Relationship between serum Nesfatin-1, Adiponectin, Resistin Concentration, and Obesity with Type 2 Diabetes Mellitus

: Diabetes mellitus caused by insulin resistance is prompted by obesity. Neuropeptide Nesfatin-1 was identified in several organs, including the central nervous system and pancreatic islet cells. Nesfatin-1 peptide appears to be involved in hypothalamic circuits that energy homeostasis and control food intake. Adiponectin is a plasma collagen-like protein produced by adipocytes that have been linked to the development of insulin resistance (IR), diabetes mellitus type 2 (DMT2), and cardiovascular disease (CVD). Resistin was first identified as an adipose tissue–specific hormone that was linked to obesity and diabetes. The aim of this study was to estimate the relationship between human serum nesfatin-1, adiponectin, resistin concentration, and obesity with T2DM. The results show a significant increase in serum neisfatin-1 and resistin levels in the obese diabetic group compared to the non-obese diabetic group. Adiponectin levels had a highly significant decrease in the obese diabetic group compared to the non-obese group and obese control group. Serum Nesfatin-1 and some variables, there was a significant positive correlation with (BMI, insulin, HOMA-IR), and serum resistin had a significant positive correlation with (BMI, WC, TG, insulin, HOMA-IR).On the other hand, there was a negative correlation between serum adiponectin and (BMI, TG, and HOMA-IR). The present results suggest that nesftin-1 may have a role in controlling food intake as well as the development of IR in obese patients.


Introduction:
Diabetes is characterized as a condition that happens on account of the absence of insulin or nearness of factors contradicting the activity of insulin, bringing about an expansion (hyperglycemia) in blood glucose level 1 .The purpose behind the profound benefit of fat tissuederived hormones lies in the increasing incidence of human population over the World.It is believed that the existence of obesity generously builds the danger of related comorbidities, for example, dyslipidemia, diabetes, insulin resistance, hypertension, and others 2 .The close connection between obesity and its related complications has been entrenched, however, the exact instrument straightforwardly connecting one to the other is not clear, as yet 3 .Obesity is generally related to hyperinsulinemia and IR 4 , it's a noteworthy risk factor for the improvement of DMT2 and CVD 5 .
Whilst free fatty acids discharged to adipose tissue have for some time been involved in the advancement of this obesity-related complications 6 .
Nesfatin-1 is an 82-amino-acid peptide generated from a hypothalamus protein precursor.It regulates appetite stimulation, body weight, food intake, and the energy balance in the body 7 .Nesfatin-1controls intracellular glucose metabolism and increase insulin sensitivity 8 .Adiponectin is a specific cytokine in adipose tissue that has an important effect against anti-inflammatory and insulin resistance and found to protect against metabolic diseases 9 .Adiponectin controls glycogenesis, glucose uptake, and fatty acid oxidation all of which are linked to diabetes etiology 10 .Resistin is a hormone produced by adipose tissue that inhibits glucose homeostasis in rats by resisting insulin action.That, in turn, causes to develop (DMT2) 11 .Resistin, an individual from the newfound group of cysteine rich secretory proteins, has been portrayed as a result of fat tissue, taking part in the inflammation in mice, adipogenesis and pathogenesis of insulin resistance 12 .The aim of this study was to high light the relationship between human serum nesfatin-1, adiponctin, resistin concentration and obesity with DMT2.

Subjects
The study was designed cross sectional study.The study included 90 subjects, divide into two groups, patients and healthy control.Sixteen patients (31 males, 29 females) and 30 control (17 males, 13 females).In this study were collected during the period from (Septemper2021 to December 2021 at National Diabetic Center/ Mustansiriyah University.
To determine if variables had a normal distribution, the Anderson-Darling test was performed.If they did, then the mean and standard deviation were applied.When there are differences between more than two groups (and if there are no major outliers and the distribution is normal), one method of analyzing these differences is with an ANOVA.The significance level was set at a P ≤ 0.05.Explanation of the regression analysis using a scatter plot, r (correlation coefficient or standardized beta is a representative of magnitude and direction of the relationship).Positive signs reflect direct relationships, whereas negative signs suggest the opposite.

