Covid-19 Infection and New Onset Type 1 Diabetes

Background

Although recognized as an autoimmune disease, the etiology of type 1 diabetes mellitus (T1D)
remains undetermined. One dominant hypothesis is that a recent virus infection elicits or
enhances an autoimmune reaction, resulting in CD4+ and CD8+ T-cells recognizing pancreatic
antigens and subsequently targeting the beta-cells of the pancreas. This results in a gradual
but irreversible loss of beta-cell function.

Various enterovirus species have been suspected as causative factors of T1D. However, many
different viruses may carry the potential to induce T1D via one of the above-mentioned
mechanisms, including respiratory infections.

Most people are presently immunologically inert to SARS-Cov-2, but a large proportion of the
world's population is expected to be infected over the next few years, with the global focus
having now shifted to slowing the spread (1). The pandemic of COVID-19 therefore provides an
opportunity to study a possible correlation between a novel type of virus infection and the
development of T1D.

Aim

Our overall aim is to study the impact of Covid-19 on the incidence and the phenotype
(beta-cell function at time of diagnosis and at follow up) of newly diagnosed adult patients
with T1D in a multicenter study, with enrolments to occur in both Denmark and Portugal.

Method

The following study populations are established over a two-year period, beginning in October
2020:

1. Study population 1: Newly diagnosed adult patients with T1D according to usual practice,
stratified for the presence of SARS-Cov-2-antibodies (+/-), in both Denmark and
Portugal.

2. Study population 2: A control population of the same age (+/- 3 years) and sex from each
participant country, potentially from the national blood banks. This will provide the
SARS-Cov-2 status of the background population. Each newly diagnosed T1D patient is
matched with five control persons.

Study 1: Clinical study: Study 1:

Inclusion criteria:

- T1D patients diagnosed according to standard practice (including Hba1c, C-peptide,
presence of GAD (or islet-cell) antibodies).

- Patient is attending a hospital unit in Denmark or Portugal, due to T1D.

- Age 18 years or above.

Exclusion criteria:

- Severe psychiatric disorder or other conditions deemed to impair the patient's informed
consent and participation in the study.

In each country, all subjects from study population 1 will undergo the following assessments
at diagnosis of T1D:

1. SARS-Cov-2 antibody measurement.

2. GAD-antibodies (and if necessary islet cell antibodies (IA-2)).

3. HbA1c, fasting blood glucose and fasting C-peptide.

4. Mixed-meal tolerance test (MMTT).

5. Follow-up one year after the diagnosis with HbA1c, fasting blood glucose, fasting
C-peptide and MMTT.

Study 2: Epidemiological study 1: In each country, the incidence of SARS-Covid-2 antibodies
in study group 1 is compared to the matched control group (Study population 2).

Study 3: Epidemiological study 2: Independently of the above mentioned study, the incidence
of newly diagnosed T1D patients in each participant country will be determined by registry
data from January 1st 2020 on a monthly basis and compared with newly diagnosed T1D patients
from the two previous years (2018 and 2019).

Outcomes

The study will have the following outcomes

Study 1 (clinical study):

Primary outcome: C-peptide AUC of the MMTT at baseline and one year follow-up, for adult T1D
patients having SARS-Cov-2 positive vs. negative antibody status.

Secondary outcomes: Fasting glucose, C-peptide, Hba1c at baseline and one year follow-up, for
adult T1D patients having SARS-Cov-2 positive vs. negative antibody status.

Study 2 (epidemiological study 1):

Outcome: Proportion of T1D patients having SARS-Cov-2 antibodies, compared to matched
controls from the background population, potentially from the national blood banks (1:5 match
on age, gender and if possible country region).

Study 3 (epidemiological study 2):

Outcome: Annual and monthly T1D incidence (cases/100.000) during 2020-2022, compared to 2018
and 2019 in Denmark and Portugal.