2130-LB: Novel Insulin Gene Variants in Antibody-Negative Adult-Onset Diabetes

Introduction and Objective: Insulin gene (INS) variants are a rare cause of monogenic diabetes, with clinical presentations including (1) permanent or transient neonatal diabetes and (2) adolescent or adult-onset diabetes sometimes referred to as maturity onset diabetes of the young (INS-MODY/MODY10). Here we report four previously undescribed INS variants in individuals with atypical adult-onset diabetes. Methods: Four rare (0-3 copies in gnomAD v.4.1) INS variants were characterized in Rare and Atypical Diabetes Network (RADIANT) study participants as well as a RADIANT investigator’s clinical patient. Selected variants were studied in vitro for splicing in INS-1 cells and/or trafficking in Min6/HEK293T cells. Results: Three variants predicted to alter proinsulin sequence were identified in three index cases and the daughter of one index case. All were nonobese and diagnosed with antibody-negative diabetes in their 20s and 30s (current HbA1c range 5.3% on lifestyle alone, to 7.8% on insulin). A fourth variant was found in the non-RADIANT patient, who was diagnosed with diabetes in her 50s (lean, antibody-negative, current HbA1c 6.7% on insulin). The variants were: a proximal intronic variant c.188-11C>A with in vitro functional evidence that enlarges the C-peptide region by three amino acids and impairs proinsulin secretion; a missense variant (p.P25S) that blocks proinsulin secretion in vitro; and two frameshift variants (p.A74Efs*57 and p.L86Rfs*36) lacking the insulin A-chain. Conclusion: This case series contributes to the growing literature on the role of rare heterozygous INS variants in adult-onset diabetes. We describe three variants that structurally alter mature insulin and one of the first reports of a proinsulin C-peptide-altering variant that does not generate an extra cysteine or create a frameshift, yet disrupts proinsulin trafficking. The identification of greater numbers of cases with INS variants will help clarify severity and penetrance of diabetes. Disclosure D. Broome: Research Support; Fractyl Health, Inc., Sanofi, T1D Exchange, Rhythm Pharmaceuticals, Inc, Novo Nordisk. K.A. Maloney: None. S.W. Greeley: Advisory Panel; Sanofi. S. Park: None. E.D. Szmuilowicz: None. L.K. Billings: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Sanofi. Consultant; Dexcom, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc. Consultant; Xeris Pharmaceuticals, Inc. Advisory Panel; Amgen Inc. Consultant; Pfizer Inc. L.H. Philipson: Other Relationship; Novo Nordisk, Dompé, Diasome Pharmaceuticals, Vertex Pharmaceuticals Incorporated. Consultant; Amylyx. Other Relationship; Bayer Pharmaceuticals, Inc, Provention Bio, Inc, Provention Bio, Inc, Microbion, Microbion. S.E. Kahn: Advisory Panel; Amgen Inc, AltPep, Biomea Fusion. Research Support; Corcept Therapeutics. Advisory Panel; Eli Lilly and Company, Merck & Co., Inc. Consultant; Neurimmune. Advisory Panel; Novo Nordisk, Oramed Pharmaceuticals. P. Arvan: None. N. Rasouli: Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. T.I. Pollin: None. Funding NIH (U54 DK118612)