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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1143-1148

A study on the effect of estrogen on the insulin signaling pathway in diabetic rats


1 Department of Clinical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Head of Molecular Biology Unit, Faculty of Medicine, Banha University, Banha, Egypt
3 Department of Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission06-Jan-2017
Date of Acceptance28-Mar-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Anwaar M Shaban
Department of Clinical Physiology, Faculty of Medicine, Menofia University, Menofia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_57_17

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  Abstract 


Background
Diabetes mellitus (DM) is a worldwide metabolic disorder that is associated with many complications. Recently, it has been noted that estrogen has a beneficial effect on type II DM.
Objective
The aim of this study was to prove that the use estrogen could improve the metabolic state in type II DM.
Materials and methods
Eighty adult female albino rats weighing 200–250 g were used. Diabetes was induced by means of a single intraperitoneal injection of streptozotocin 40 mg/kg. Rats were divided into the following groups: the control group (group C); the ovariectomized control group (group OVX C); the diabetic group (group D); the diabetic ovariectomized group (group OVX D); the diabetic insulin-treated group (group DI), in which insulin was administered at a dose of 10–20 IU/kg for 6 days/week by means of subcutaneous injection; the diabetic ovariectomized insulin-treated group (group OVX DI); the diabetic nonovariectomized estrogen and insulin treated group (group DEI), in which estradiol was administered at a dose of 50 μg/kg; and the diabetic ovariectomized estrogen and insulin treated group (group OVX DEI). After 12 weeks, fasting blood glucose level, glycosylated hemoglobin level, and fasting serum lipids were measured. Retroperitoneal adipose tissue was taken for measurement of insulin receptor substrate 1 (IRS1) gene expression using reverse transcriptase-PCR.
Results
Combined estrogen and insulin treatment induced a significant decrease in fasting blood glucose, HbA1C Glycated hemoglobin, and fasting serum lipid profile with an increase in IRS1 protein gene expression level.
Conclusion
Results should be considered in prediabetic and or diabetic postmenopausal women.

Keywords: diabetes, estrogen, insulin, ovariectomy


How to cite this article:
Hana GY, Ali AI, Donia SS, Shaban AM. A study on the effect of estrogen on the insulin signaling pathway in diabetic rats. Menoufia Med J 2017;30:1143-8

How to cite this URL:
Hana GY, Ali AI, Donia SS, Shaban AM. A study on the effect of estrogen on the insulin signaling pathway in diabetic rats. Menoufia Med J [serial online] 2017 [cited 2024 Mar 28];30:1143-8. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1143/229233




  Introduction Top


Diabetes mellitus (DM) is a worldwide metabolic disorder that is associated with many system complications[1].

It is of two types: type-I, which is due to lack of insulin secretion, and type-II DM, in which the body cells become resistant to insulin because of defects in the insulin signaling pathway with reduced IRS I tyrosine phosphorylation[2].

Recently, it has been noted that estrogen may have some beneficial effect in type-II DM[3], especially its stimulatory effect on the insulin signaling pathway[1]. Estrogen action in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation. Estrogen action on pancreatic β-cells regulates insulin secretion and nutrient homeostasis[4],[5].

The aim of the present work was to prove that the use of estrogen can improve the metabolic state in type II DM.


