# Adipolin, Chemerin, Neprilysin and Metabolic Disorders Associated with Obesity
## 4 Discussion
### Adipokines and Glucose Metabolism  
The hypoglycemic effects of adipolin primarily consist of inhibiting hepatic gluconeogenesis and stimulating glucose uptake by hepatocytes and adipocytes through activation of the PI3K-Akt signaling pathway and improved insulin sensitivity [21]. Adipolin can improve glucose homeostasis and IR. It is involved in the regulation of insulin signaling by phosphorylating proteins such as AMP-activated protein kinase (MAPK), protein kinase B (PKB), and insulin receptor substrate (IRS). Experimental studies have demonstrated that adipolin administration decreased levels of enzymes engaged in hepatic gluconeogenesis, such as glucose-6-phosphatase, and increased levels of phosphoinositide 3-kinases (PI3K) related to the insulin signaling pathway [32]. In insulin-resistant obese mice and hyperinsulinemic healthy lean subjects, mRNA and serum levels of adipolin, on the other hand, were inhibited [33]. The results of studies evaluating adipolin levels in people with abnormal glucose metabolism are inconclusive. Based on one of them, patients with newly diagnosed type 2 diabetes had lower adipolin concentrations compared to healthy controls [19]. [PERSON] et al., evaluating the levels of adipolin in patients with diabetes, found a negative correlation between its levels and insulinemia and the HOMA-IR [4]. A negative association between HOMA-IR and fasting insulinemia was also shown by [PERSON] et al. [22]. [PERSON] et al. observed a positive correlation between blood adipolin levels and fasting glycemia, and glycated hemoglobin in subjects with metabolic syndrome, which included groups of patients with both normal and impaired glucose metabolism [23]. In contrast, [PERSON] et al. found a negative correlation between levels of this adipokine and fasting glycemia in a group of overweight subjects [20]. A similar relationship among women with obesity was shown by [PERSON] et al. [21]. Innovative results were presented by [PERSON] et al. in a group of patients with type 2 diabetes. They observed that adipolin levels were inversely correlated with diabetes duration [34]. We cannot relate this observation to our study because all of our patients had newly diagnosed abnormal glucose tolerance, but it can be assumed that the duration was short, and the lack of differences in adipolin concentrations between the study and control group may be due to this. Also, our study disclosed a positive association between adipolin concentrations and WHR values in subjects with obesity and normal glucose tolerance. This relationship was not present in subjects with abnormal glucose tolerance. Therefore, it can be hypothesized that high blood adipolin concentration is a protective factor for obese individuals against the occurrence of metabolic dysfunction. However, this needs to be confirmed in further studies, as no significant correlations were found between blood adipolin levels and exponents of glucose metabolism and insulin resistance in the other groups. The higher concentration of adipolin in diabetic patients, observed by some investigators, may be a compensatory mechanism leading to the reduction of insulinemia and HOMA-IR values [4]. Therefore, adipolin and other therapeutic agents that increase its blood concentration may be effective treatments for patients with type 2 diabetes and insulin resistance [23]. There is increasing scientific evidence suggesting an effect of neprilysin on glucose metabolism. By activating glucagon, it indirectly acts antagonistically to insulin, thus stimulating an increase in glycemia and enhancing gluconeogenesis, glycogenolysis, and fatty acid oxidation. Some of its substrates, such as glucagon-like peptide-1 (GLP-1), natriuretic peptides, and bradykinin, modulate glucose metabolism [35; 36]. Due to the potential role of neprilysin in glucose metabolism, associations between its levels and parameters such as glycemia, insulinemia, and insulin sensitivity exponents in humans have been sought. [PERSON] et al.