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The bone hormones and their potential effects on glucose and energy metabolism

Abstract

The bones form the framework of our body. We know that bones protect our vital organs, regulate calcium and phosphorous homeostasis, and function as a site of erythropoiesis. More recently, however, the identification of bone hormones has allowed us to envision bones as endocrine organs too. Within the last few years, the bone hormones osteocalcin and lipocalin 2 have been implicated with glucose and energy metabolism. We systematically reviewed articles surrounding this subject and found a clear relationship between the osteocalcin levels and glucose tolerance and insulin sensitivity. We also found that many journals have shown the detrimental effects of an absences of lipocalin 2 from adipocytes. As osteocalcin administration to mice showed decreased blood glucose levels and promoted glucose tolerance and insulin sensitivity. Future studies could perhaps explore the use of osteocalcin as a supplement for type 2 diabetes.

Open access
The coexistence of infundibular pituicytoma and Cushing’s disease due to pituitary adenoma: A case report

Abstract

Objectives. Pituicytomas are rare, solid, well-circumscribed, low grade (grade I), non-neuroendocrine, and noninfiltrative tumors of the neurohypophysis or infundibulum, which appear in the sellar/suprasellar regions. Herein, we present a case with Cushing’s disease (CD) caused by an ACTH-secreting pituitary adenoma in association with an infundibular pituicytoma.

Subject and Results. A 37-year-old male patient presented to the hospital with a six-month history of blurry vision. Physical examination demonstrated plethora, excessive sweating, weight gain, moon facies, and acne. Basal serum cortisol and ACTH levels were 16 µg/dl and 32 pg/ml, respectively. The results of screening tests were suggestive of Cushing syndrome. It was also 1.97 µg/dl following 8 mg dexamethasone suppression test which was consistent with CD. Pituitary MR imaging revealed a single lesion measuring 6x6.5 mm on the pituitary stalk. Infundibular mass excision and pituitary exploration by extended endoscopic endonasal approach were applied. On immunohistochemistry, strong diffuse immunolabeling for both S100 and TTF-1 was noted for the cells of infundibular mass, diagnosed as pituicytoma. Because the developed panhypopituitarism postoperatively, patient was discharged with daily desmopressin, levothyroxine, hydrocortisone, and intramuscular testosterone, once a month.

Conclusions. Pituicytoma is an uncommon noninvasive tumor of the sellar and suprasellar regions. In this case report, we described a patient with Cushing’s disease to whom MRI displayed only an infundibular well-circumscribed lesion, but not any pituitary adenoma. Despite the absence of any sellar lesion, awareness of other undetected possible lesion and exploring hypophysis during the transsphenoidal surgery is mandatory for the correct diagnosis.

Open access
Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase

Abstract

Objectives. Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine.

Methods. Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 μg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured.

Results. All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation.

Conclusions. NaHS was more effective in AP amelioration than the leptin and curcumin.

Open access
Early postnatal hypothalamic-pituitary-adrenal axis activity and reduced insulin sensitivity in adult rats

Abstract

Objective. Early life stress influences the development of metabolic disorders, including functional changes in the developing of pancreas mediated hypothalamic-pituitary-adrenal (HPA) axis. In the present study, the role of an early postnatal stress on corticosterone, glucose, and insulin levels was investigated during young adulthood.

Methods. Two groups of pups were studied, including control group (pups not receiving foot shock by communication box), and early stress group (pups receiving foot shock by communication box 2 times/day for 5 consecutive days). In rats, concentration of plasma corticosterone, glucose, and insulin was detected before and after placing them into the communication box at 2 weeks of age. At 8–10 weeks of age, concentrations of plasma corticosterone, glucose, and insulin and glucose tolerance were measured in young adult rats.

Results. Our results showed that early postnatal foot shock stress increased the corticosterone, insulin, and glucose levels in the postnatal age (p<0.01) that did not last until young adult age, but it caused a significant increase in plasma glucose and insulin levels (p<0.05) following the intraperitoneal glucose tolerance test (IPGTT) in young adult rats.

Conclusions. These results suggest that impaired IPGTT in young adult rats who experienced early postnatal stress can indicate insulin resistance or reduced insulin sensitivity that make it at risk of the type 2 diabetes later in life.

