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.