PATHOGENESIS OF DIABETES MELLITUS

设计了一个模型来研究溶酶体和非溶酶体加工 胰岛素的分泌。 尝试描绘非溶酶体途径 将被制造。 一种新的检测胰岛素分泌的方法 MVB中所含的蛋白质将用于确定血细胞增多症在 胰岛素加工 两个或多个通路在受体中的作用 回收也将进行评估。 我们将研究一些影响， 影响胰岛素加工的因素。 这些因素包括各种 能量燃料到激素和抗糖尿病药物。 诱导的效果 受体后缺陷和糖尿病状态也将进行测试， 对胰岛素加工的影响。 该提案的第二部分涉及研究一种医源性原因， 胰岛素抵抗--胰岛素抗体 使用血浆置换法的研究将 以确定抗体在胰岛素抵抗中的作用 在胰岛素依赖型糖尿病患者中观察到。 体内和体外研究将 以确定胰岛素抗体饱和度对 清除抗体。 此外，肝脏和肝细胞的作用 将研究Fc受体对抗体清除的影响。 抗独特 抗体（胰岛素抗体）将在 胰岛素治疗的糖尿病患者的血浆。 如果存在， 将研究这些抗体在体外系统上的作用， 抗体抑制胰岛素与受体的结合 胰岛素样作用。

A model has been designed to study lysosomal and non-lysosomal processing of insulin by hepatocytes. Attempts to delineate the non-lysosomal pathway will be made. A novel technique to assess emiocytosis of the insulin contained in MVB is to be used to determine the role of emiocytosis in insulin processing. The role of the two or more pathways in receptor recycling will also be assessed. We will examine the effect of a number of factors on processing of insulin. These factors range from a variety of energy fuels to hormones and anti-diabetic drugs. The effect of induced post-receptor defect and diabetic states will also be tested for their effect on insulin processing. A second part of the proposal involves a study of an iatrogenic cause of insulin resistance--insulin antibodies. Studies using plasmapheresis will be performed to determine the role of antibodies in the insulin resistance observed in insulin dependent diabetics. In vivo and in vitro studies will be performed to determine the effect of saturation of insulin antibodies on clearance of antibody. In addition, the role of the liver and hepatocyte Fc receptors on antibody clearance will be studied. Anti-idiotypic antibodies (antibodies to insulin antibodies) will be searched for in plasma of insulin treated diabetic patients. If present, the effect of these antibodies on in vitro systems will be studied to determine if the antibodies inhibit insulin binding to the receptor as well as exhibit insulin-like effects.