Early activation of the fatty acid metabolism pathway by chronic high glucose exposure in rat insulin secretory β‐cells

Abstract

Pancreatic beta-cells are responsible for insulin secretion that regulates blood glucose homeostasis. In the development of type II diabetes, a progressive impairment of insulin secretion by the pancreatic beta-cells occurs called beta-cell dysfunction or beta-cell failure. Chronic hyperglycemia has been shown being involved in beta-cell dysfunction, a phenomenon known as glucotoxicity. The molecular mechanisms underlying the impairment of insulin secretion by beta-cells induced by glucotoxicity are still not fully understood. In this work, quantitative proteomics was employed to identify early key players involved in beta-cell dysfunction induced by glucotoxicity. For this, the stable isotope labeling by amino acids in cell culture strategy was used on the slowly-growing rat beta-cell line INS-1E. We showed that the stable isotope labeling by amino acids in cell culture approach did not induce any detectable biological effects on these beta-cells, as measured at both the transcriptomic and proteomic levels. Proteins differentially expressed between control cells and cells submitted to chronic high glucose concentrations were identified and verified. The results obtained reinforce the link between glucotoxicity and lipogenesis and suggest that the fatty acid metabolism pathway may rapidly be stimulated in beta-cells submitted to chronic high glucose concentrations.

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

“…38 We observed that % tail DNA significantly increased in hyperglycemia treated 1.1B4 cells, which is similar to observations with RINm5F, INS-1E cells, and isolated mouse islets. [39][40][41][42] Execution of apoptosis was evident from a slight increase in caspase 3/7 activity after 72 h exposure which has also been observed in hyperglycemia treated INS-1 cells and isolated human islets. 43,44 In conclusion, this study has demonstrated multiple effects of glucotoxicity on gene expression and insulin secretory function in 1.1B4 cells, suggesting that this novel human-derived pancreatic β-cell line is useful for further investigations of β-cell dysfunction and its correction with novel therapeutic agents.…”

Differentiation of Mesenchymal Stem Cells Derived from Pancreatic Islets and Bone Marrow into Islet-Like Cell Phenotype

“…In addition it has been related to chronic glucose stimulation, as seen in an insulinoma cell model, and in diabetes type II [24].…”

Modulation of Neuronal Pentraxin 1 Expression in Rat Pancreatic β-Cells Submitted to Chronic Glucotoxic Stress

“…Among the proteins found to be differentially expressed, CRABP-1 was already shown to exhibit a differential expression level between control and INS-1E cells submitted to high glucose concentration (4). This was also the case for other fatty acid metabolism-related proteins, giving predominance to a link between glucotoxicity and fatty acid metabolism.…”

“…However chronic hyperglycemia is not involved in the initiation of T2D but is rather implicated in the worsening of the pathology. Notably, in recent years, the notion of"glucotoxicity " has emerged to describe the toxic effects of glucose (2)(3)(4)(5). Glucotoxicity exerts deleterious effects on ␤-cells, leading to the increase of apoptosis and therefore the decrease of ␤-cells mass observed in T2D pathology (6 -8).…”

“…It can be explained by two main factors: 1) very early events of the glucotoxicity process have been studied in this work, and 2) the effects of a high glucose (30 mM) were not compared with those of low and nonstimulatory glucose concentrations (e.g. 5 mM) as is classically the case, but rather to those of a "medium" glucose concentration (11 mM) because we reported previously that 5 mM glucose induced a rapid decrease of INS-1E cell viability (4).…”