Abstract
BackgroundProteins of the insulin signaling pathway are needed for cell proliferation and development and glucose homeostasis. It is not known whether insulin signalling markers (Foxo1, Gsk3β) can be correlated with the expression on PI3K-Akt-mTOR pathway, which are needed for cell survival and maintenance of glucose homeostasis. In the present study, we studied the expression of Foxo1, Gsk3β and PI3K-Akt-mTOR in the brain of streptozotocin-induced type 2 diabetes mellitus Wistar rats.MethodsThe study was performed both in vitro (RIN5F cells) and in vivo (male Wistar rats). Gene expression of Nf-kB, IkB, Bax, Bcl-2 and Pdx1 gene was studied invitro by qRT-PCR in RIN5F cells. In STZ (65 mg/kg i.p.)-induced type 2 DM Wistar rats, blood glucose and insulin levels, iNOS, Foxo1, NF-κB, pGsk3β and PPAR-γ1 levels along with PI3k-Akt-mTOR were measured in brain tissue.ResultsRIN5F cells treated with STZ showed increase in the expression of NF-kB and Bax and decrease in IkB, Bcl-2 and PDX1. Brain tissue of STZ-induced type 2 DM animals showed a significant reduction in secondary messengers of insulin signalling (Foxo1) (P < 0.001) and Gsk3β (P < 0.01) and a significant alteration in the expression of phosphorylated-Akt (P < 0.001) mTOR (P < 0.01) and PI3K.ConclusionThese results suggest that STZ induces pancreatic β cell apoptosis by enhancing inflammation. Significant alterations in the expression brain insulin signaling and cell survival pathways seen in brain of STZ-treated animals implies that alterations neuronal apoptosis may have a role in altered glucose homeostasis seen in type 2 DM that may also explain the increased incidence of cognitive dysfunction seen in them.
Highlights
Proteins of the insulin signaling pathway are needed for cell proliferation and development and glucose homeostasis
Altered glucose homeostasis seen in in STZ-induced type 2 DM could be attributed to alterations in insulin signalling pathway proteins Akt and Mechanistic target of rapamycin (mTOR) in the brain that may explain neurodegeneration that is common in diabetes mellitus
Homogenization was Effect of Brain-derived neurotrophic factor (BDNF) on STZ-induced cytotoxicity The results of this study shown in Fig. 1b revealed that though BDNF is effective in preventing the cytotoxic action of STZ at all the three doses (10 ng, 50 ng and 100 ng/ml) tested, the most effective doses are 50 ng (P < 0.01) and 100 ng (P < 0.001) (100 ng > 50 ng) when BDNF was added to RIN5F cells simultaneously with STZ
Summary
Proteins of the insulin signaling pathway are needed for cell proliferation and development and glucose homeostasis It is not known whether insulin signalling markers (Foxo, Gsk3β) can be correlated with the expression on PI3K-Akt-mTOR pathway, which are needed for cell survival and maintenance of glucose homeostasis. We studied the expression of Foxo, Gsk3β and PI3K-Akt-mTOR in the brain of streptozotocin-induced type 2 diabetes mellitus Wistar rats. Of the several factors that are known to enhance the PI3K/Akt pathway, insulin is an important inducer [11]. This pathway is necessary to promote growth and proliferation over differentiation of adult stem cells neural stem cells [13]. Interference with PI3K/Akt/ mTOR pathway may lead to apoptosis of neurons and cause memory impairment
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