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          Diabetes is a major health problem globally. It is usually associated with devastating complications as a result of high blood sugar affecting the microcirculation. The prevalence of diabetes is rapidly increasing worldwide 115. In this work, the cytokine response was studied in diabetic patients with and without neuropathic complication to examine the effect of C peptides in regulating the immune response to preserve the homeostasis and protect from diabetic complications mainly peripheral neuropathy in T2DM.5.1 Population demographics and the clinical characteristics of DM in Bahraini patients.     The initial part of the examination comprised of a cross-sectional aimed at exploring the general demographics and clinical characteristics of DM patients.  The rationale behind this was mainly to gain an overall understanding of the population of patients at the hospital, and the proportions of DM complications among Bahraini people. Body composition and plasma glucose levels in the studied groups were compared. Healthy individuals had body mass indices ranging from 18 to 24, averaging at 20.9. Higher BMI, systolic and diastolic blood pressure (BP) readings were noted in T2DM  groups, accounting for 27.6 and 28 (in the broad range between 21 to 33) in the patients without or with neuropathy in the anamnesis, correspondingly. In diabetics, the duration of the disease was, on average 11-12 years. Higher BMI and BP readings were noted in T2DM than in controls group. Not surprising, serum glucose levels were also high in diabetics compared to the healthy subjects. Our data are compatiple with the study by Mahroos and Al-Roomi, 2007 that illustrated older age, poor glycaemic control, longer length of DM, lifted cholesterol levels, current smoking, obesity characterized by body mass index, expansive abdomen boundary, hoisted triglycerides levels and hypertension – however not gender, were altogether viewed as noteworthy hazard factors for DPN in both the univariate and the multivariate examinations 70. Obesity accompanying T2DM and hypertension are known to be closely connected with insulin resistance and elevated sympathetic nervous activity 116. Obesity, however, was not a significant hazard factor for DPN in logistic regression examination conducted by Katulanda et al. 2012 who explored predominance, designs, and indicators of DPN in creating nations 117. Several studies from Asian nations have also reported comparative comes about or no association between obesity and presence of DPN. Subsequently, further studies are needed to characterize the body weight in DPN in the Asian population 118.5.2 Part 2. Relationship between DPN and serum C-peptide levels            In our findings, the lowest amounts of C-peptide were observed in the diabetics with neuropathy. The highest amounts of C-peptide were detected in the diabetics without neuropathic complications. The differences in the levels of endogenous C-peptide were dramatic: the five-fold difference was demonstrated between the diabetics with and without neuropathy An examination in Korea demonstrated that the hazard for diabetic neuropathy was related with the lower fasting serum C-peptide quartile and lower C-peptide quartile in T2DM patients subsequent to changing for numerous bewildering factors  117. A review companion examine with a middle follow-up of 14 years demonstrated that the dangers for occurrence neuropathy were contrarily connected with the most astounding C-peptide tertile. Zhao et al. 107 reasoned that a larger amount of region under the bend of C-peptide AUC (C-pep) was contrarily connected with the prevalence of neuropathy. However, Sari et al. 118 shown that C-peptide did not associate with sensorial neuropathy. Additionally, another investigation found that patients with parasympathetic neuropathy had elevated fasting plasma C-peptide (P<0.001) 119.         According to Rubenstein et al. (1969), C-peptide is a little peptide included 31 amino acids, with a short half-existence of around 30 minutes. It was the primary distinguished by Steiner et al. (1967) as a side-effect of proinsulin and its primary part is in aiding the course of action of the right structure of insulin. 23. C-peptide is cleaved from proinsulin, stored in secretory granules, and eventually discharged into the circulation system in sums equimolar to those of insulin. In the course of recent decades, C-peptide has emerged as has developed a possibly useful endocrine hormone because of how it is additionally a hormone co-released with insulin from pancreatic beta-cells. It has a more drawn out circulatory half-life when contrasted with insulin. C-peptide has been seemed to apply helpful useful outcomes, potentially through pertussis toxin-sensitive intracellular signaling mechanism. Notably, C-peptide inadequacy is a sign of T1DM and furthermore the later phases of T2DM, which indicates and emphasized the need to learn more about C-peptide clinical importance. Quite outstanding efforts have been achieved from investment in the last few decades towards comprehension the physiological benefits of C-peptide and towards the development of restorative techniques to diminish diabetic complications.               