Geniposide protects pancreatic β cells from high glucose-mediated injury by activation of AMP-activated protein kinase.

Our previous works indicated that geniposide could regulate glucose-stimulated insulin secretion (GSIS), and improved chronic high glucose-induced dysfunctions in pancreatic β cells, but the molecular mechanisms remain largely unknown. In the present study, we investigated the role of 5'-AMP-activated protein kinase (AMPK) in high glucose induced cell injury and explored the associated molecular mechanisms in rat INS-1 pancreatic β cells. Data suggested that geniposide obviously prevented the cell damage induced by high (25 mM) glucose in INS-1 cells, which increased the protein levels of cell apoptosis-associated enzymes, including heme oxygenase-1 (HO-1), and Bcl-2, but apparently attenuated the protein level of Bax, an apoptotic protein. In addition, Compound C, an AMPK inhibitor, remarkably inhibited the effects of geniposide on the protein levels of HO-1, Bcl-2, and Bax, but AICAR, an AMPK activator, potentiated the role of geniposide on the protein levels of HO-1, Bcl-2, and Bax. More importantly, geniposide directly prevented the cleavage of caspase-3 induced by high glucose, and this effect was also evidently prohibited by the pre-incubation of compound C in high glucose-treated INS-1 cells. Furthermore, using the method of RNA interfere, we further proved that treatment with AMPK siRNA attenuated the effects of geniposide on the apoptosis-associated proteins and cell viability. All these data suggest that AMPK plays a crucial role on geniposide antagonizing high glucose-induced pancreatic β cells injury.

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

5'-AMP-activated protein kinase plays an essential role in geniposide-regulated glucose-stimulated insulin secretion in rat pancreatic INS-1 β cells.

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

Geniposide improves insulin production and reduces apoptosis in high glucose-induced glucotoxic insulinoma cells.

Our previous work revealed that in the pancreatic β cell line, geniposide modulated ATP production and glucose-stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of β-cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS-1 cells with 33mM of glucose (high glucose). Our results indicate that the glucose-induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10μM of geniposide. Moreover, induction of the phosphorylation of AMP-activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS-1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO-1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high-glucose concentrations. We have shown that these effects were associated with an increased apoptosis-related Bcl-2/BAX protein ratio. In conclusion, geniposide dose dependently improves β-cell function and increases the proliferation of β-cells exposed to prolonged hyperglycemia.

Guo LX ，Liu JH ，Zheng XX ，Yin ZY ，Kosaraju J ，Tam KY ... -  《-》

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 ... -  《-》

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

Guo LX ，Liu JH ，Yin F 《-》