  Materials and Methods Top


The present study was conducted at the Medical Physiology Department, Faculty of Medicine, Menoufia University, Egypt. It was approved by the research ethics committee at the Faculty of Medicine, Menoufia University. A total of 80 adult female albino rats of local strain weighing 200–250 g each were included. Rats were obtained from a licensed trainer, maintained on standard laboratory chow and water, and housed in the animal house at the Faculty of Medicine, Menoufia University, in cages measuring 70 × 70 × 60 cm, five animals/cage. They were classified into the following groups: the control group (group C) (n = 10); the ovariectomized control group (group OVX C) (n = 10); the diabetic control group (group D) (n = 10); the ovariectomized diabetic nontreated group (group OVX D) (n = 10); the insulin-treated nonovariectomized diabetic group (group DI) (n = 10); the insulin-treated ovariectomized streptozotocin (STZ) diabetic group (group OVX DI) (n = 10); the estradiol and insulin treated nonovariectomized diabetic group (group group DEI) (n = 10); and the estradiol and insulin treated ovariectomized STZ diabetic group (group OVX DEI) (n = 10). Rats in the ovariectomized control group were subjected to ovariectomy. In the diabetic control group (group D) (n = 10), rats were rendered diabetic through a single intraperitoneal injection of STZ (SIGMA-Aldrich, Saint Louis, Missouri, USA) (40 mg/kg) in 0.2 ml of 10 mmol/l citrate buffer (pH 4.5)[6]. Intraperitoneal 0.5 ml dextrose 5% was administered as a protective dose 30 min before the STZ injection to avoid sudden hypoglycemia[7]. Rats were considered diabetic when fasting blood glucose (FBG) levels exceeded 113 mg/dl[8]. In the ovariectomized diabetic nontreated group (OVX D) (n = 10)[9], rats received a single injection of STZ (Sigma)[10] 2 weeks after complete cure. In the insulin-treated nonovariectomized diabetic group (group DI) (n = 10), rats received a single injection of STZ (Sigma), and then received daily subcutaneous injection of mixtard insulin (MUP, Inc., Cairo, Egypt) at a dose of 10 or 20 IU/kg/day, 6 days/week, according to their blood glucose level on the first day[10]. In the estradiol and insulin treated nonovariectomized diabetic group (group DEI) (n = 10), rats were rendered diabetic, and then administered subcutaneous injection of estradiol (Sigma) at a dose of 50 μg/kg/day in a virgin olive oil vehicle, 6 days/week for 12 weeks[11]. In addition to this, they received daily subcutaneous injection of mixtard insulin. In the estradiol and insulin treated ovariectomized STZ diabetic group (group OVX DEI) (n = 10), rats were subjected to bilateral ovariectomy, and 2 weeks later they were rendered diabetic. On the next day, they received subcutaneous injections of estradiol and insulin. After 12 weeks of treatment, FBG sample was taken for measurements of FBG level, glycosylated hemoglobin (HbA1C) level, and fasting serum lipids, and then scarified for adipose tissue sample collection.

Method of overiectomy: anesthesia was induced by placing the rat in a large jar containing a pad of cotton sprinkled with ether, and the jar was covered. Anesthesia was maintained throughout the operation with the use of a mask containing cotton pad moistened with ether[12]. Rat was fixed in the supine position and a single ventral midline skin incision was made in the abdomen extending from the symphysis pubis upward for about 2 cm, and then the skin was retracted laterally and the abdominal muscle and peritoneum were incised from the level of the urinary bladder to the level of the lower poles of the kidneys. The ovary on each side was exposed. Hemostasis was ensured through ligation of the upper horns of the uterus with a chromic catgut suture 2-0, and each ovary together with its surrounding fat and oviduct was removed. The abdominal muscles and the skin were closed with interrupted stitches[9].

Reverse transcriptase-PCR method: about 1 g of adipose tissue was obtained from each rat under aseptic condition and stored in phosphate buffer saline at −80°C for further quantitation of gene expression using reverse transcriptase-PCR. Total RNA was extracted from about 50 mg of adipose tissue sample from each rat using Pure Link RNA mini kit (Life Technologies, Woburn, MA, United States) following the manufacturer's instructions, in addition to DNase digestion using Purelink RNase free DNase set to remove trace amounts of genomic DNA (Life Technologies). Eluted RNA (30 μl) was collected immediately and stored at −20°C for further processing. Ultraviolet Spectrophotometric Quantification of RNA using nano drop 2000 Spectrophotometer (Thermo Fisher Scientific, Wilmington, Delaware, USA) was carried out to ensure significance. A260 readings should be greater than 0.15. An absorbance of 1 U at 260 nm corresponds to 40 μg of RNA/ml. The ratio between the absorbance values at 260 and 280 nm gives an estimate of RNA purity; pure RNA has an A260/A280 ratio of 1.9–2.3.

Statistical analysis

All data were collected, tabulated, and statistically analyzed using statistical package for the social sciences 19.0 for windows (SPSS; SPSS Inc., Chicago, Illinois, USA) and Med Calc 13 for windows (MedCalc Software BVBA, Ostend, Belgium). All data were expressed as mean ± SD and the analysis of variance test was used to compare the mean difference between groups. The sample size was 10 rats. A P value less than 0.05 was considered significant.


