Serum Level of Preptin in Children with Diabetes Mellitus Type 1 and Its Relation to Diabetic Nephropathy
Nader GuimaSasi(1), WafaaFathy Mohamed Elsaeed(2)Hadeel Mohamed Abdel Rahman(2),andHaidyEssamEldinZidan(3)
(1) Department of Pediatrics, Faculty of Medicine – Elzawya University, Libya
(2) Department of Pediatrics, Faculty of Medicine – Zagazig University
(3) Department of Biochemistry and Molecular Biology, Faculty of Medicine – Zagazig University
Corresponding author :Nader GuimaSasi E-mail: [email protected] ABSTRACT
Background:Diabetic nephropathy (DN), a chronic and progressive process leading to end- stage renal failure, has a prevalence of approximately 20%– 40% in patients with diabetes.
Metabolic and hemodynamic alterations caused by hyperglycemia and hypertension are considered to be regulators in the pathogenesis of DN. This study aimed to evaluate new biomarkers such as preptin in patients with type 1 diabetes and to assess its relation to diabetic nephropathy.Patients and methods :This study was a case control study carried out at the Pediatric Endocrinology Unit, Pediatric Department, Zagazig University Hospitals, from June 2020 to April 2021. included 34 children and adolescents with type 1 diabetes mellitus in addition to 17 healthy children.Results:Theuse of Preptin for detection of diabetes, AUC with cutoff <122 showed sensitivity 100% and specificity 100%. This study showed that Preptin for detection of diabetic nephropathy, AUC with cutoff <93.5 showed sensitivity 80.0% and specificity 83.3%.Conclusion:We can conclude there was a significant correlation between serum preptin and renal function.
Keywords: Type-1 Diabetes Mellitus, Preptin, Diabetic nephropathy (DN), INTRODUCTION
Type 1 diabetes is one of the most prevalent long term diseases of childhood globally.
It has major health consequences for individuals and society (Yeşilkaya et al., 2017).
Diabetic nephropathy (DN), a chronic and progressive process leading to end-stage renal failure, has a prevalence of approximately 20%–40% in patients with diabetes. There are no effective treatments for DN except delaying the progression of DN or renal replacement therapies. Hence, it is essential to look for new biomarkers for early diagnosis and perform some reasonable treatments for patients at risk (Wang et al., 2019).
Preptin is a peptide of 34-amino acid synthesized and secreted accompanied with insulin from pancreatic β cells. Preptin is derived from its precursor called pro-insulin-like growth factor II (Buchanan et al., 2001).Preptin acts as a physiological enhancer of glucose- mediated insulin release (Mohammad et al., 2020).
Elevated preptin levels were observed in both patients with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) (Aydin et al., 2013, Yang et al., 2009).
Previous investigations have demonstrated the association of preptin with diabetes.
However, few studies focuses on the correlation between preptin with type 1 diabetes and its diabetic complication. Here, we aimed to evaluate a new biomarkers such as preptin in patients with type 1 diabetes and to assess its relation to diabetic nephropathy.
Patients AND METHODS Sample size calculation:
As the preptin level was 82.78 ± 44.3 vs 138.6 ± 96 among cases and control respectively. At 80% power and 95% CI. The estimated sample will be 51 cases, 17 cases in each group. (Open Epi)
Each of the eligible children was randomly divided into:
Group I :consists of 17 children recently diagnosed with type 1 diabetes.
Group II : consists of 17 children previously diagnosed with type 1 diabetes for more than five years and further stratified to group complicated with diabetic nephropathy and group have no diabetic nephropathy.
Group III (control group): consists of 17 healthy children without any infection or chronic disease and with no family history of age and sex matched with diabetic children.
Inclusion criteria:Patients with type 1 diabetes diagnosed according to the criteria for diagnosis of diabetes. Patients under the age of 18 years. Active diabetic nephropathy diagnosed in the form of microalbuminuria (urinary albumin excretion [UAE] 30–299 mg/g creatinine in two of three samples over a 3- to 6- months period despite angiotensin converting enzyme inhibitors) (Molitch et al., 2004).
Exclusion criteria: Patients unable or unwilling to give informed consent. Patients during acute diabetic complications, for example, diabetic ketoacidosis (DKA) or hypoglycemia.
Patients with urinary tract infections, urolithiasis, liver cirrhosis, cardiac disease, congestive heart failure, overt proteinuria, or other known major diseases.Patients on long term steroids, and chemotherapy.
Method:
All patients were subjected to detailed medical history, thorough clinical examination.
Laboratory investigations including fasting blood glucose levels, HbA1c, kidney function tests, lipid profile and serum albumin, urinary albumin, albumin creatinine ratio, glomerular filtration rate (GFR) and Serum preptin.
