254-OR: Islet Autoimmunity Is Highly Prevalent and Associated with Diminished Beta-Cell Function in Patients with Type 2 Diabetes (T2D) in the GRADE Study
Authors: BROOKS-WORRELL BARBARA , HAMPE CHRISTIANE S. , GONZALEZ ERICA V. , PALOMINO BRENDA M. , ZANGENEH SAHAR Z. , UTZSCHNEIDER KRISTINA , KAHN STEVEN E. , LARKIN MARY E. , JOHNSON MARY L. , MATHER KIEREN J. , YOUNES NAJI , RASOULI NEDA , DESOUZA CYRUS , COHEN ROBERT M. , PARK JEAN Y. , FLOREZ HERMES , VALENCIA WILLY MARCOS ,   GRADE BETA CELL ANCILLARY STUDY NETWORK, SHOJAIE ALI , PALMER JERRY P. , BALASUBRAMANYAM ASHOK ,   GRADE RESEARCH GROUP
Published: June 2020

We hypothesized that islet autoimmunity, hitherto considered the pathophysiologic basis of type 1 diabetes (T1D) and latent autoimmune diabetes of adults (LADA), could contribute to ß cell dysfunction in patients with type 2 diabetes (T2D). To evaluate this question, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study - Beta Cell Ancillary Study Network measured humoral islet autoimmunity (autoantibodies against 65 kDa glutamic acid decarboxylase (GAD65-Ab), islet autoantigen-2 (IA2-Ab) and zinc transporter-8 (ZnT8-Ab)) in 392 participants (age 57.2 ± 10.1 y; BMI 33.5 ± 6.2 kg/m2; diabetes duration 4.0 ± 3.0 y; HbA1c 7.5 ± 0.5 %; on metformin as the sole glucose-lowering medication), and cellular islet autoimmunity (T cell autoreactivity against a broad range of islet antigens) in 322 of the same participants. 41.4% had evidence of cellular islet autoimmunity and 13.5% had evidence of humoral islet autoimmunity, but only 5.4% had both. T cell autoreactivity to islet antigens, but not autoantibody-positivity, was associated with diminished ß cell function, as assessed by the ratio of incremental area under the curve (iAUC) of C-peptide to iAUC of glucose during 0-120 min of an OGTT (ß = -0.1403; se = 0.0612; p = 0.0219) or ∆C-peptide/∆glucose during 0-30 min of an OGTT (ß = -0.2113; se = 0.0728; p = 0.0037), adjusted for insulin sensitivity. T cell positive participants also had higher fasting plasma glucose (p = 0.045) and HbA1c (p = 0.001) than T cell negative participants. These findings indicate that islet autoimmunity in T2D patients is far more prevalent than previously recognized; T cell mediated islet autoimmunity is associated with diminished ß cell function.

Disclosure
B. Brooks-Worrell: None. C.S. Hampe: None. E.V. Gonzalez: None. B.M. Palomino: None. S.Z. Zangeneh: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. M.E. Larkin: None. M.L. Johnson: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, JDRF, Lilly Diabetes, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. N. Younes: None. N. Rasouli: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., Novo Nordisk Inc. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb. J.Y. Park: None. H. Florez: None. W. Valencia: None. A. Shojaie: None. J.P. Palmer: None. A. Balasubramanyam: None.

Funding
National Institutes of Health (R01DK104832, U01DK098246)