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The GM2-1 Ganglioside Islet Autoantigen in Insulin-Dependent Diabetes Mellitus Is Expressed in Secretory Granules and Is Not ß-Cell Specific¹

Departments of Endocrinology (F.D., M.P., S.D.) and Experimental Medicine (L.L.) University of Rome "La Sapienza," Rome; the Department of Internal Medicine, University of Messina (M.P., D.C.), Messina; and the Department of Experimental and Clinical Medicine, University of Reggio Calabria (U.D.M.), Catanzaro, Italy; and Laboratoires de Recherche Louis Jeantet, University of Geneva (M.N.-A., P.A.H.), Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Francesco Dotta, c/o Diabetes, Endocrinology Metabolism Foundation, Largo Marchiafava 1, 00161, Rome, Italy.

The pancreatic islet monosialo-ganglioside (GM2-1), an autoantigen in insulin-dependent diabetes mellitus (IDDM) recently shown to be the target of autoantibodies associated with diabetes development in relatives of IDDM patients, is islet specific within the pancreas, and its expression is metabolically regulatable. In the present study we sought to establish 1) whether GM2-1 is ß-cell specific, and 2) its intracellular localization. To this end, we analyzed the pattern of ganglioside expression in highly purified ß- and non-ß-cells isolated from rat islets. In addition, ganglioside levels were determined in subcellular fractions of a rat ß-cell line (INS). No qualitative or quantitative difference was found in the pattern of ganglioside expression between ß and non-ß rat islet cells, with GM3, GM2-1, and GD3 gangliosides expressed in both cell populations. Within INS cells, GM2-1 ganglioside was expressed in the fraction containing secretory granules and, to a lesser extent, in plasma membranes; GM3 was expressed in secretory granules, whereas GD3 was found only in plasma membranes. These data indicate that the GM2-1 autoantigen is not ß-cell specific within the islets, in accordance with the observation that this molecule is a target of islet cell autoantibodies that bind to the whole pancreatic islet. Interestingly, this autoantigen is present in secretory granules similarly to other autoantigens in IDDM (insulin, carboxypeptidase H, 38-kDa protein, etc.), suggesting that the autoimmunity to the components of this organelle may be central to the pathogenesis of the disease.

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