Open access
Effect of glucose deprivation on the expression of genes encoding glucocorticoid receptor and some related factors in ERN1-knockdown U87 glioma cells

Abstract

Objective. The aim of the present study was to examine the effect of glucose deprivation on the expression of genes encoded glucocorticoid receptor (NR3C1) and some related proteins (NR3C2, AHR, NRIP1, NNT, ARHGAP35, SGK1, and SGK3) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1) for evaluation of their possible significance in the control of glioma growth through endoplasmic reticulum stress signaling mediated by IRE1 and glucose deprivation.

Methods. The expression of NR3C1, NR3C2, AHR, NRIP1, NNT, ARHGAP35, SGK1, and SGK3 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control cells) and cells without ERN1 signaling enzyme function (transfected by dnERN1) under glucose deprivation was studied by real time quantitative polymerase chain reaction.

Results. It was shown that the expression level of NR3C2, AHR, SGK1, SGK3, and NNT genes was up-regulated in control U87 glioma cells under glucose deprivation condition in comparison with the control cells growing with glucose. At the same time, the expression of NRIP1 gene is down-regulated in these glioma cells under glucose deprivation, but NR3C1 and ARHGAP35 genes was resistant to this experimental condition. We also showed that inhibition of ERN1 signaling enzyme function significantly modified the response of most studied gene expressions to glucose deprivation condition. Thus, effect of glucose deprivation on the expression level of NR3C2, AHR, and SGK1 genes was significantly stronger in ERN1 knockdown U87 glioma cells since the expression of NNT gene was resistant to glucose deprivation condition. Moreover, the inhibition of ERN1 enzymatic activities in U87 glioma cells led to up-regulation of ARHGAP35 gene expression and significant down-regulation of the expression of SGK3 gene in response to glucose deprivation condition.

Conclusions. Results of this study demonstrated that glucose deprivation did not change the expression level of NR3C1 gene but it significantly affected the expression of NR3C2, AHR, NRIP, SGK1, SGK3, and NNT genes in vector-transfected U87 glioma cells in gene specific manner and possibly contributed to the control of glioma growth since the expression of most studied genes in glucose deprivation condition was significantly dependent on the functional activity of IRE1 signaling enzyme.

Open access
Effect of letrozole on spermogram parameters and hormonal profile in infertile men: A clinical trial study

Abstract

Objective. There is no reliable treatment for men with idiopathic infertility, but the relationship between severe sperm production and the ratio of estrogen to testosterone levels has been shown. Aromatase is an enzyme that plays an important role in converting testosterone to estradiol and androstenedione to estrogen. Aromatase inhibitors can increase testosterone and androgen production without increasing the amount of estrogen in circulation. The aim of this study was to evaluate the effect of aromatase inhibitor letrozole on the male infertility.

Method. This pre- and post-quasi-experimental clinical trial was carried out on 41 men with an infertility diagnosis. The basic hormonal profile included FSH, LH, testosterone, and estradiol. The ratio of testosterone to serum estradiol was also calculated and recorded. The sperm analysis was performed before the treatment and the seminal parameters were evaluated and recorded. Patients were then treated with letrozole 2.5 mg daily for 4 months. At the end of 4th months, the hormonal profile was studied and seminal analysis performed and recorded.

Results. The levels of FSH, LH, testosterone, and estradiol, and the ratio of testosterone to estradiol increased significantly after letrozole treatment. The sperm concentration, sperm motility, and sperm forward motion significantly increased after letrozole treatment. Sperm morphology only lightly altered.

Conclusion. The ratio of testosterone to estradiol levels in infertile men treated with aromatase inhibitor improved and caused changes in sperm parameters. Letrozole may be used to improve sperm parameters in infertile men with low serum testosterone to estradiol ratio.

Open access
Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

Abstract

Objective. The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia.

Methods. The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction.

Results. It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells.

Conclusions. Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth.

Open access
Aldosterone rapidly activates p-PKC delta and GPR30 but suppresses p-PKC epsilon protein levels in rat kidney

Abstract

Objectives. Aldosterone rapidly enhances protein kinase C (PKC) alpha and beta1 proteins in the rat kidney. The G protein-coupled receptor 30 (GPR30)-mediated PKC pathway is involved in the inhibition of the potassium channel in HEK-239 cells. GPR30 mediates rapid actions of aldosterone in vitro. There are no reports available regarding the aldosterone action on other PKC isoforms and GPR30 proteins in vivo. The aim of the present study was to examine rapid actions of aldosterone on protein levels of phosphorylated PKC (p-PKC) delta, p-PKC epsilon, and GPR30 simultaneously in the rat kidney.

