Rosiglitazone Inhibits Early Stage of Glucolipotoxicity-Induced Beta-Cell Apoptosis

Abstract

Aim: We investigated whether rosiglitazone protects β-cells from glucolipotoxicity directly. Methods: INS-1 cells were incubated with 25 mM glucose and 0.5 mM palmitate in the absence or presence of 2.5 µM rosiglitazone. We evaluated caspase-3 expression and nuclear DAPI staining. An in vivo study was performed, in which 18-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were treated with rosiglitazone (4 mg/kg/day, n = 6) and with placebo (n = 6) for 10 weeks. At 28 weeks of age, an oral glucose tolerance test, insulin sensitivity test, TUNEL assay and histologic examination were performed. Results: Rosiglitazone attenuated glucolipotoxicity-induced nuclear change and caspase-3 expression for 8 h after treatment, but this effect was not observed at 12 h in INS-1 cells. Rosiglitazone treatment decreased β-cell apoptosis, preserved β-cell mass and improved glucose tolerance in OLETF rats. Conclusion: The present in vitro findings suggest that rosiglitazone can inhibit the early stage of glucolipotoxicity-induced β-cell apoptosis. Our results suggest that the antidiabetic action of rosiglitazone is, at least in part, related to a direct effect on β-cells rather than simply an indirect effect of improving insulin sensitivity.

Both sitagliptin analogue & pioglitazone preserve the β-cell proportion in the islets with different mechanism in non-obese and obese diabetic mice

“…This may be a consequence of unresolved hyperglycemic excursion or a characteristic difference specifically inherent to the db/db mouse itself. In this study, islet mass did not increase after administration of either SITA or PIO in either model, which is inconsistent with the results of other studies (7,18,31).We suggest that the 4-6-week treatment period used in this study was not sufficiently long for the β-cell mass to be altered significantly in either animal model. Moreover, the β-cell mass at any specific time should not be viewed as an accurate reflection of the actual β-cell reservoir, since islet cells retain their plasticity via a dynamic mechanism involving regeneration, proliferation, and apoptosis (32)(33)(34).…”

Minireview: Meeting the Demand for Insulin: Molecular Mechanisms of Adaptive Postnatal ß-Cell Mass Expansion

“…Recent work has shown that Foxo1 mediates ER stress-and fatty acidinduced ß-cell death in vitro (115). Additionally, PPAR␥ agonism by the thiazolidinedione rosiglitazone decreases islet amyloid polypeptide-induced apoptosis in cultured human islets and enhances ß-cell mass in the OLETF rat model of type 2 diabetes (116,117). Given the critical role of apoptosis in ß-cell failure during the progression to type 2 diabetes and our increasing understanding of the mechanisms underlying this loss of ß-cells, therapeutic strategies to enhance ß-cell survival are likely to be fruitful in improving the course of the disease.…”

Safety and efficacy of rosiglitazone in the elderly diabetic patient

“…The free fatty acid storage in adipose tissue as opposed to liver and skeletal most likely exerts a protective effect on these tissues. In addition, advantageous effects on the beta cells of the pancreas may occur by inhibiting glucolipotoxicity 26. Taken together, the mechanisms of action are complex and multifold and the many effects of TZDs in various tissues make it impossible to define all the exact mechanisms underlying their insulin-sensitizing effects in vivo in humans 9…”