Peripheral blood samples were collected on potassium ethylene diamine tetra-acetic acid (K2- EDTA) in sterile vaccutainer tubes (final concentration of 1.5 mg/mL) (Beckton Dickinson, Franklin Lakes, NJ, USA) for assessment of HbA1c. For biochemical analysis, and preptin, clotted blood samples were obtained and serum was separated by centrifugation for 15 minutes at 1000 x. Serum was stored at -80ºC till subsequent use. Urine samples were collected for assessment of urinary albumin excretion.
Measurement of preptin:
The Human preptin (Enzyme-Linked Immunosorbent Assay) kit is designed for quantitative measurement of preptin level in the sample. Add preptin to monoclonal antibody Enzyme well which is pre-coated with Human preptin monoclonal antibody, incubation; then, add preptin antibodies labeled with biotin, and combined with Streptavidin-HRP to form immune complex; then carry out incubation and washing again to remove the uncombined enzyme. Then add Chromogen Solution A, B, the color of the liquid changes into the blue, and at the effect of acid, the color finally becomes yellow. The chroma of color and the concenthumanion of the Human Substance preptin of sample were positively correlated.
Statistical Analysis
Data collected throughout history, basic clinical examination, laboratory investigations and outcome measures coded, entered and analyzed using Microsoft Excel software. Data were
then imported into Statistical Package for the Social Sciences (SPSS version 20.0) (Statistical Package for the Social Sciences) software for analysis. P value was set at <0.05 for significant results &<0.001 for high significant result.
RESULTS
Table (1): Basic demographic and anthropometric measures among studied groups.
Group I (no = 17)
Group II (no = 17)
Group III
(no = 17) F/ X2 P Age (years)
Mean ±SD 10.23±2.63 13.58±2.34* 11.23±3.01 7.024 0.002*
Weight (kg)
Mean ±SD 31.35±8.54 41.94±10.9* 34.88±8.9 5.462 0.007*
Height (m)
Mean ±SD 1.37±0.1 1.46±0.09 1.40±0.12 3.333 0.044 BMI ( kg/m2)
Mean ±SD 16.31±1.94 19.16±3.05* 17.34±1.87 6.386 0.003*
Gender
Female N 8 8 8
0.00 1.00
% 47.1% 47.1% 47.1%
Male N 9 9 9
% 52.9% 52.9% 52.9%
Family history of
DM
No N 14 13 17
2.33 0.31
% 82.4% 76.5% 100.0%
Yes N 3 4 0
% 17.6% 23.5% 0.0%
* Group cause significant
Table 1;showed age is distributed as 10.23±2.63, 13.58±2.34 and 11.23±3.01 and group II is significantly higher regard age also weight and BMI are significantly higher among group II with no significant difference between group I and II by LSD and also there is no significant difference among groups regard gender or FH of DM.
Table (2): Area under curve, cutoff and validity for suggested cutoff regard Preptin for detection of diabetes
Area Cutoff P
95% Confidence Interval
Sensitivity Specificity Lower
Bound
Upper Bound
1.000 <122 0.00** 1.000 1.000 100.0% 100.0%
Table 2; showed that significant AUC with cutoff <122 with sensitivity 100% and specificity 100%.
Figure1;this study showedthat preptin is significantly positive correlate with GFR, onset of diabetes, HDL and serum albumin but significantly negative correlate with ACR, Urinary albumin, Creatinine, BUN, Duration of Diabetes, SBP, FBS, Cholesterol, Triglycerides, LDL, BMI and age.
Correlation between preptin and GFR Correlation between preptin and ACR
Correlation between preptin and Urinary – albumin
Correlation between preptin and Serum – albumin
Figure 2;this study showed that significant AUC with cutoff <93.5 with sensitivity 80.0% and specificity 83.3%.
Figure (2): ROC Curve for detection of Nephropathy cases cutoff regard Preptin.
DISCUSSION
This study regarding gender showed that the male to female ratio is 1:1, this is because type 1 diabetes mellitus is a genetic disease equally affect male and female. This finding is in agreement with studies done by Kalyva et al. (2011), Emmanouilidou et al. (2008) in Greece. (Table 1).
Also, Abd El Dayem et al. (2015) found thatthere was no significant difference between the different groups regarding gender withpatients with type 1 diabetes (50% males and 50% females) and healthy volunteers (50% males and 50% females).
In the present study, weight and BMI were significantly higher in DN group than control group and T1DM without DN.
In agreement with our study,Dawood et al. (2017) found that BMI was significantly higher in DN groups compared with the control group.
In disagreement with our study,Jabar, (2019) found that there was no significant difference concerning the body mass index between the patients (24.31 ± 0.54 kg/cm2) and the control (26.18 ± 0.57 kg/cm2). This difference may be because of the species differences and differences in study design.