According to Panero et al. (2009) lower C-peptide levels because of the autoimmune attack on the beta-cells of pancreas, increased risk in the development of vascular dysfunction 96. Truth be told, in a center based partner of T1DM, lack or low of C-peptide levels were found to be linked with neuropathy. Additionally, in different outcomes from explore led by Kamiya et al. (2006) and Ekberg et al. (2007) from clinical trials of C-peptide supplanting treatment in T1DM patients with smaller scale neural deformities, have exhibited huge advancement side effects of fringe neuropathy and renal capacity 118, 119.5.3 Part 3: Case Control analysis, DPN and inflammatory mediators          The case control analysis aimed to investigate the relationship between DPN and pro-inflammatory and autoimmune markers by comparing the levels of specific markers in the PBMCs obtained from the three groups. The study results demonstrated significant differences between the levels of pro-inflammatory markers in the PBMCs obtained from the samples in the neuropathy group when compared to the two control groups.              From our results, in general, the responses are more pronounces in the cells treated with higher doses of C-peptide in patients with neuropathy. Healthy subject and diabetics without neurological complications had cytokine responses of same polarity at different C-peptide treatment.              From the study findings, in healthy subject, PBMCs obtained after treatment with C-peptide were found to contain markedly lower levels of mRNA for TNF-? (27.5% in 0.5 U; 30.1% at 0.25U), IL-8 (13.5% in 0.5U; and 20% at 0.25U), IL-6 (20.1% in 0.5U; and 20.2% in 0.25U) and IFN-? (20.1% in 0.5 U; 27.2% at 0.25U). In addition, in T2DM without neuropathy treated PBMCs with C-peptide were obtained with lower expression of IL-6 (26.5 % 0.5 U and 33.9 % in 0.25U), IL-8 (14.3% 0.5 U and 11.5% in 0.25U), TNF-? (28.2% 0.5 U and 23.1 % in 0.25U)   and IFN-? (20.1% 0.5 U and 30.6% in 0.25U).  Similarly, in T2DM with neuropathy, a visible inhibitory effect on cytokine expression were seen for IL-6 (20.8%  0.5 U and  24.5% in 0.25U), IL-8 ( 15.1%  0.5 U and  12.8% in 0.25U), TNF-? ( 20.1%  0.5 U and 22.1 % in 0.25U) and IFN-? ( 35.6%  0.5 U and  20.1% in 0.25U). This is similar to findings from the studies by Ido et al. (1997), Kunt et al. (1998), and Sugimoto et al. (1999) which demonstrated that joined exploratory and clinical information gave confirm that the C-peptide measurements might be associated with enhancing nerve brokenness in type 1 diabetes 41, 99, 118. This is additionally like discoveries by Abdolreza et al.  (2002) which found that simvastatin treatment prompts a diminished articulation of mRNA of peptide cytokines in flowing PBMCs and of serum MCP-1, IL-8, and IL-6 levels in hypercholesterolemic patients.          This study showed that both diabetic groups have lowest INF-? and TNF-? immune responses for both C-peptide treatment conditions. The differences in INF-? responses were near marginal significance between the both diabetes groups when PBMC were treated with C-peptide (p=0.484). Also, there was no significant difference of INF-? responses between healthy subjects and diabetics without neuropathy (p=0.4343) and with neuropathy (p=0.9803).  The difference in TNF-? responses between the healthy and the diabetic groups. There was less response detected at different doses treatment of C-peptide in all studied groups. There was a significance difference in TNF-? response between healthy group and diabetes with neuropathy (p=0.03323) and between both diabetes (p=0.0154). In contrast, only no significant differences of TNF-? responses were detected between healthy subject and diabetes without neuropathy (p=0.7984).The IL-8 responses were near-marginal significance between healthy subjects and diabetics without neuropathy (p=0.2092), as well as with diabetics with neuropathy (p=0.211).  