g(m2)-ganglioside and Diabetes-Mellitus--Type-1

Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of insulin-producing pancreatic beta-cells that takes place in genetically prodisposed individuals. Autoantibodies and autoreactive T lymphocytes reacting with islet target molecules or protein of glycolipid nature have been shown in the circulation of individuals and of animal models of type 1 diabetes (NOD mouse and BB rat) before and at the onset of the disease. As far as autoantigens of glycolipid nature is concerned, gangliosides such as GT3, GD3 and especially GM-1, have been shown to be target of autoantibodies associated to autoimmune diabetes. Of particular interest is the islet-specific monosialo-ganglioside GM2-1, which is target of an autoimmune response highly associated to future progression to diabetes development in first degree relatives of type 1 diabetic individuals. This molecule is recognized by IgG autoantibodies which have been detected before the appearance if clinical diabetes both in man and in the NOD mouse, representing a novel marker of beta-cell autoimmunity.

Topics: Animals; Diabetes Mellitus, Type 1; Female; G(M2) Ganglioside; Gangliosides; Humans; Islets of Langerhans; Male; Mice; Pancreas; Pregnancy; Rats

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 beta-cell specific, and 2) its intracellular localization. To this end, we analyzed the pattern of ganglioside expression in highly purified beta- and non-beta-cells isolated from rat islets. In addition, ganglioside levels were determined in subcellular fractions of a rat beta-cell line (INS). No qualitative or quantitative difference was found in the pattern of ganglioside expression between beta and non-beta 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 beta-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.

Topics: Animals; Autoantigens; Cytoplasmic Granules; Diabetes Mellitus, Type 1; G(M2) Ganglioside; Islets of Langerhans; Male; Rats; Rats, Sprague-Dawley

Recently, the GM2-1 pancreatic islet ganglioside, proposed as a potential autoantigen in type I diabetes autoimmunity, has been biochemically characterized and found to be a novel ganglioside structure. In the present study, we aimed to determine whether an autoimmune response toward this novel islet molecule is 1) present in type I diabetes and is specifically directed against this molecule and not to gangliosides in general and 2) predictive of disease in high-risk subjects. To this end, the following patients have been studied: 1) 24 newly diagnosed type I diabetic subjects, 20 islet cell autoantibody (ICA)-negative first-degree relatives of type I diabetic subjects, and 25 age-matched normal control individuals; and 2) 31 prospectively evaluated ICA+ first-degree relatives of type I diabetic subjects who were followed for up to 10 years, during which 14 of them developed type I diabetes. A direct assay for autoantibodies to GM2-1 and to other pancreatic gangliosides (GM3, GD3, GD1a) was developed using an indirect immunoperoxidase technique performed directly on thin layer chromatography plates. Anti-GM2-1 autoantibodies (all belonging to the IgG class) were expressed in a high percentage of newly diagnosed type I diabetic subjects (71%), while no significant difference was found in the expression of antibodies directed against other pancreatic gangliosides (GM3, GD3, GD1a) among the different groups studied. Anti-GM2-1 autoantibodies were also present in ICA+ relatives (64%) (P < 0.001 vs. control subjects and ICA-relatives): in this group, life table analysis of progression to diabetes showed that anti-GM2-1 autoantibodies were significantly (P < 0.001) associated with disease, occurring in all relatives developing type I diabetes within 5 years and thus identifying a cohort of ICA+ subjects with markedly increased diabetes risk.

Topics: Autoantibodies; Autoantigens; Autoimmunity; Diabetes Mellitus, Type 1; Family; G(M2) Ganglioside; Gangliosides; Humans; Islets of Langerhans; Prediabetic State; Reference Values