In the current study, family history of DM was positive in 17.6% and 23.5% in group I and II (Table 1).
This came in agreement withHjort et al. (2017) who found that family history of diabetes is a strong predictor of diabetes risk. Previous studies have indicated that diabetes in first-degree relatives confers a nine-fold greater risk of type 1 diabetes.
The validity for suggested cutoff regard Preptin for detection of diabetes showed significant AUC with cutoff <122 with sensitivity 100% and specificity 100% (Table 2).
This came in agreement withJabar, (2019) who found that the children affected with type-1 diabetes mellitus had a significantly lower serum level of preptin hormone (82.79 ± 4.3 ng/ml) compared with the control group (138.62 ± 6.1 ng/ml) at a p value of fewer than 0.05.
Also,wang et al. (2012) found that the preptin was significantly lower in the diabetics than controls.
Pancreatic islet beta-cells secrete the preptin along with insulin and amylin. Preptin may enhance the insulin-like growth factor receptor linked to the protein kinase to enhance the calcium-dependent insulin secretion under great glucose levels. This result may provide a new insight about the autocrine action of preptin (EL-Eshmawy and Abdel Aal 2015). It had been suggested that unstable blood glucose concentrations similar those seen during the postprandial hyperglycemic condition in people with type I-DM, which may contribute to a significant oxidative stress – even more than that seen in chronically elevated blood glucose (Hirsh and Brownlee, 2005).
Dysfunction of the mitochondria could be one of many chief underlying imperfections that linking obesity to type I diabetes, by decreasing insulin sensitivity and by compromising β-cell function of pancreas. The results clears that there is a negative correlation between preptin hormone level and glucose level in patients group. Preptin level may decreased with insulin level decreasing therefore it decreases with diabetic patients and increases with controls group with increasing insulin concentration (Cadenas and Davies, 2000, Martin and Brand, 2010, Robert et al., 2011).
In disagreement with our study, an investigation performed in patients with type 1
diabetes showed that patients with type 1 diabetes
had significantly increased preptin concentrations than in the controls (Abd El Dayem et al., 2015).
Furthermore, Hamzah et al. (2020), Wang et al. (2019) and Yang et al. (2009) found that serum preptin concentrations were elevated in DM and DN groups compared to control group.
Although Ahmad et al. (2019) and Kalayci et al. (2019) and Abd El Dayem et al.
(2015) found that preptin, was significantly higher in patients with diabetes than in controls.
This difference was due to these studies were done in adult patient with T2DM.
In addition, GDM patients had elevated plasma, cord blood, and colostrum preptin than the control women (Aslan et al., 2011). However, another study demonstrated that there was no statistical difference in preptin between GDM patients and controls (Baykus et al., 2012). As for the status of prediabetes, IGT subjects had elevated serum preptin than subjects with normal glucose tolerance (Bu et al., 2012). However, Yang et al. (2009) reported that serum preptin concentrations showed no significant differences between IGT and healthy controls. These conflicting results may be explained by different enrolled populations and different ELISA kits.
In the present study, preptin is significantly positive correlated with GFR, onset of diabetes, HDL and serum albumin but significantly negative correlate with ACR, Urinary albumin, Creat, BUN, Duration of Diabetes, SBP, FBS, Cholesterol, Triglycerides, LDL, BMI and age. (Figure 1)
This result demonstrated decrease serum preptin was correlated with DN and with renal function declines.
The validity for suggested cutoff regard preptin for detection of Nephropathy showed significant AUC with cutoff <93.5 with sensitivity 80.0% and specificity 83.3% (Figure 2).
Our result came in agreement with other studies that found serum preptin was correlated with metabolic syndrome characteristics including obesity (Ozkan et al., 2013, El- Eshmawy and Abdel Aal. 2015) hypertension, (Bu et al., 2012, Cai et al., 2018) and hyperlipidemia (Bu et al., 2012, Yang et al., 2009). Also, El-Eshmawy and Abdel Aal.
(2015) found that preptin was correlated with BMI. This confirms the important role of preptin in body metabolic mechanism.
We found association between preptin and systolic blood pressure which may suggest early renal injury and DN progression.
Furthermore the association between preptin and systolic blood pressure may suggest and indirect prediction role of preptin as a cardiovascular morbidity marker in diabetic patient (Wang et al.2019)
But, Kalayci et al. (2019) and Yang et al. (2009) found thatpreptin level showed a positive correlation with glucose, and HbA1c levels.
This results came in disagreement with Wang et al. (2019) who found that increased serum preptin concentrations were correlated with DN and renal functional parameters this difference may be due to that their study was on T2DM in adults.
Conclusion:
We can conclude there was a significant correlation between serum preptin and renal function. Preptin may play an important role in the development of diabetic nephropathy.
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