In addition, no significant differences in IL-8 responses were detected between both diabetic condition (p=0.971). There was no noteworthy contrasts detected for IL-6 responses between diabetics of with different neuropathy features (p=0.8888). This is comparable to finding from Luppi et al. (2008) study, which demonstrated that while the expansion of C-peptide diminished IL-8 concentration to levels comparable to normal glucose (p<0.05), the heat-inactivated C-peptide control had no huge impact 35. The high glucose-instigated IL-8 emission by (HAEC) was intervened by NF-?B activation, since, the treatment with PDTC (10 ?mol/l), a NF-?B inhibitor, decreased IL-8 discharge to basal levels was likewise recognized in ordinary glucose (p<0.01 vs 25 mmol/l glucose).This is contrary to studies by Vincent et al. (2011) and Tesfaye et al. (2005) in T1DM and animal models suggest C-peptide beneficial effects on DN by enhancing neuronal function and endoneural blood flow 119, 120. This is also supported by finding by Piga et al. (2007) and Srinivasan et al. (2003) where the high glucose levels were noticed to stimulate the secretion of the chemokines IL-8 and MCP-1by endothelial cells 121, 122.  Tumor rot factor-? overproduction has illustrated the pathogenicity in diabetic neuropathy 123. It has been recommended that its overproduction stimulates the blend of other pro-inflammatory cytokines such as interferon gamma (IFN-?) which has an essential part in the acceptance of immune mediated inflammatory 80. TNF-? has been found to initiate neuronal damage and is considered as a major initiator of inflammation. In pre progression stage of diabetic peripheral neuropathy circulating levels of TNF-? are lifted in T2DM 124.The study data showed that C-peptide treatment is capable of stimulate the expression of anti-inflammatory cytokines in PBMCs of healthy subjects. The exposure to C-peptide treatment resulted in an increase in cytokine mRNA expression of IL-1-ß (82.6% in 0.5 U and 90.6% in 0.25 U), Rantes (92.3% in 0.5 U and 88.7% in 0.25 U) and IL-10 (85.6% in 0.5 U and 81.9% in 0.25 U). These information showed that C-peptide treatment can fortify the expression of anti-inflammatory cytokines in PBMCs of healthy subjects.  Moreover, In PBMCs of T2DM without neuropathy, increased levels of mRNA for Rantes (90.1% in 0.5 U and 92.3% in 0.25 U), IL-10 (88.2% 0.5 U and 80.6% in 0.25U) and IL-1-ß (96.6 % 0.5 U and 96.3 % in 0.25U) were detected.  In addition, maximum levels on cytokines expression at the level of RNA after treatment with different concentration of C-peptide in T2DM with neuropathy were detected:  Rantes (86.3 % in 0.5 U and 77.5% in 0.25 U), IL-10 (78.9% 0.5 U and 80.5 % in 0.25U) and IL-1-ß (77.6% 0.5 U and 62.1n 0.25U).           Moreover, Rantes responses were also not significantly different between both diabetics conditions (p=0.377) as well as between healthy subject with diabetics without neuropathy (p=0.720) and with neuropathy (p=0.7600). In addition, the differences in IL-1-ß show the no significant differences between both diabetes cases (p=0.9404) as well as between healthy subject with diabetics without neuropathy (p=0.6576) and with neuropathy (p=0.1756). Moreover, no significant differences in IL-10 responses was detected between all studied groups. These finding are agreed with a randomized, double-blinded study carried out by Ekberg et al. (2003), where fake treatment controlled investigation showed that a 3-month C-peptide substitution treatment directed to T1DM patients with early indications of  DV enhanced nerve dysfunction 125. This impact was achieved by enhancing the sensory nerve conduction velocity (80% correction), which was joined by enhanced vibration observation. In this same examination by Ekberg, a 6-month regimen of C-peptide substitution treatment additionally improved sensory nerve work in patients with beginning time DV. In another study by Bo et al. (2012), results indicated that initially complication-free T2DM with higher baseline fasting C-peptide levels had essentially reduced incidence of neuropathy, nephropathy, and retinopathy after a 14-year follow-up 126.The stimulatory impact of C-peptide on nerve Na+-K+-ATPase movement and eNOS may give a foundation to their discoveries. The possibility that C-peptide might be helpful in the treatment of DV warrants further studies involving more prolonged periods of C-peptide doses. All of the above outcomes relate to experimental and clinical T1DM. Whether C-peptide might exert a similar influence on nerve function in patients with T2DM, a disorder characterized by elevated levels of both insulin and C-peptide during its first phase remains to be determined. Notwithstanding, there is preliminary confirmation to demonstrate that there might be protection from the activity of C-peptide in muscle tissue from T2DM patients in another examination by Zierath (1995) 127. This additionally was appeared by our own particular discoveries as well as there were no critical contrast between diabetics with various anamnesis.Finally, in consideration of a study on C-peptide by Luppi et al. (2008), the currently available information establishes that C-peptide isn't as naturally latent as beforehand accepted 35. Instead, it is now emerging as an active peptide hormone with potentially important physiological effects. Despite the fact that C-peptide is framed from proinsulin and co-discharged with insulin, we ought to think