Islet Autoimmunity Is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the GRADE Study

Islet autoimmunity may contribute to beta-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration of 4.0 +/- 3.0 years (HbA(1c) 7.5 +/- 0.5% on metformin alone). We measured T-cell autoreactivity against islet proteins, islet autoantibodies against 65-kDa GAD antigen, IA-2, and zinc transporter-8, and beta-cell function. Cellular islet autoimmunity was present in 41.3%, humoral islet autoimmunity in 13.5%, and both in 5.3%. beta-Cell function calculated as incremental area under the curve of glucose from 0-120 min (iAUC-CG) and Delta C-peptide(0-30)/Delta glucose(0-30) from an oral glucose tolerance test was lower among T-cell-positive (T+) than T-cell-negative (T-) individuals using two different adjustments for insulin sensitivity (iAUC-CG: 13.2% [95% CI 0.3, 24.4] or 11.4% [95% CI 0.4, 21.2] lower; Delta C-peptide[0-30]/Delta glucose[0-30]: 19% [95% CI 3.1, 32.3] or 17.7% [95% CI 2.6, 30.5%] lower). T+ patients had 17% higher HbA(1c) (95% CI 0.07, 0.28) and 7.7 mg/dL higher fasting plasma glucose levels (95% CI 0.2, 15.3) than T- patients. We conclude that islet autoimmunity is much more prevalent in patients with T2D than previously reported. T-cell-mediated autoimmunity is associated with diminished beta-cell function and worse glycemic control.