  Results Top


Statistically significant differences were found in the FBG level between groups (P< 0.001); F-test value was 39.1. FBG was 270.5 ± 9.62 (mg/dl) in the D group, which was significantly higher (P< 0.001) when compared with the C and OVX C groups. It was 326.5 ± 7.58 (mg/dl) in the D OVR group, which was nonsignificantly different (P = 0.165) when compared with the D group, but it was significantly different (P< 0.001) when compared with the C and OVX C groups. It was 142.3 ± 3.24 (mg/dl) in the DI group, which was significantly lower (P< 0.001) when compared with the D, OVX D, C, and OVX C groups. It was 166.6 ± 2.29 (mg/dl) in the OVX DI group, which was significantly lower when compared with the D, OVX D, C, and OVX C groups, but it showed a nonsignificant change (P = 0.058) when compared with the DI group. It was 98.7 ± 4.72 (mg/dl) in the DEI group, which was significantly lower (P< 0.001) when compared with the C, OVX C, D, OVX D, DI, and OVX DI groups. It was 102.4 ± 6.92 mg/dl in the OVX DEI group, which was significantly lower (P< 0.001) when compared with the C, OVX C, D, OVX D, DI, and OVX DI groups, but the change was nonsignificant when compared with the DEI group (P = 0.179) [Table 1].
Table 1: The mean±SD value of fasting blood glucose in mg/dl in all studied groups

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Statistically significant differences were found in HbA1C% level between groups (P< 0.001) (F = 104.3). HbA1C% level in the D group was 16.08 ± 1.58%, which was significantly higher (P< 0.001) when compared with the C and OVX C groups. It was 15.99 ± 0.60% in the OVR D group, which was nonsignificantly lower (P = 0.863) when compared with the D group, but it was significantly higher when compared with the C and OVX C groups. It was 8.88 ± 0.88% in the DI group, which was significantly lower (P< 0.001) when compared with the C, OVX C, D, and OVX D groups. It was 10.52 ± 1.53% in the OVR DI group, which was significantly lower when compared with the C, OVX C, D, OVX D, and DI groups. It was 5.64 ± 0.52% in the DEI group, which was significantly lower when compared with the D group, but nonsignificantly different (P = 0.387) when compared with the OVX C, and C groups (P = 0.0.056). It was 6 ± 0.45% in the OVR DEI group, which was significantly lower when compared with the C, D, OVX D, and DI groups, but the difference was nonsignificant (P = 0.614) when compared with the OVX C and DEI groups (P = 0.113) [Figure 1].
Figure 1: The % of glycosylated hemoglobin level in the control group (group C), the ovariectomized control group (group OVX C), the diabetic group (group D), the ovariectomized diabetic group (group OVX D), the diabetic insulin-treated group (group DI), the ovariectomized diabetic insulin-treated group (group OVX DI), the diabetic estrogen and insulin treated group (group DEI), and the ovariectomized diabetic estrogen and insulin treated group (OVX DEI). (*)Significant when compared with the control group. #Significant when compared with the overectomized control group. @Significant when compared with the diabetic group. $Significant when compared with the diabetic insulin-treated.

