Unfolded protein response is involved in geniposide-regulating glucose-stimulated insulin secretion in INS-1 cells.

The growing evidence shows that in the early stage of type 2 diabetes mellitus (T2DM) development, when challenged by hyperglycemia and/or insulin resistance, pancreatic islets would produce more insulin to maintain the balance of blood sugar, but at the same time, endoplasmic reticulum (ER) stress will be initiated for the reason of over-compensation, which might be a crucial caused factor of dysfunction and death of pancreatic beta cell. In this study, we showed that high glucose induced a remarkably unfolded protein response (UPR) with the phosphorylation of PERK/eIF2α and IRE1α in INS-1 cells, but geniposide prevented the role of high glucose on the phosphorylation of PERK/eIF2α and IRE1α, respectively. Although inhibition of Txnip expression by siRNA had no significant effect on geniposide-regulating UPR, PERK and IRE1α were associated with geniposide-regulating Txnip degradation and glucose-stimulated insulin secretion (GSIS) in high glucose-cultured INS-1 cells. All these data suggest that geniposide might be an important regulator of ER stress and GSIS, and a promising compound for the treatment of T2DM. SIGNIFICANCE OF THE STUDY: Mounting evidence indicates that endoplasmic reticulum (ER) stress plays an essential role to maintain the normal cellular functions and dysfunction. In this study, we revealed that geniposide might be an important regulator of ER stress and glucose-stimulated insulin secretion in pancreatic beta cells.

Hao Y ，Shen S ，Yin F ，Zhang Y ，Liu J ... -  《-》

Geniposide inhibits glucolipotoxicity and cooperates with Txnip knockdown to potentiate cell adaption to endoplasmic reticulum stress in pancreatic beta cells.

Thioredoxin-interacting protein (Txnip), a negative regulator of thioredoxin, has become an attractive therapeutic target to alleviate metabolic diseases. Our previous data demonstrated that geniposide improved glucose-stimulated insulin secretion by accelerating Txnip degradation and prevented the early-stage apoptosis of pancreatic β cells induced by palmitate, but the underlying mechanisms are still unclear. The objective of this study is to identify the role of Txnip in geniposide preventing the apoptosis of pancreatic β cells induced by high glucose and palmitate (HG/PA). The results revealed that geniposide attenuated HG/PA-induced cell apoptosis and the expression of Bax and caspase-3, while increasing mitochondrial membrane potential and the anti-apoptotic protein levels of heme-oxygenase-1 (HO-1) and Bcl-2 in INS-1 rat pancreatic β cells. Knockdown of the Txnip gene raised the levels of anti-apoptotic proteins HO-1 and Bcl-2 and geniposide potentiated the effect of Txnip when the INS-1 cells were challenged by HG/PA. Furthermore, geniposide enhanced the adoptive unfolded protein response by increasing the phosphorylation of PERK/eIF2α and IRE1α in HG/PA-treated INS-1 cells. The results together suggest that geniposide might be useful to antagonize glucolipotoxicity and Txnip might be a pleiotropic cellular factor in pancreatic β cells.

Liu M ，Liu C ，Shen S ，Liu J ，Yin F ... -  《-》

Geniposide accelerates proteasome degradation of Txnip to inhibit insulin secretion in pancreatic β-cells.

Liu CY ，Hao YN ，Yin F ，Zhang YL ，Liu JH ... -  《-》

Regulation of insulin secretion by geniposide: possible involvement of phosphatidylinositol 3-phosphate kinase.

Guo LX ，Liu JH ，Yin F 《-》

Prednisolone-induced beta cell dysfunction is associated with impaired endoplasmic reticulum homeostasis in INS-1E cells.

Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.

Linssen MM ，van Raalte DH ，Toonen EJ ，Alkema W ，van der Zon GC ，Dokter WH ，Diamant M ，Guigas B ，Ouwens DM ... -  《-》