Results:
The results of this study demonstrateda high significant difference in (FBG, HbA1c) (p<0.001), and (TC, TG) (p<0.05) in diabetic patients group is comparison with thecontrol group.While high significant difference in Nesfatin-1 and resistin levels (4.96±1.03),(14.89 ± 5.4) in diabetic patients compared to that of control group (1.71±0.80)(9.6 ± 3.39) p<0.05.There was a significant decrease in adiponectin levels in diabetic group when compared to that of control group (9.79 ± 1.97) vs. (15.63± 2.57, p< 0.01), as presented in Table 1..05 is considered significant,**P<0.01 is a highly significant when compared to obese non-obese patients.# Significant at p < 0.05, and ## significant at p < 0.001 as compared DM to obese control group.
Table 3 showed the Pearson Chi-square correlation coefficient among serum nesfatin-1 and some variables, there was a significant positive correlation with (BMI, insulin, HOMA-IR), and significant negative correlation with age.Serum resistin had a significant positive correlation with (BMI, WC, TG, insulin, HOMA-IR), and significant negative correlation with HDL.On the other hand there was negative correlation between adiponectin and (BMI, TG and HOMA-IR), and a positive correlation between adiponectin and HDL in obese patients.

Results:
The results of this study shows that a significant higher resistin levels in diabetic patients compared to control group (14.89 ± 7.4 vs 9.6 ± 3.39, p<0.05).On the other hand, there was a significant decrease in adiponectin levels in diabetic group compared to control group (9.79 ± 1.97 vs 15.63 ± 2.57 , p< 0.01 ), as shown in table 1.
Table2 show a significant increase in serum resistin level in obese diabetic group compared to non-obese diabetic group (16.87 ± 3.4 vs 11.6 ± 2.4, p< 0.05) and a higher significant increase compared to obese control group (16.87 ± 3.4 vs 10.04 ± 2.14, p<0.01).On the other hand, there was a highly significant decrease in adiponectin levels in obese diabetic group compared to non-obese group and obese control group (7.98 ± 1.81 vs 12.63 ± 2.17, p<0.01; 7.98 ± 1.81 vs , 0.01, respectively).
Moreover, there was a significant increase in serum insulin, cholesterol, triglycerides, and HOMA-IR in obese diabetic group compared to non-obese diabetic group, and obese controlgroup (16.43  Table 3 show the pearson Chi-square correlation coefficient between serum resistin and some variables and metabolic syndrome components, there was a significant positive correlation with (BMI, WC, TG, insulin, HOMA-IR), and significant negative correlation with HDL.On the other hand there was negative correlation between serum adiponectin and BMI, TG, and HOMA-IR.And there was positive correlation between adiponectin and HDL in obese patient

