13.5 (10.2; 16.2) years, T1D duration 4.5 (2.1; 7.8) versus 4.5 (2.0; 7.8) years, and hemoglobin A1c (HbA1c) 60.7 (53.0; 73.8) versus 59.6 (50.8; 70.5) mmol/mol [7.8 (7.0; 8.9) versus 7.6 (6.8; 8.6) %]. Across all country quartiles of COVID-19 mortality, HbA1c and rate of severe hypoglycemia remained comparable to the year before the first wave, while diabetic ketoacidosis rates increased significantly in the centers from countries with the highest mortality rate, but returned to baseline after the wave. Continuous glucose monitoring use decreased slightly during the first wave (53% vs. 51%) and increased significantly thereafter (55% vs. 63%, P < 0.001). Conclusions: Although glycemic control was maintained, a significant rise in DKA at follow-up was seen during first wave in the quartile of countries with the highest COVID mortality. Trial Registration: NCT04427189.