24 neuronal functions related to the 10 genes found in pancreas based on Gene ontology database search. Neuronal processes related to the 10 genes are numbered from 1 to 24 (left side of Figure) and corresponded with numbers 1 to 24 shown in pancreas Figure. Abbreviations are in Table 1 and 2. 

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... 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. When blood glucose levels rise (hyperglycemia), pancreatic β-cells synthesize and secrete insulin to the bloodstream to regulate glucose levels. On the contrary, when circulating glucose levels fall below normal values (hypoglycemia), pancreatic α -cells produce and release glucagon to the bloodstream to tune up glucose concentrations via conversion of stored glycogen into glucose and its release into the circulation [1, 2]. Thus, a disruption in blood glucose regulation leads to the hyperglycemia state so-called diabetes. There are two types of aged-related [3, 4] diabetes; type 1 diabetes (T1D) and type 2 diabetes (T2D). Diminished or dysregulation of insulin by β-cells in T1D and T2D respectively are caused by cell aging process. T1D is an autoimmune disease that pancreatic β-cells are targeted to be broken down by antibodies produced by immune B cells. In this regard, the main production site of insulin is diminished by β-cells [5–9]. In contrast, in age-related-T2D the pancreatic β-cells are still active and do synthesize insulin but at dysregulated levels and not sensitive enough [10–13]. In a normal state, 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, 2- stimulates glycogenesis and suppress glucose formation and release from the liver, and 3- stimulates adipogenesis and prevent lipolysis in AT-associated adipocytes [14]. In an obese state, insulin shows a function completely opposite to the normal state in these three organs. Moreover, it has been recently shown that other cells such as adipocytes, macrophages also synthesize insulin [15]. Patients with either T1D or T2D diabetes are at high risk for serious complications such as cardiovascular diseases (CVDs) [16] and diabetic neuropathy (DN) [17–23]. 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]. DNs are the most common micro-vascular complications that occur in both T1 and T2 diabetes (40–60%) [18–20, 25, 26]. DNs-associated syndromes are classified into two groups; diffuse and focal. The former neuropathies are usually chronic and more common among diabetic patients, while focal neuropathies are acute [25]. In general, DNs occur in progressive damages of neuronal cells that commonly appear with symptoms such as severe pain, loss of sensation and disability [19, 22, 25]. Despite the general agreement that hyperglycemia plays a key role in initiation and development of DNs, the underlying mechanisms for the development of DNs is unknown and remains to be investigated [19, 22, 27]. Numerous studies have shown that hyperglycemia leads to the overload of electron transport chain in mitochondria and subsequent oxidative stress. The imbalance in the mitochondrial redox state, in favor of oxidation conditions, leads to the accumulation of reactive oxygen species (ROS). Subsequently, oxidative stress affects several metabolic pathways [such as insulin signaling pathway and protein kinase C (PKC) pathway; advanced glycation end products (AGEs) and mitogen activated protein kinase (MAPKs)] associated with glucose metabolism with enhanced oxidative stress and, in turn, inflammatory reactions [20, 21, 25, 28–32]. Although numerous drugs and therapies have been proposed to treat the DNs, the majority of these drugs and treatments were restricted to target the redox and glucose metabolic pathways [20, 32]. None of the drugs that targeted glucose metabolic pathways showed any efficient effect in the treatment of DNs [19, 22]. Also, despite identification of the genes [19] and metabolic pathways associated with DNs, the molecular causes of DNs events still occur in a large scale. These studies suggest that beside hyperglycemia other genetic components and factors may contribute to the development of DNs. For instance, tight links between oxidative stress and obesity were recently reported, which may provide new insight for investigation of the genes associated with DNs [21]. Meijer et al. have recently shown that metabolic dysfunction leads to the adipocytes hypertrophy (the main cause of obesity), which primes inflammation in AT [15, 16] and, in turn, is implicated in pathophysiological states such as energy storage disruption within adipocytes (e.g. triglycerides breakdown, FFAs, glycerol et cetera), insulin resistance (IR), and hyperglycemia as hallmark of T2D. Feldman et al . reported several pathways involved in lipid, carbohydrate and energy metabolism modulating gene expression patterns in peripheral nerves on BKS db/ db mouse sciatic nerve. Although this study support the hypothesis that hyperglycemia play an important role in nerve damage, lipid metabolism may involve neuronal damage and development of DNs as well [19]. Since both pancreas and AT are key tissues involved in age-induced T2D and its complications, this study was designed to investigate whether T2D alters the expression of genes with a function in neuronal processes in human pancreas and AT and that might be implicated in the insurgence of DNs. To investigate whether there are genes with a neuronal function that could show highly and clear changes in expression and that caused by age-induced T2D, we measured mRNA expression in human pancreas and adipose tissue (AT) with T2D. As depicted in Table 1 Table 1 and Figure 1, two genes OLIG1 and BAG3 were highly up-regulated and eight genes PRDM16 , GLDNA , APOA1 , CCKBR , EDN3 , VAV3 , CXCR4 , and GHRL were down regulated in pancreas with T2D as compared to pancreas control. Based on Gene Ontology database search, OLIG1 gene shows functions in neuron fate commitment, neurogenesis, generation of neurons, and neuron differentiation as shown in Figure 2. Based on database search, BAG3 gene showed only a neural function (i.e. neuron part). 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). (Figure 2). Among eight down-regulated genes in pancreas with T2D, VAV3 gene was highest down-regulated gene with approximately 246-fold (Table 1 and Figure 1). The expression of 15 genes were found to be highly altered in AT caused by age-induced T2D (Table 2 and Figure 3). From these 15 genes, 8 gens were highly up- regulated and 7 genes highly down-regulated (Table 2, and Figure 3). The expression of synaptotagmin-4 ( SYT4 ) gene were tremendously high up-regulated (approximately 392-fold) in AT-T2D as compared to AT-control, while VGF (neurosecretory protein) is highly down-regulated (approximately 119-fold) Table 2 and Figure 3). Another gene, which is very highly up-regulated in AT-T2D as compared to AT-control was MYRF (Myelin regulatory factor) as displayed in Table 2 and Figure 3. The fold changes of all 15 genes were reported in Table 2. Based on g ene o ntology database search, 52 neural functions were found for these 15 genes (Figure 4). (Figure 4). Although VGF gene was highly down-regulated, only one neural function (i.e. neuropeptide hormone activity) was shown to be linked with this gene (Figure 4). SYT4 gene showed a link with 5 neural functions; 1- neurological system process, 2- neurotransmitter secretion, 3- neurotransmitter transport 4- neuron part and 5- neuron projection. Based on Gene Ontology search, PTN and LRNN4 genes showed only link with one neural function (Figure 4) and both genes were up-regulated, while the other genes showed multiple neural functions. The in-silico functional analysis conducted on the list of 25 genes, led to the identification of several molecule-function/disease connections, as shown in Figure 5. Focusing on SYT4 , VGF , BAG3 , APOA1 , and VAV3 and on their tightly related interactors, which in turn participated to lipid metabolism, insulin, protein kinase C (PKC), advanced glycation end (AGE) products and MAPK signaling pathways, as well as to the electron transport chain, oxidative stress and glucose metabolism biological processes, we have drawn a global interaction network (Figure 6). It contained 198 (13.8%) multi- process genes, with 31 ( AKT2, CALM1, CALM2, ...