about how conceivable it is that C-peptide is an alternate substance with biochemical and physiological characteristics that are not the same as those of insulin. When C-peptide was added, IL-8 and MCP-1 emission contrasted with basal medium without C-peptide. The majority of the data described from previously conducted researches suggests that that C-peptide may advance sore improvement in subjects with insulin resistance and T2DM. Whereas, the utilization of C-peptide in T1DM subjects who need C-peptide has been appeared to enhance diabetic microvascular complications, for example, diabetic neuropathy. Therefore, more investigations are required in future expected to distinguish the C-peptide receptor to better comprehend and balance the physiological capacity of C-peptide.In the present survey, we sort to provide a general overview of present-day emerging clinical and experimental evidence that has upheld the useful part of C-peptide against diabetic neuropathy (DN), which is one of the real inconvenience that prompts diabetes-related dismalness and mortality. We also assess the justification made from a study by Gerstein et al. (2008), which bordered on concerns that clinical approaches targeting glycaemic control have not been successful in preventing diabetic complications and that C-peptide plays vasoprotective role, and supplemental C-peptide therapy in conjunction with insulin might become an important clinical approach to prevent DN and DV 117. Although, late remedial systems against diabetes have concentrated on glycemic control; be that as it may, different variables, including insulin inadequacy, hyperglycemia, and C-peptide insufficiency appear to bring about the advancement of diabetic complexities. Therefore, it is important to oversee both T1DM and late phase of T2DM with combinational treatment for both glycaemic control and neuropathy aversion. Findings have demonstrated that in T1DM and late stage of T2DM, insulin can be utilized to accomplish normoglycaemia, and C-peptide supplementation might be gainful in avoiding neuropathy and vasculopathy organ-specific entanglements.In diabetes, the length and level of hyperglycemia are imperative determinants of microvascular complications, including neuropathy, which prompts chronic pain, numbness, and significant diabetic morbidity. Aside from serious glycaemic control, no other proof based medicines are accessible to improve or anticipate DN, and the greater part of patients with great glycaemic control still build up this confusion.5.4 Theoretical and clinical implications of the studyAs shown above, this study will be the first to address and provide insights and mechanisms on how C-peptide can mediate beneficial immune response and minimize the complications of diabetes. Also, as the study has been conducted in Bahrain, where patients were recruited from various hospitals' adult endocrinology units, so it is anticipated that results obtained from this study will help in shaping future strategies to search for better therapy and prevention of complications of diabetes.  In summary, our results support the theory that C-peptide play an effort on the lessened generation of pro-inflammatory cytokines and chemokines. These revelations underscore C-peptide capacity in diabetic neuropathy. Our outcomes bolster the idea of calculated dose of C-peptide to T1DM patients with an end goal to inhibit neurological complications.        Several hypothetical and clinical suggestions developed from outcomes from this consider. DPN is a complex disorder with a variety of pathological hypotheses contributing to its pathogenesis. Inhibition of both inflammatory cytokines and their activators/regulators may give extra scope to treating DM complications. As advance considers rise to address current limitations, progressed treatments focusing on DM micro-vascular complications may eventually shift the focus from treating the pathology to avoidanceories behind the improvement of DPN.        The presence of major contrasts between the DPN group and the two control groups conceivably shows that the watched changes may related to the presence of neuropathy or maybe than DM itself. Anti-inflammatory cytokines block the process or at least suppress the intensity of the pro-inflammatory cascade. Cytokines such as IL-4, IL-10, IL-13, and transforming growth factor (TGF)-b suppress the production of IL-1, TNF-?, chemokines such as IL-8, and vascular adhesion molecules. Therefore, a "balance" between the effects of pro-inflammatory and anti-inflammatory cytokines is thought to determine the outcome of disease, whether in the short term or long term. In fact, some studies have data suggesting that susceptibility to disease is genetically determined by the balance or expression of either pro-inflammatory or anti-inflammatory cytokines. 

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