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There was a highly significant change in the fasting serum lipids between groups (P< 0.001). Values of total cholesterol, triglycerides, low-density lipoproteins (LDL-c), and high-density lipoproteins (HDL-c) in mg/dl in the D group were 263.2 ± 1.13, 103.1 ± 3.03, 130.35 ± 4.41, and 22.8 ± 2.35 (mg/dl), respectively; they were significantly higher when compared with the corresponding values in the C and OVX C groups. The values were 264.3 ± 3.95, 119.4 ± 6.03, 134.1 ± 5.03, and 25.9 ± 2.93 (mg/dl), respectively, in the DOVR group. The values were significantly different (P< 0.001) when compared with the corresponding values in the C and OVX C groups, but nonsignificantly different when compared with the D group (P = 0.911, 0.142, and 0.103, respectively), except for HDL-c, which was significantly different (P< 0.001). The values were 225.5 ± 4.57, 87.1 ± 6.90, 113.1 ± 3.11, and 34 ± 2.11 (mg/dl) in the DI group; the difference was highly significant when compared with the corresponding values in the C, OVX C, and OVX D groups, except for triglycerides (TGS) value, which was nonsignificant when compared with the D group. The values were 211.8 ± 2.67, 90.9 ± 5.38, and 115 ± 1.82 (mg/dl), respectively, in the OVX DI group, which were significantly different when compared with the corresponding values in the C, OVX C, D, and OVX D groups, except for TGS value, which showed a nonsignificant difference when compared with the D group (P = 0.32). However, all components of fasting serum lipids showed a nonsignificant difference (P = 0.42, 0.15, 0.738, and 0.851, respectively) when compared with the DI group. The values were 167.9 ± 1.51, 78.1 ± 3.99, 66.9 ± 33.41, and 47.33 ± 1.78 (mg/dl), respectively, in the DEI group, which was significantly different (P< 0.001) when compared with the C, OVX C, D, OVX D, DI, and OVX DI groups, except for LDL value, which showed a nonsignificant difference when compared with the OVX C group (P = 0.066). The values were 162 ± 6.46, 82.3 ± 8, 79.5 ± 9.3, and 42.79 ± 2.41 (mg/dl), respectively, in the OVX DEI group; the difference in values was significant when compared with the C, OVX C, D, OVX D, DI, OVX DI, and DEI groups, except for total cholesterol value, which showed a nonsignificant difference when compared with the C, OVX C, and DEI groups (P = 0.83, 0.15, and 0.569, respectively). Moreover, TGS showed a nonsignificant change when compared with the D, DI, and DEI groups (P = 0.069, 0.114, and 0.155, respectively) [Table 2].
Table 2: The mean±SD level of fasting serum lipids in mg/dl in all studied groups

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The logarithmic value of insulin signaling pathway protein gene in retroperitoneal adipose tissue (IRS1) was significantly changed between all studied groups (P< 0.001). It was 5.13 ± 0.031 in the D group, which was significantly different (P< 0.001) when compared with the corresponding value in the C and OVX C groups. It was 4.44 ± 0.57 in the OVX D group, which was significant (P< 0.001) when compared with the corresponding value in the C, OVX C, and D groups. It was 5.74 ± 0.62 in the DI group, which was highly significantly (P< 0.001) increased when compared with the corresponding value in the D and OVX D groups, but it was nonsignificantly different when compared with the corresponding values in the C and OVX C groups (P = 0.056 and 0.248, respectively). It was 5.72 ± 0.39 in the OVX DI group, which was significantly higher (P< 0.001) when compared with the corresponding value in the C, D, and OVX D groups but still lower compared with the C grou P value. Moreover, it was nonsignificantly different when compared with the OVR C and DI groups (P = 0.123 and 0.926, respectively). It was 6.09 ± 0.02 in the DEI group, which was highly significantly lower (P< 0.001) when compared with the corresponding values in the C, OVX C, D, OVX D, and OVX DI groups. It showed a nonsignificant difference (P = 0.069) when compared with the DI group. It was 6.05 ± 0.02 in the OVX DEI group, which was significantly higher (P< 0.001) when compared with corresponding values in the C, OVX C, D, D OVR, and OVX DI groups, but the difference was nonsignificant when compared with the DI group (P = 0.064) [Table 3].
Table 3: The mean±SD of the logarithmic value of insulin signaling pathway protein mRNA level in retroperitoneal adipose tissue (IRS-1)

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  Discussion Top


In the present investigation, administration of STZ resulted in the elevation of FBG and HbA1C in the ovariectomized and nonovariectomized groups when compared with the corresponding value in the nondiabetic group. STZ is reported to produce diabetogenic effect in rats, ranging from mild-to-moderate diabetes to severe ketotic stage at higher doses[13]. This is in agreement with the findings of El-Nasr et al.[14] and Gardner et al.[15], who concluded that ∼90% of the STZ-treated rats develop hyperglycemia during the first 72 h after injection.

STZ is a relatively selective β-cytotoxic in certain animal species. It reduces the level of nicotine adenine dinucleotide by both decreasing its synthesis and increasing its breakdown. Histopathologically, β-cell necrosis is found as a result of highly toxic carbonium ions (CH3), which is formed from decomposition of nitroso moiety. In addition, STZ causes methylation of DNA and subsequently leads to strand breaks and deactivation of the polymerase enzyme that was essential for DNA repair[16],[17].

