3-Deoxyglucosone induces insulin resistance by impairing insulin signaling in HepG2 cells

Abstract

3-Deoxyglucosone (3DG), a highly reactive dicarbonyl intermediate generated during glycation, has been confirmed to be markedly elevated in the plasma of patients with diabetes. Our previous study found that there is an association between increasing accumulation of plasma 3DG and impaired glucose regulation in non-diabetic seniors (females, >50 years old; males, >55 years old). It was also found that 3DG led to impaired plasma glucose homeostasis in healthy mice, however, the mechanisms underlying the deleterious effect of 3DG in diabetes remain to be fully elucidated. The present study aimed to investigate the ability of 3DG to cause hepatic insulin resistance in a cell model by assessing glucose uptake and glycogen content. In addition, the molecular signaling events, including the phosphoinositide 3‑kinase (PI3K)/AKT/glucose transporter 2 (GLUT2) and PI3K/AKT/glycogen synthase kinase‑3 (GSK‑3) pathways, which affect hepatic insulin resistance, were further investigated using Western blot analysis. The results showed that 3DG (10‑300 ng/ml) had no significant effect on HepG2 cell viability, however, the viability of the HepG2 cells decreased with exposure to concentrations of 500 and 1,000 ng/ml. Treatment with non‑cytotoxic 3DG concentrations resulted in decreased uptake of glucose and glycogen content with insulin stimulation, but not under basal conditions. The insulin‑induced expression of GLUT2 and p‑GSK‑3 were eliminated by 3DG (80 and 300 ng/ml), in addition to inhibiting the phosphorylation of downstream effectors of the insulin signaling pathway, including insulin receptor substrate 1, PI3K and AKT. In conclusion, the findings of the present study indicated that the addition of exogenous 3DG directly contributed to the induction of insulin resistance by impairing insulin signaling in the HepG2 cells, which suggested that 3DG may be involved in worsening of the diabetic condition.

Lin28a expression protects against streptozotocin‐induced β‐cell destruction and prevents diabetes in mice

“…33 One of the several mediators regulated by these pathways, Akt, belongs to this case. 35,36 Indeed, we observed that the expression of Glut2 was slightly but significantly higher in MIN6 cells overexpressing Lin28a. These findings suggest that Akt plays an important role in the regulation of the insulin secretory pathway.…”

“…34 Furthermore, insulin signalling and the IR-IRS-PI3K-Akt pathway are important in enhancing the expression of Glut2 and GSK-3, which is critical in insulin secretion and functions. 35,36 Indeed, we observed that the expression of Glut2 was slightly but significantly higher in MIN6 cells overexpressing Lin28a. Our results suggest that Lin28a overexpression potentiates glucose-stimulated insulin secretion in mice, indicating a possible Akt-dependent synergistic effect on pancreatic β-cell functions.…”

Accumulation of intestinal tissue 3-deoxyglucosone attenuated GLP-1 secretion and its insulinotropic effect in rats

“…According to the method of Kato et al [32], 3DG was synthesized from glucose as previously described [13]. …”

“…Methods for quantification of whole protein content and western blot have been described previously [13]. Antibodies against TAS1R2, TAS1R3 and TRPM5 were obtained from Cell Signaling Tech (Massachusetts, USA).…”

“…Based on an investigation of the content of 1,2-dicarbonyl compound in a great variety of commonly consumed foods, 3-deoxyglucosone (3DG) was proved to be the predominant 1,2-dicarbonyl compound [10]. In addition to intensively investigate as a precursor for AGEs, 3DG itself has certain biological activities [11–13], specifically on the ability to induce insulin resistance in vitro [13]. The further reports in clinical and animal research indicated that 3DG had been linked to an impaired glucose tolerance [6, 14, 15], thereby constituting an independent factor for the development of prediabetes.…”