Positive islet autoantibodies confirm classical type 1 diabetes in patients treated as type 2 diabetes who have early progression to insulin

Objective: Early progression to insulin following initial management as type 2 diabetes may indicate missed type 1 diabetes. Recent guidelines advise islet-autoantibody testing in all adults who progress to insulin within 3 years, though this has not been directly tested. We aimed to determine whether positive islet autoantibodies in this setting confirm the genetic characteristics and C-peptide progression of classical type 1 diabetes. Research Design and Methods: We compared genetic susceptibility to type 1 and type 2 diabetes (T1DGRS and T2DGRS) and prospectively assessed C-peptide loss over 3 years after diagnosis among islet-autoantibody-positive adults initially treated as having type 2 diabetes (without insulin) who progressed to insulin within 3 years (n=86), versus participants with classical type 1 (n=499) and type 2 (n=603) diabetes. Results were replicated in cross-sectional data from the DARE/GoDARTS studies (n=9466). Results: Participants who progressed to insulin within 3 years and had positive islet autoantibodies had the genetic characteristics and C-peptide loss of classical type 1 diabetes: T1DGRS -0.04 (-0.27, 0.18) vs 0.00 (-0.09, 0.09) [p=0.71], T2DGRS -0.35 (-0.59, -0.11) vs -0.35 (-0.44, -0.26) [p=0.99] and annual change in urine C-peptide creatinine ratio -47% (-55%, -40%) vs -49% (-52%, -46%) [p=0.6] respectively. In contrast, autoantibody-positive participants without early insulin (n=51) had genetic and C-peptide characteristics consistent with type 2 diabetes. Findings were similar in cross-sectional cohorts. Conclusion: Islet-autoantibody-positive individuals with early insulin requirement following initial treatment as type 2 diabetes have similar genotype and progression to classical type 1 diabetes. This supports recent guidance that they should be diagnosed and treated as type 1 diabetes.