Markers Predicting Cure With Combinatorial Treatment in a Mouse Model of Latent Autoimmune Diabetes in Adults

Abstract

Diabetes encompasses a range of diseases characterized by chronic hyperglycemia and serious health complications. However, predicting therapeutic response in latent autoimmune diabetes in adults (LADA) remains a major challenge, limiting the development of personalized treatment strategies. LADA is a relatively newly defined diabetes type that shares features of Type 1 diabetes (T1D) and Type 2 diabetes and is estimated to be more prevalent than T1D. We developed a LADA model in NOD mice and assessed combination treatment (CT) comprising GABA, sitagliptin, and omeprazole. Surprisingly, ∼30% of the CT-treated mice completely recovered, exhibiting normoglycemia and insulin independence. We identified two cell-free RNA markers, Adgrb1 and Chd5, that distinguish responders from nonresponders, indicating promising predictive ability. These discoveries offer a potential diagnostic tool for identifying LADA patients who could benefit from CT, representing an advance in personalized diabetes treatment. CT-induced β-cell neogenesis involved replication, providing valuable insights into β-cell regeneration mechanisms. Furthermore, the cured mice exhibited insulitis primarily populated by T regulatory Type 1 cells, potentially suppressing autoimmunity and facilitating β-cell survival and regeneration. This study opens new avenues for targeted LADA therapies and paves the way for precision medicine in diabetes management.

Keywords

β-cell regeneration / autoimmunity / autoimmune diabetes / diabetes cure / T regulatory cells

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