In the present study, the insulin-treated groups showed a significant decrease in FBG and HbA1C when compared with the diabetic not-treated groups. This is in agreement with the findings of El-Nasr et al.[14]. Ovariectomy also leads to loss of the protective effect of endogenous 17β-estradiol on energy metabolism and this explains the increased blood glucose level and HbA1C level in the ovariectomized control group and the diabetic overectomized nontreated group when compared with the control group. This is in agreement with the findings of El-Nasr et al.[14].

Adipose tissue releases various modulators to insulin action, such as adipocytokines and free fatty acids, into the circulation leading to a negative feedback effect and insulin resistance. Women have only two-thirds of the skeletal muscle mass and twice the adipose mass as men leading to insulin resistance; however, women usually do not develop hyperinsulinemia and the incidence of diabetes remains equal between the two sexes until the time of menopause[18].

Gupte et al.[19] proposed the idea that 17β-estradiol at physiological concentrations closes KATP channels, which are also targets for antidiabetic sulfonylurea. Furthermore, in synergy with glucose, 17β-estradiol depolarizes the plasma membrane, elicits electrical activity, and enhances the intracellular calcium signals, which in turn enhances insulin secretion. These effects occur through a receptor located at the plasma membrane, distinct from the classic cytosolic estrogen receptor (ER). The same hypothesis was also confirmed by Nadal et al.[20], who observed a rapid depolarizing effect of 17β-estradiol on β cells leading to an influx of extracellular Ca 2+ and the initiation of insulin secretion by the consequent elevations in (Ca 2+) i, and they suggested that this may offer a mechanism through which the circulating estradiol can influence β-cell responsiveness to other signals. Thus, estrogen replacement therapy improves insulin sensitivity in postmenopausal women[21],[22].

In vivo, estradiol treatment rescued STZ-induced B-cell apoptosis, helped sustain insulin production, and prevented diabetes. In vitro, in mouse pancreatic islet B-cells exposed to oxidative stress, estradiol prevented apoptosis and protected insulin secretion. Estradiol protection was through the activation of ER as it was partially lost in B-cells and islets treated with an ER antagonist[23].

In this study, lipid profile assessment in the diabetic group showed a clear picture of dyslipidemia in the form of significant elevation of serum cholesterol, triglycerides, and LDL-c, whereas there was a significant decrease in fasting serum HDL-c when compared with the nondiabetic group. Moreover, combination of ovariectomy with diabetes resulted in more worsening of lipid profile. This is in agreement with the finding of Ali et al.[24], Grant, and Kirkman[25], who observed that there is a marked increase in serum lipids in poorly controlled diabetes due to insulin deficiency, which is reflected by the increased concentration of all serum lipid fractions and failure of the free fatty acid level to fall after ingestion of glucose. According to Li et al.[26] and Huang[27], insulin is essential in the process of degradation of LDL-c, and hence its deficiency may cause hypercholesterolemia. In this study, the diabetic and overectomized diabetic groups showed a significant decrease in IRS1 expression when compared with the control group. This is in agreement with the findings of Li et al.[26], who proved that type II DM decreases IRS-1 gene expression in all tissue (bone, skeletal muscle, liver, and adipose tissue) and this defect worsened with ovariectomy and loss of endogenous estrogen. Copps and White[28] stated that the cellular protein levels of IRS-1 are regulated by the Cullin7 E3 ubiquitin ligase, which targets IRS-1 for ubiquitin-mediated degradation by the proteasome. Different serine phosphorylation of IRS-1 are caused by various molecules such as fatty acids and tumor necrosis factor-α that have different effects on it, but most of these effects include cellular relocalization and conformational and steric changes. These processes lead to a decrease in tyrosine phosphorylation by insulin receptors. Altogether, these mechanisms stimulate IRS-1 degradation and insulin resistance[29].


  Conclusion Top


It can be concluded that estrogen deficiency with diabetes worsens its metabolic consequences. Partial improvement was found with either insulin or estrogen therapy, whereas the best cure was found with combined estradiol and insulin therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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