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Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium¹ Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda 20891, MD, USA

(Correspondence should be addressed to J-C Henquin; Email: jean-claude.henquin{at}uclouvain.be)

Islet antigen-2 (IA-2 or ICA 512) and IA-2β (or phogrin) are major autoantigens in type 1 diabetes. They are located in dense core secretory vesicles including insulin granules, but their role in β-cell function is unclear. Targeted disruption of either IA-2 or IA-2β, or both, impaired glucose tolerance, an effect attributed to diminution of insulin secretion. In this study, we therefore characterized the dynamic changes in cytosolic Ca²⁺([Ca²⁺]_c) and insulin secretion in islets from IA-2/IA-2β double knockout (KO) mice. High glucose (15 mM) induced biphasic insulin secretion in IA-2/IA-2β KO islets, with a similar first phase and smaller second phase compared with controls. Since the insulin content of IA-2/IA-2β KO islets was 45% less than that of controls, fractional insulin secretion (relative to content) was thus increased during first phase and unaffected during second phase. This peculiar response occurred in spite of a slightly smaller rise in [Ca²⁺]_c, could not be attributed to an alteration of glucose metabolism (NADPH fluorescence) and also was observed with tolbutamide. The dual control of insulin secretion via the K_ATP channel-dependent triggering pathway and K_ATP channel-independent amplifying pathway was unaltered in IA-2/IA-2β KO islets, and so were the potentiations by acetylcholine or cAMP (forskolin). Intriguingly, amino acids, in particular the cationic arginine and lysine, induced larger fractional insulin secretion in IA-2/IA-2β KO than control islets. In conclusion, IA-2 and IA-2β are dispensable for exocytosis of insulin granules, but are probably more important for cargo loading and/or stability of dense core vesicles.