We have read with great interest the Review by Maria J. Redondo and Noel G. Morgan (Redondo, M.J., Morgan, N.G. Heterogeneity and endotypes in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 19, 542–554 (2023))1. The authors propose a new concept to clarify the intrinsically unique pathological processes in the heterogenous atypical endotype of type 1 diabetes mellitus (T1DE2) and to explore specific approaches for prediction, prevention and treatment. T1DE2 is sometimes assumed to be a mix of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) because a proportion of people with insulin-independent diabetes mellitus have islet autoantibodies, a marker of T1DM, as well as obesity and insulin resistance, markers of T2DM1. However, systematic data on pathobiological findings in pancreas tissue from people with T1DE2 are rarely reported, but there are some systematic studies on the endotype of typical type 1 diabetes mellitus (T1DE1)2,3.

To make the concept of T1DE2 clearer, we present the distinct pathobiological findings of an atypical form of T1DM, slowly progressive insulin-dependent diabetes mellitus (SPIDDM)4,5,6,7, as cited in the article1. SPIDDM onset predominantly occurs during adolescence or adulthood, and β-cell function usually decreases gradually until reaching the insulin-dependent stage4,5. In our study, people with SPIDDM had no history of obesity (defined as BMI >30.0 kg m−2) (refs. 6,7). Most people with SPIDDM had T1DM-susceptible HLA-DR and HLA-DQ haplotypes4,6.

The most predominant features of SPIDDM examined by in situ hybridization and immuno-histochemical methods indicate persistent enterovirus infection in the islet cells as well as in exocrine acinar cells7. Persistent enterovirus infection over decades in typical T1DM is not reported2,3. In addition, innate immune responses including melanoma associated protein 5 (MDA5), innate immune receptor and IFNβ1 expression gradually decreased with the duration of SPIDDM7. The suppressed innate immunity in SPIDDM was histologically related to the cleavage of MDA5 and IFNβ1 in islet cells by protease 2 (2Apro) (ref. 7). 2Apro is encoded by enteroviruses to cleave the enterovirus-preprotein to enable the assembly of the virus envelope protein8. 2Apro potentially has proteolytic activity and could therefore damage neighbouring β-cells7. 2Apro activity in coxsackie virus B3-induced chronic cardiomyopathy was reported to have a causative role on the cleavage and/or damage of cardiomyocyte dystrophin-glycoprotein complex9.

The inflammation of islets in SPIDDM is less aggressive than in typical T1DM, probably due to a weakened innate immune response. This weakened innate immunity can be seen in the low numbers of infiltrating CD8+ T cells in the pancreatic islets and the weak chemokine expression and MHC class I hyperexpression on β-cells in SPIDDM6,7, sharply contrasting with the aggressive attack of CD8+ T cells and cytopathic effects on β-cells observed in fulminant T1DM10. We could not find islet amylin polypeptide (IAPP)-positive amyloid deposition in the residual islet β-cells in SPIDDM6, a marker of T2DM.

In summary, SPIDDM is strongly associated with persistent enterovirus infection that disables innate immunity through the MDA5–IFNβ1 axis and is associated with autoimmunity and T1DM-asssociated HLA haplotypes4,6. Association was not found with T2DM in our study; people with SPIDDM had no islet IAPP-amyloid deposition6. Our findings will contribute to the clarification of the T1DE2 endotype proposed by Redondo and Morgan1.

There is a reply to this letter by Redondo, M. and Morgan, N. G. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-024-00977-x (2024).