A substantial proportion of patients diagnosed with idiopathic type 1b diabetes may have underlying monogenic forms of the disease that remain unrecognized due to limited diagnostic testing, according to a new systematic review of global studies.
Investigators found that 30% of patients with autoantibody-negative diabetes had mutations linked to genetic subtypes such as maturity-onset diabetes of the young (MODY), neonatal diabetes, and syndromic forms like Wolfram and H syndrome.
The review analyzed 17 studies involving 290 idiopathic type 1b diabetes (T1bD) cases. Applying American Diabetes Association (ADA) criteria—diabetes onset before age 35, absence of diabetes-associated autoantibodies, non-obese phenotype, and lack of high-risk HLA genotypes—201 patients were classified as true T1bD. Among these, 87 carried pathogenic variants in genes commonly associated with monogenic diabetes.
Despite these findings, comprehensive genetic screening was rarely performed. Only 60 patients underwent whole-exome sequencing (WES), and none received whole-genome sequencing (WGS), which could have identified a broader range of genetic mutations. Investigators concluded that many idiopathic cases may be misclassified due to these limitations.
Pathogenic variants were found in several key genes, including INS, KCNJ11, KLF11, HNF1A, and WFS1. Most mutation-positive cases were MODY (~57%), followed by INS gene variants (~13%), and syndromic forms (~9%). Inheritance patterns were occasionally documented, though many mutations appeared to be de novo.
Among the 174 patients ultimately classified as idiopathic T1bD without confirmed genetic or autoimmune markers, the average age at diagnosis was 8 years. Most were of Asian descent—primarily Chinese, Japanese, Indian, or Taiwanese—and about one-third presented with diabetic ketoacidosis. Nearly all required lifelong insulin therapy.
C-peptide levels, which reflect endogenous insulin production, were low in most insulin-treated patients, consistent with insulin deficiency. However, the absence of autoimmune markers remained unexplained in many cases. The study noted that limited antibody panels and delayed seroconversion in younger patients could lead to false-negative results. Some cases also had HLA genotypes typically associated with autoimmune diabetes, further complicating classification.
The findings underscore the complexity and heterogeneity of idiopathic diabetes. The authors highlighted inconsistencies across studies in antibody testing and genetic screening protocols, which likely contributed to diagnostic inaccuracies.
They called for broader adoption of WES and WGS—particularly in pediatric patients with atypical diabetes presentations—and emphasized the need for collaborative genomic data sharing to improve variant classification and disease management.
Refining the classification of idiopathic cases could reduce unnecessary insulin use, facilitate appropriate treatment strategies, and help families understand potential inherited risks. Expanding access to advanced genetic testing, the authors argued, may be key to unlocking the true etiology of many so-called idiopathic diabetes cases.
The authors reported no conflicts of interest.
Source: Endocrine Practice