Methods. Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (150 µg/kg body weight). After 30 minutes, abundance and immunoreactivity of p-PKC delta, p-PKC epsilon, and GPR30 were determined by Western blot analysis and immunohisto-chemistry, respectively.

Results. Aldosterone administration significantly increased the renal protein abundance of p-PKC delta by 80% (p<0.01) and decreased p-PKC epsilon protein by 50% (p<0.05). Aldosterone injection enhanced protein immunoreactivity of p-PKC delta but suppressed p-PKC epsilon protein intensity in both kidney cortex and medulla. Protein abundance of GPR30 was elevated by aldosterone treatment (p<0.05), whereas the immunoreactivity was obviously changed in the kidney cortex and inner medulla. Aldosterone translocated p-PKC delta and GPR30 proteins to the brush border membrane of proximal convoluted tubules.

Conclusions. This is the first in vivo study simultaneously demonstrating that aldosterone administration rapidly elevates protein abundance of p-PKC delta and GPR30, while p-PKC epsilon protein is suppressed in rat kidney. The stimulation of p-PKC delta protein levels by aldosterone may be involved in the activation of GPR30.

Open access
Efficacy and safety of dulaglutide in patients with absolute insulin deficiency

Abstract

Objective. While dulaglutide has been approved inpatients with type 2 diabetes (T2DM) in combination with insulin, it has not been studied in insulin-deficient patients, not whether they have type 1 diabetes (T1DM) or T2DM. The aim of this study is to assess the efficacy and safety of dulaglutide 0.75 mg/once weekly (QW) in patients with absolute insulin deficiency (n=10).

Subjects and Results. Significant reductions of HbA1c (9.30±1.03% to 8.61±1.21%; p<0.02) and body mass index (BMI; 23.61±3.95 to 23.41±4.24; p<0.02) levels were observed at 3 months with the addition of dulaglutide to the existing pharmacotherapy. However, in all the patients, post-meal C-peptide levels remained undetectable. One patient had gastrointestinal adverse events and discontinue dulaglutide within the first month. One patient was a non-responder, who had little if any changes in HbA1c levels at 3 months.

Conclusions. The results indicate that dulaglutide is effective in patients with T1DM or T2DM with absolute insulin deficiency, though gastrointestinal adverse events might be of concern. The improvements in glycemic control could not be due to enhanced insulin secretion, but may be as a result of a combination of the other effects of glucagon like peptide 1 (GLP-1), such as postprandial glucagon suppression, delayed gastric emptying, and weight loss.

Open access
Implantation and pregnancy outcome of Sprague-Dawley rats exposed to pirimiphos-methyl

Abstract

Objective. This study was designed to investigate the effect of sublethal doses (10, 60, and 120 mg/kg of pirimiphos-methyl on implantation and pregnancy in female Sprague-Dawley rats. Pirimiphos-methyl is a pesticide widely used worldwide, especially in Africa to protect food against pests and has gained widespread acceptance.

Methods. Pregnant Sprague-Dawley rats used for this study had access to food and water ad libitum and were divided into a control group and three experimental groups based on dose of chemical given. The pregnant rats were given pirimiphos-methyl orally on days 1–5, 1–7, 7–18th day of gestation and from day 1 to term. Implantation studies were carried out on days 6 and 8 of pregnancy, while the fetal parameters were ascertained on day 19 of pregnancy and at term. Serum levels of progesterone and estradiol were measured on days 6, 8 and 19 of pregnancy.

Results. Sublethal administration of pirimiphos-methyl showed decreased number of implantation sites on days 6 and 8, fetal weight, crown-to-rump length, length of umbilical cord and placenta weight (day 19), birth weight, litter size and total number (at term) in rats administered with pirimiphos-methyl when compared with control.

Conclusion. Administration of pirimiphos-methyl resulted in a reduced implantation rate due to decreased uterine receptivity caused by an imbalance in the level of estradiol and progesterone and impaired reproductive outcome during pregnancy.

Open access