Discussion:
Obesity is a serious cause of death and illness across the world 14 .Under situations of poor glucose metabolism, nesfatin-1 is said to have an anti-hyperglycemic action 15 .In reaction to hyperglycemia, it may also operate in the brain to up regulate insulin sensitivity and enhance insulin release in beta cells.Food intake was also discovered to be inhibited by Nesfatin-1 in the central nervous system 16 .Nesfatin-1 has also been proven to increase lipid metabolism and have antiinflammatory properties in several studies 17 .Obesity is a common cause of T2DM inflammation, eating disorder, and insulin action dysfunction 18 .Anther studies have discovered higher circulatinesfatin-1 levels in DMT2 as a result of lowering blood glucose, improving lipid metabolism, restricting food consumption, and decreasing inflammation 19 .The results in this study is also agreed with the results done by Zhang Z, ET al. 20 , In individuals with Type 2 diabetes, nesfatin-1 levels were shown to be higher.In diabetic groups with severely impaired glucose metabolism, HOMA-IR was shown to be substantially higher than in control groups 6 .The results in this study is also agreed with the results done by Anwar GM et al. 21, who found that obese people had considerably greater nesfatin-1 levels than healthy people.Prepronesfatin was shown to be localized in the islets of both rats and mi in a recent research, suggesting that prepones fat in-derived peptides may play a role in insulin production and glucose metabolic.The Result in Table 3, demonstrated a direct significant relationship between nesfatin-1 and BMI .which agreed with Başar Ö et al 22 .
Resistin is a tiny secreted protein generated mostly by mononuclear cells in the peripheral blood, macrophages in humans, and bone marrow cells in humans.
Resistin pro-inflammatory function has been demonstrated in a variety of illnesses, including DMT2, CVD, kidney disease, and rheumatoid arthritis 23 .In the present work serum resistin levels are higher significant in diabetic and obese diabetic patient when compared to normal subjects.Serum resistin, delivered by adipose tissue, in Individuals have higher fat content the resistin available at greater circulating levels.Notwithstanding, the greater generation of resistin by the non-fat fraction of adipose tissue 24 , May be because of absence of organization found in our overweight patients, in whom the adipocyte part of the fat tissue may be more noteworthy concerning the stromo vascular fraction 25 .The commonness of obesity has increased significantly lately and is related with a few chronic illnesses, for example, coronary artery disease, hypertension, metabolic disorder, and, specifically T2DM.One of the features of these diseases is IR 26 .Adipose tissue saving body fat reserves, privileged insights a few peptide hormones and cytokines that assume essential parts in vitality homeostasis and are captured in several chronic diseases 27 .Adiponectin is a fat tissue specific cytokine has a protective role against IR and anti-inflammatory activity and protect against metabolic diseases 28 .We additionally found in this study two important discovering.first, its agree with anther studies that the low plasma adiponectin concentration is related with DMT2 and obesity and through different ethnic groups with marked differences in propensity for obesity, 29 and T2DM indicated for hypoadiponectinemia.Second, the results showed that the fasting insulinemia and insulin sensitivity plasma are more closely related to adiponectin concentration than to glycemia and adiposity, in patients with fatness and DMT2 in large part attributable to IR and hyperinsulinemia which propose that the hypo adioponectinemia.Past studies agreement with our study demonstrated that is negatively correlation between plasma adiponectin concentration with BMI, triglyceride and HOMA-IR 30 .
Adiponectin, an anti-inflammatory adipocyte, is copiously emitted by fat tissue and straightforwardly sharpens body tissues to insulin.A diminishing in levels of adiponectin because of hereditary or hormonal factors has been emphatically embroiled in the improvement of IR, DMT2, metabolic disorder, and other chronic diseases that are related with corpulence 6 .Although anther studies have exhibited a significant relationship among IR in fatness DMT2 Individuals and patients with other fatness related diseases with adiponectin levels 31 .This study, affirming a portion of the distributed discoveries, recognized a significant opposite relationship between fasting adiponectin levels and IR in obese DMT2 patients.Accordingly, steady with the discoveries of past reports, the aftereffects of this investigation demonstrated that adiponectin level can be utilized as a prescient list for IR in fat patients with DMT2 24 .
Although adipose tissue was principle wellspring of adiponectin, inquire about discoveries recommend that the blood level of adiponectin is lessened in obese or T2DM who have huge stores of fat tissue [32][33][34][35][36] .Lessening of adiponectin levels has been proposed to assume a focal part in the expanded rate of T2DM and IR disorder [37][38][39][40] .In obese animal models the Adiponectin levels have reduced, which decreases insulin sensitivity and induce DMT2 start 32,[41][42] .
Moreover, in this study a significant opposite relationship was observed between fasting glucose levels and adiponectin.That refer to an increase in fasting glucose level has connected with a decrease in adiponectin level, which is the main determinant of T2DM in patients with obesity.

Conclusion:
Our findings suggest that nesfatin-1 may have a role in the control of food intake as well as the development of IR in obese patients.Serum resistin raised in response to hyperglycemia and further in response to hyperinsulinemia.These study demonstrates that fatness and T2DM have connected with low plasma adiponectin and demonstrate that the level of hypoadiponectinemia is all the more firmly identified with the level of IR and hyperinsulinemia than the level of glucose and adiposity.As a biomarker for DMT2 related IR and obesity, adiponectin can be used.

Table 1 . Comparison between patients and control. Characteristics Control No: 30 (mean± SD) Diabetic patients: No 60(mean± SD) P value
The data was evaluated using either the mean (mean) , and the standard deviation (± SD ).