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

Abstract

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.

The Effects of Natural Iridoids and Anthocyanins on Selected Parameters of Liver and Cardiovascular System Functions

“…These results are consistent with outcomes of other studies [61,62]. Moreover, geniposide protects rat insulinoma cells from apoptosis in high-glucose concentrations [63] and regulates endoplasmic reticulum (ER) stress, which might be an important factor of dysfunction and death of pancreatic β cells [64]. The antioxidative properties of geniposide eventuates from either the inhibition of numerous pathological processes (e.g., production of some inflammatory cytokines, LPS-induction of nitric oxide, and blocking upstream of TLR4, NF-κB, and MAPK pathways) or the activation of various proteins associated with cell survival, e.g., heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) or a combination of both.…”

The Beneficial Effects of Geniposide on Glucose and Lipid Metabolism: A Review

“…Geniposide regulates Txnip degradation and GSIS through endoplasmic reticulum (ER) stress by accelerating the phosphorylation of Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and Inositol-requiring enzyme-1α (IRE1α). 42 The main roles of GLP-1R are stimulation of GSIS, induction of pancreatic β-cell proliferation, inhibition of postprandial glucagon release, and delay in gastric emptying. 43 Geniposide inhibits the early stage of lipotoxicityinduced β-cell apoptosis, and GLP-1R plays a critical role by counteracting lipotoxicity in INS-1 pancreatic islet β cells.…”

“…Geniposide regulates Txnip degradation and GSIS through endoplasmic reticulum (ER) stress by accelerating the phosphorylation of Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and Inositol-requiring enzyme-1α (IRE1α). 42 …”

Jiedu Tongluo Tiaogan Formula Protects Pancreatic Islet Cells Against Dysfunction by Relieving Endoplasmic Reticulum Stress and Excessive Autophagy via Regulating CaMKKβ/AMPK Pathway

“…Epidemiological evidence in humans and recent mechanistic studies in rodents indicate that ERS predisposes pancreatic β-cells to develop pathophysiologic disorders [35]. Due to the functional importance of the ER to the biosynthesis, folding, modification and trafficking of secretory and membrane proteins, it is critically important that β-cells maintain ER homeostasis [36]. When mechanisms that maintain ER homeostasis fail, activation of cellular dysfunction-sensing signaling pathways retore homeostasis [37].…”