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ketoacidosis other than autoimmunity. Acute infections such as the coronavirus infectious disease of 2019
[48]
(COVID-19) have been shown to increase the risk of type 2 diabetes . It remains to be proven whether
these viral infections might precipitate acute or subacute forms of type 1 diabetes [49-51] .

Our immune system is tightly regulated to control viral infections and suppress cancer growth while
avoiding host damage. In developing areas with endemic viral infections, chronic activation of the immune
system may lead to immunological tolerance. The latter can contribute to the low prevalence of
autoimmune disease but a high prevalence of chronic viral infection and cancer in these areas. Immune
checkpoint inhibitor (ICI) increases the activity of cytotoxic T cells of the host to kill cancer cells, but may
activate the autoimmune process and cause type 1 diabetes and other endocrine dysfunction [52,53] . Given the
[54]
increasing trend of young-onset cancer and the use of immune-modulating treatment, physicians should
[55]
be aware of these atypical forms of ICI-associated type 1 diabetes .
Latent autoimmune diabetes in adults
A subacute form of type 1 diabetes, often referred to as LADA, can be missed or undiagnosed, especially in
adult patients with obesity or slow disease progression. The availability of many oral glucose-lowering drugs
can inadvertently delay insulin treatment. Given the legacy effect of early glycemic control on increasing
glycemic durability [56,57] and reducing long-term complications [58-60] in both type 1 and type 2 diabetes,
misdiagnosis of LADA should be avoided.

In patients with type 2 diabetes, the presence of one anti-islet autoantibody, for example, glutamic acid
decarboxylase antibodies (GADA), and that against IA2 and ZnT8 can be use used to diagnose LADA.
There is no agreed cut-off age for diagnosing LADA, although some experts proposed an age below 35.
There is a need to standardize the assays of these autoantibodies. The suboptimal quality of these assays
hinders the interpretation of low titers with uncertain significance. Additionally, many reports related to the
diagnosis and treatment of LADA were of low quality in terms of study design, definitions, and
methodologies. That said, the prevalence of LADA appeared to range from 3% to 12% in patients with type
2 diabetes, in whom high titers of antibodies predicted early insulin requirement . Although titers of these
[61]
autoantibodies tend to decline after diagnosis, GADA could be detected up to 8 years after initial diagnosis.
Patients with LADA tended to have an earlier age of diagnosis and lower BMI and were highly responsive to
insulin treatment compared to their counterparts without LADA. In patients with LADA and residual beta-
cell function, the use of sulphonylureas (SU) might hasten, while that of dipeptidyl peptidase 4 inhibitor
(DPP4i) might slow the decline in beta-cell function . These findings underlie the need to assess beta-cell
[62]
function and autoimmunity, especially in lean patients with type 2 diabetes, to avoid misclassification and
inappropriate treatment.

MATURITY ONSET DIABETES OF THE YOUNG AND MONOGENIC DIABETES
[63]
The 90% concordance rates for type 2 diabetes amongst monozygotic twins and the 3- to 9-fold increased
lifetime risk of diabetes amongst family members of affected individuals supported its strong genetic
component [64-66] . Monogenic diabetes is caused by a single gene mutation and maturity onset diabetes of the
young (MODY) is the most common form of monogenic diabetes. Traditionally, MODY is characterized by
absence of obesity, presentation before the age of 25 years, strong family history suggestive of autosomal
dominant inheritance, absence of β-cell autoimmunity, and sustained pancreatic β-cell function. However,
many patients with MODY had older age of diagnosis with considerable phenotypic heterogeneity. This
complexity calls for more phenotypic and multiomic analysis in family-based cohorts to test for
cosegregation of genetic variants amongst affected family members .
[67]