AUTHOR=Brooks-Worrell Barbara M. , Tjaden Ashley H. , Edelstein Sharon L. , Palomino Brenda , Utzschneider Kristina M. , Arslanian Silva , Mather Kieren J. , Buchanan Thomas A. , Nadeau Kristen J. , Atkinson Karen , Barengolts Elena , Kahn Steven E. , Palmer Jerry P. , The RISE Consortium , Ehrmann David A. , Temple Karla A. , Rue Abby , Barengolts Elena , Mokhlesi Babak , Van Cauter Eve , Sam Susan , Miller M. Annette , Kahn Steven E. , Atkinson Karen M. , Palmer Jerry P. , Utzschneider Kristina M. , Gebremedhin Tsige , Kernan-Schloss Abigail , Kozedub Alexandra , Montgomery Brenda K. , Morse Emily J. , Mather Kieren J. , Garrett Tammy , Hannon Tamara S. , Lteif Amale , Patel Aniket , Chisholm Robin , Moore Karen , Pirics Vivian , Pratt Linda , Nadeau Kristen J. , Gross Susan , Zeitler Philip S. , Williams Jayne , Cree-Green Melanie , Reyes Yesenia Garcia , Vissat Krista , Arslanian Silva A. , Brown Kathleen , Guerra Nancy , Porter Kristin , Caprio Sonia , Savoye Mary , Pierpont Bridget , Buchanan Thomas A. , Xiang Anny H. , Trigo Enrique , Beale Elizabeth , Chow Ting , Hendee Fadi N. , Katkhouda Namir , Nayak Krishan , Martinez Mayra , Montgomery Cortney , Wang Xinhui , Wu Jun , Edelstein Sharon L. , Lachin John M. , Tjaden Ashley Hogan , Tripputi Mark T. , Marcovina Santica , Harting Jessica , Albers John , Hill Dave , Savage Peter J. , Leschek Ellen W. TITLE=Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.640251 DOI=10.3389/fimmu.2021.640251 ISSN=1664-3224 ABSTRACT=

The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(−) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(−) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(−), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(−) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(−) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.