Abstract
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
Highlights
The homeostasis of blood glucose levels is maintained by both insulin and glucagon synthesis, which is functionally tightly regulated by the pancreatic β-cells and α-cells respectively
There were 24 neuron functions found for these 10 genes in pancreas of which chemokine C-X-C receptor (CXCR4) gene was shown to have a role in 17 neural functions based on Gene Ontology database (Figure 2)
The underlying mechanisms for the development of human type 1 diabetes (T1D) are completely different from type 2 diabetes (T2D), insulin signaling pathway, glucose levels, and energy storage components are involved in both types of diabetes
Summary
The homeostasis of blood glucose levels is maintained by both insulin and glucagon synthesis, which is functionally tightly regulated by the pancreatic β-cells and α-cells respectively. There is a homeostatic balance and cross talk between skeletal muscle, liver and adipose tissue (AT) organs with respect to glucose levels, which is strictly under control of insulin [14] In this regard, insulin 1- promotes glucose uptake and inhibits lipolysis by the skeletal muscle, 2stimulates glycogenesis and suppress glucose formation and release from the liver, and 3- stimulates adipogenesis and prevent lipolysis in AT-associated adipocytes [14]. Obesity plays an important role in the development of T2D and its complications via the promotion of an inflammatory state [16] In this regard, Systems biology could be a solution to find etiology of aged-related diseases such as T1D, T2D, neurodegenerative and cardiovascular diseases [24]
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