DIABETES

          Type I diabetes is associated with the loss of insulin-producing islet cells of the pancreas, primarily via targeting and destruction by the immune system. Type II diabetes is typically characterized by normal insulin production by pancreatic islet cells but an increase in insulin resistance resulting in elevated blood glucose levels. Several reports confirm the ability of TUDCA to improve the hyperglycemia associated with both types of diabetes. It has been shown that high glucose levels cause ER stress and defective autophagy, which facilitate podocyte injury in the glomerulus.TUDCA inhibited the defective autophagy and prevented podocyte injury. Adipocyte autophagy was suppressed in an insulin resistant mouse model, and this resulted in both increased inflammation and ER stress. Treatment with TUDCA reduced the ER stress and inflammation, but the suppression of autophagy was not entirely reversed.

          Acinar cells are another important factor in diabetes and pancreatitis. Acinar cells in the pancreas are exocrine glands that are signalled to secrete their hormones and substances by cholecystokinin (CCK) signalling. When rat acinar cells were stimulated with CCK-8 and TUDCA, there was increased amylase secretion and 50% reduction in activation of trypsin, a molecule that hydrolyzes proteins. TUDCA treatment resulted in increased chaperone binding, reduced ER stress, and stabilization of the UPR in a model of acute pancreatitis.

         The incubation of free fatty acids with β cells has been shown to initiate type II diabetes. Reduction of ER stress by administration of TUDCA significantly reduced the effects of the free fatty acids on the β CELLS. Type I diabetes is characterized by the death and dysfunction of pancreatic β-cells, and deficits in the expression of UPR mediators activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1). Mice with type I diabetes and exhibiting deficits in ATF6 and XBP1 expression were treated with TUDCA in the pre-diabetic stage. With treatment, they exhibited restored expression of ATF6 and XBP1, reduced infiltration of immune cells in the pancreas, decreased β-cell apoptosis, and preserved insulin secretion.

          ER stress also contributes to insulin insensitivity. In vivo tissues were tested with TUDCA and insulin sensitivity increased 30%. TUDCA also restored impaired islets and insulin secretion by reduc- ing ER stress. TUDCA in pig islets also increased ATP content, which is beneficial for islet protection after transplantation. ER stress also activates protein tyro- sine phosphatase 1B (PTP1B), which lowers insulin sig- naling, and TUDCA administration was found to lower expression of PTP1B. Together, these studies demonstrate the pleiotropic effects of TUDCA on correcting deficits associated with type I and II diabetes.