Tissue-specific regulation of insulin-PI3K/Akt, KEAP1-NRF2 and PKC/NF-κB signaling in high fat diet-fed and nicotinamide/streptozotocin-induced diabetic rats
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1
Faculty of Dentistry, Mahsa University, Malaysia
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2
Putra Malaysia University, Malaysia
Background
Type 2 diabetes mellitus (T2DM), a heterogeneous metabolic disorder, is due primarily to complex interplay of multiple inherited and acquired factors that adversely impair glucose metabolism. In particular, impaired insulin actions at multiple target tissues lead to eccentric glucose, lipid and redox homeostasis. While it is widely recognized that insulin resistance underlies the pathophysiology of T2DM, the complicated tissue-specific gene expression regulation and phenotypic association of the disease, particularly in diabetic animal model, remain largely under-studied. The present study aims to determine the correlated tissue-specific gene expression changes in experimental diabetic rat model.
Methods
The high fat diet-fed and nicotinamide/streptozotocin-induced mild diabetic (DIA) rats were used in the present study. Normal diet- (NOD) and high fat diet-fed (HFD) rats served as controls. The expressions of key genes involved in insulin-PI3K/Akt, KEAP1-NRF2 and PKC/NF-κB signaling, as well as correlation between gene expression changes, were profiled from white adipose, skeletal muscle, and liver tissues. The differential and non-differential molecular network interactions were further identified.
Results
Consistent with previous literature, statistical analyses revealed severe inflammation and perturbed metabolic functions in both HFD and DIA groups. Interestingly, potential tissue-specific compensatory antioxidant mechanisms were also observed across all the target tissues. Further dynamical analyses on differential and non-differential expression networks demonstrated tissue-specific modulations of inflammatory and antioxidant responses in relation to deranged insulin signaling.
Conclusion
The present study suggested tissue-specific and inter-tissue gene expression interactions in the mild diabetic rat model. Further studies and association with tissue-specific gene expression changes in human diabetic patients may further validate the use of present animal model to be verified fit for diabetes translational research purpose.
Keywords:
type 2 diabetes mellitus,
tissue-specific gene expression,
insulin-PI3K/Akt signaling,
KEAP1-NRF2 signaling,
PKC/NF-κB signaling
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Oral Presentation
Topic:
Metabolic diseases
Citation:
Ooi
D and
Ismail
M
(2019). Tissue-specific regulation of insulin-PI3K/Akt, KEAP1-NRF2 and PKC/NF-κB signaling in high fat diet-fed and nicotinamide/streptozotocin-induced diabetic rats.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2018.63.00063
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Received:
07 Nov 2018;
Published Online:
17 Jan 2019.
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Correspondence:
Dr. Der Jiun Ooi, Faculty of Dentistry, Mahsa University, Jenjarum, Malaysia, ooiderjiun@gmail.com