INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes.

BACKGROUND: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. METHODS: In this context, we have developed a Master Protocol, based on the "backbone" of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. DISCUSSION: The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

COVID-19, Hyperglycemia, and New-Onset Diabetes.

Certain chronic comorbidities, including diabetes, are highly prevalent in people with coronavirus disease 2019 (COVID-19) and are associated with an increased risk of severe COVID-19 and mortality. Mild glucose elevations are also common in COVID-19 patients and associated with worse outcomes even in people without diabetes. Several studies have recently reported new-onset diabetes associated with COVID-19. The phenomenon of new-onset diabetes following admission to the hospital has been observed previously with other viral infections and acute illnesses. The precise mechanisms for new-onset diabetes in people with COVID-19 are not known, but it is likely that a number of complex interrelated processes are involved, including previously undiagnosed diabetes, stress hyperglycemia, steroid-induced hyperglycemia, and direct or indirect effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the ß-cell. There is an urgent need for research to help guide management pathways for these patients. In view of increased mortality in people with new-onset diabetes, hospital protocols should include efforts to recognize and manage acute hyperglycemia, including diabetic ketoacidosis, in people admitted to the hospital. Whether new-onset diabetes is likely to remain permanent is not known, as the long-term follow-up of these patients is limited. Prospective studies of metabolism in the setting of postacute COVID-19 will be required to understand the etiology, prognosis, and treatment opportunities.

SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic ß-Cells and in the Human Pancreas Microvasculature.

Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2) is a necessary step for SARS-CoV-2 infection permissiveness. In light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyze ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies. Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing ß-cells. ACE2 is also highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human ß-cells. Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increase ACE2 expression in the ß-cell line EndoC-ßH1 and in primary human pancreatic islets. Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct ß-cell virus tropism.

Women with Mild Fasting Hyperglycemia in Early Pregnancy Have More Neonatal Intensive Care Admissions.

AIMS: To determine impact of mild fasting hyperglycemia in early pregnancy (fasting plasma glucose [FPG] 5.1-5.5 mmol/L) on pregnancy outcomes. METHODS: We measured FPG at 11.9 ± 1.8 weeks in 2006 women from a prospective cohort study. Women with FPG ≥5.6 mmol/L (19) received treatment and were excluded from further analyses. A total of 1838 women with FPG <5.6 mmol/L received a 75 g oral glucose tolerance test (OGTT) between 24 and 28 weeks of pregnancy. RESULTS: Of all participants, 78 (4.2%) had FPG 5.1 to 5.5 mmol/L in early pregnancy, of which 49 had a normal OGTT later in pregnancy (high fasting normal glucose tolerance [NGT] group). Compared with the NGT group with FPG <5.1 mmol/L in early pregnancy (low fasting NGT group, n = 1560), the high fasting NGT group had a higher body mass index (BMI), higher insulin resistance with more impaired insulin secretion and higher FPG and 30 minute glucose levels on the OGTT. The admission rate to neonatal intensive care unit (NICU) was significantly higher in the high fasting NGT group than in the low fasting NGT group (20.4% [10] vs 9.3% [143], P = .009), with no difference in duration (7.0 ± 8.6 vs 8.4 ± 14.3 days, P = .849) or indication for NICU admission between both groups. The admission rate to NICU remained significantly higher (odds ratio 2.47; 95% confidence interval 1.18-5.19, P = .017) after adjustment for age, BMI, and glucose levels at the OGTT. CONCLUSIONS: When provision of an OGTT is limited such as in the Covid-19 pandemic, using FPG in early pregnancy could be an easy alternative to determine who is at increased risk for adverse pregnancy outcomes.