Adult-onset type 1 diabetes: early detection, differential diagnosis, and emerging disease-modifying therapies

Adult-onset type 1 diabetes (T1D) likely exceeds childhood-onset in absolute numbers, yet many cases are underestimated due to misclassification as type 2 diabetes. This pragmatic review synthesizes current evidence on epidemiology, pathophysiology, diagnosis, and early disease-modifying therapy in adults. Incidence data from 32 countries indicate that adults account for a median 42% of new T1D diagnoses. Autoimmunity follows the pediatric, HLA-restricted paradigm, but β-cell dysfunction appears slower, reflected by measurable C-peptide for years. Misdiagnosis delays insulin initiation, increases ketoacidosis risk, and forfeits opportunities for β-cell-sparing interventions. We present a four-step diagnostic algorithm integrating an islet autoantibody panel with a fasting or random C-peptide-to-glucose ratio, and highlight red-flag scenarios warranting repeat testing. We also propose a hypothetical, risk-enriched four-step pathway to identify presymptomatic T1D in adults that begins with a higher HbA1c trigger, uses enrichment to raise pretest probability, and reserves full autoantibody testing for high-probability individuals. Given low prevalence and false-positive risk, this pathway needs prospective validation before routine care. We review adult and adolescent evidence for targeted immunomodulators, including teplizumab, abatacept, rituximab, low-dose anti-thymocyte globulin, ustekinumab, golimumab, baricitinib and alefacept, as well as β-cell-directed agents such as verapamil and imatinib, and discuss emerging HLA- and autoantibody-defined endotypes that may predict response. Collectively, current evidence supports routine autoimmune diabetes screening in adults with new-onset diabetes.