Diagnosis and Phenotypes of Idiopathic Diabetes: A Systematic Review.

Objective: Diabetes classification includes various forms, primarily type 1 and type 2, along with atypical types like type-1b diabetes (T1bD), which lack classic autoimmune markers or high-risk human leukocyte antigen (HLA) alleles, presenting diagnostic challenges and suggesting alternative pathogenic mechanisms. This review explores the potential genetic basis of these cases and the need for comprehensive testing.

Methods: Seventeen studies, including case reports, cross-sectional, and cohort studies, were analyzed from PubMed, Web of Science, and Scopus databases up to March 14, 2024, covering 290 T1bD cases.

Results: The cases were reclassified using the American Diabetes Association's criteria (autoantibody-negative, onset <35 years old, nonobese, and not HLA-associated). Genetic testing results were reviewed, focusing on identified mutations. Reclassification identified 201 T1bD cases, of which 30% of autoantibody-negative T1bD cases had pathogenic variants linked to monogenic diabetes, such as maturity-onset diabetes of the young, and mutations in INS, KCNJ11, and KLF1 genes linked to neonatal diabetes. Only 60 T1bD cases underwent exome sequencing, and none had whole genome sequencing, indicating limited genetic exploration.

Conclusion: A significant proportion of T1bD cases may have an undetermined genetic basis, emphasizing the need for more comprehensive diagnostic assessments. Increased use of advanced genetic screening, such as whole genome sequencing, and data sharing are vital for improving diagnosis and management, potentially enabling personalized treatment for idiopathic diabetes.