Glucose Toxicity

Since over time insulin secretion appears to decrease in most patients, it has been proposed that glucose itself is toxic to beta cells. This is in analogy with the situation in the "honeymoon period" in type 1 diabetes subjects: after the initial diagnosis of type 1 diabetes mellitus plasma glucose levels are lowered by injections with exogenous insulin. It has often been observed that dosages of exogenous insulin can be markedly decreased or even omitted during several months. It has been established that residual beta cells of these patients resume their insulin secretory function. Inevitably, in type 1 diabetes this is only a temporary improvement (due to the ongoing autoimmune destruction of remaining beta cells). It may well be that in type 2 diabetes glucose is toxic as well (55). In pancreas beta cells oxidative glucose metabolism will also lead to formation of reactive oxygen species (ROS), which would damage beta cells (Fig. 6). Indeed, beta cells have low amounts of catalase and superoxide dismutase, proteins which normally metabolize the ROS (56). ROS can activate NF-kB activity, which would be proapoptotic. Since it has been observed in an animal model of diabetes that pancreas duodenum homeobox-1 (PDX-1), a regulator of insulin gene transcription, is diminished by hyperglycemia, this could also be a mechanism of "glucose toxicity."

Yet another mechanism may involve upregulation of uncoupling protein 2 (UCP-2) by high glucose that would lead to uncoupling of oxidative glucose metabolism from ATP formation in the mitochondrion leading to lower ATP (57).

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