Clinical use of thiazolidinediones consistently results in reduced plasma insulin levels and reduced insulin requirements in patients with type 2 diabetes taking insulin, reflecting an increase in insulin sensitivity. Although these agents do not directly stimulate P-cell insulin secretion, studies indicate that they can restore aspects of defective glucose-coupled insulin responsiveness in humans and animals with type 2 diabetes.
There are several potential mechanisms whereby thiazolidinediones might enhance P-cell function, in addition to simply lowering ambient levels of glycemia and reducing "glucotoxic" signaling abnormalities in P-cells. Recently, abnormal P-cell secretory responsiveness and potential cell death (apoptosis) have been attributed to chronic effects of accumulated triglycerides and FFA derivatives in the pancreatic islet cells in obesity with insulin resistance, a phenomenon that has been dubbed "lipotoxicity" [12,13]. This hypothesis also postulates that the effect of thiazolidinediones to redistribute fat stores in the body, including from the pancreatic islets, and to reduce circulating levels of FFA, may improve P-cell function . In diabetes-prone, obese rodents, pre-clinical data has shown a potent effect of thiazolidinediones to restore P-cell insulin content and preventing loss of P-cell mass in models of type 2 diabetes [12,15,16].
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