Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 8, 2021

Berberine is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and hypolipidemic activities. The research proves that it also strongly impacts carbohydrate metabolism. The compound also protects pancreatic β-cells and increases sensitivity to insulin in peripheral tissues via the induction of GLUT-1, GLUT-4 and insulin type 1 (Ins-1) receptors activity. It also stimulates glycolysis and leads to a decrease in insulin resistance by macrophages polarization, lipolytic processes induction and energy expenditure enhancement (by reducing body mass and limiting insulin resistance caused by obesity). In liver berberine inhibits FOX01, SREBP1 and ChREBP pathways, and HNF-4α (hepatocyte nuclear factor 4 alpha) mRNA that hinder gluconeogenesis processes. In the intestines it blocks α-glucosidase contributing to glucose absorption decrease. Its interference in intestinal flora reduces levels of monosaccharides and suppresses diabetes mellitus complications development.

The management of subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) in pregnancy is still uncertain. Over the years, several scientific societies published guidelines on the management of thyroid dysfunction before, during, and after pregnancy, the most recent ones being published by the American Thyroid Association (ATA) in 2017. This study aimed to review the published literature in the field from 2017 onward to investigate whether new findings can change ATA recommendations. A literature search was conducted in PubMed between March 2017 (date of the publication of the ATA guidelines) and March 2020. The research was restricted to randomized controlled trials (RCTs), having pregnancy-related complications in patients with SCH and TAI as the main focus. A total of 5 RCTs were retrieved, 2 of which investigated pregnant women with SCH and 3 with TAI. Selected studies displayed proofs against treating maternal SCH and hypothyroxinemia because no benefit from LT4 was demonstrated in offspring intelligence quotient and in pregnancy outcomes; moreover, they reported proofs against treating TAI patients because no benefit from LT4 was demonstrated in improving pregnancy rate or live birth rate or reducing miscarriage rate.RCTs published from 2017 to 2020 might have a significant impact on current ATA guidelines. In particular, they suggested that isolated hypothyroxinemia and SCH should not be treated and that considering treatment in antibodypositive women, especially those with TSH of 2.5–4.0 mIU/L, would not be justified; they suggested that infertility and miscarriage rates are not decreased by LT4 treatment in euthyroid antibody-positive women seeking pregnancy.

The complications of the SARS-CoV-2 infection and its COVID-19 disease on mothers and their offspring are less known. This review aimed to determine the transmission, severity, and complications of SARS- CoV-2 infection during pregnancy. This review showed the influence of COVID-19 disease on neonatal neurogenesis. Owing medicines that were reported for the treatment of COVID-19 disease, this review suggested some control strategies like treatments (medicinal plants, antiviral therapy, cellular therapy, and immunotherapy), nutrition uptake, prevention, and recommendations. This overview showed that severe infection of SARS-CoV-2 during the early stage of pregnancy might increase the risk of stress, panic, and anxiety. This disorder can disturb the maternal immune system, and thus causing a neurodevelopmental disturbance. This hypothesis may be depending on the severity and intensity of the SARS-CoV-2 infection during pregnancy. However, vertical transmission of SARS-CoV-2 from dams to their fetuses is absent until now. During this global pandemic disease, maintaining safety during pregnancy, vaginal delivery, and breastfeeding may play a vital role in a healthy life for the offspring. Thus, international, and national organizations should be continuing for perinatal management, particularly during the next pandemic or disaster time.

Background: Adult growth hormone deficiency (GHD) is considered a rare condition. Current guidelines state that GH provocative test is indicated in patients affected by organic hypothalamic/ pituitary disease or with a history of head injury, irradiation, hemorrhage or hypothalamic disease with multiple pituitary deficiencies. Nevertheless, the clinical picture related to GHD may be subtle. Objective: We have retrospectively evaluated the indication to GHRH+arginine test in our monocentric cohort of patients treated with hrGH in order to assess whether other conditions had been considered as a rationale for provocative testing. Methods: Ninety-six patients (51 females and 45 males), aged 19-67 years were included. The GHRH+arginine test had been performed in 29 patients with organic hypothalamic/pituitary disease and in 4 patients for Childhood onset-GHD (CoGHD). In other patients, the diagnosis was suspected for “non classical” reasons in the clinical picture suspected for GHD. Results: Classical indications included previously known primary empty sella (n=15), pituitary surgery (n=14), pituitary cyst (n=1), non-secreting pituitary tumors (n=3) but more than half of the patients (57.3%) had been studied for “non classical” indications: metabolic syndrome (n=25), asthenia (n=13), heart failure (n=4), osteoporosis (n=6), unexplained hypoglycaemia (n=1) and infertility (n=6). The latter represented a significant percentage in the male subgroup under 45 ys. IGF-1 levels were lower than 50th percentile in 63% of patients. Finally, among non-classical reasons, organic pituitary disease was discovered in 22 patients. Conclusion: Idiopathic GHD may be unrecognized due to its subtle manifestations and that an extended use of dynamic GH tests may reveal such conditions. A potential field of investigation could be to identify subsets of patients with clinical conditions caused or worsened by underlying unrecognized GHD.

Leptin levels and oxidative stress are implicated in obesity risk. Reports of association of leptin gene (LEP) and leptin receptor gene (LEPR) polymorphisms with leptin elevation are contradictory in a diverse population. Only a few studies report the linkage of obesity with biochemical markers and genetic factors. Objective: The aim of this study was to examine whether plasma lipid peroxidation, antioxidant capability, leptin levels are associate selected LEP -2548 A/G and LEPR Q223R polymorphisms in mestizo and indigenous obesity Mexican population. Methods: We identified and characterized 50 overweight or obese subjects and 50 healthy, normal- weight volunteers with indigenous Tepehuana or Mexican mestizo ethnicity from Durango, Mexico. LEP -2548 A/G and LEPR Q223R polymorphisms were determined by genotyping. Concentrations of leptin, antioxidant capacity (CA) and lipoperoxidation (LIPX) were determined in fast conditions on plasma with Enzyme-Linked ImmunoSorbent Assay (ELISA) in all participants. Results: The highest genotype frequency was the heterozygous LEPR, which was associated with lipid peroxidation levels in normal-weight Tepehuan populations. A positive correlation was observed (r = 0.5; p <0.01) between LEP polymorphism and lipoperoxidation in normal weight Tepehuan subjects. On the other hand, the LEPR polymorphism was associated with the level of lipoperoxidation (r = 0.13; P <0.05) in mestizo populations of normal weight. Conclusion: It is probable that there is a synergistic effect for obesity, where the presence of oxidative stress and single nucleotide polymorphisms (SNP) of leptin and its receptor contributes to the generation of pathological subcutaneous fat of obesity, together with the environmental conditions of the populations.

Aims: The study aimed to assess the antihyperglycemic effect of Cleome arabica. Background: Cleome arabica L. or spider flower belongs to the Capparidaceae family and it is used for treating inflammation and diabetes mellitus in traditional medicine. Objective: This study aimed to evaluate the antihyperglycemic activity and acute toxicity of the aqueous extract of Cleome arabica L (CAAE). Methods: The acute toxicity of CAAE was evaluated at doses of 500, 1000, or 2000 mg/kg. Parallelly, body weight, signs of toxicity, and/or mortality were observed for 14 days. The effect of oral administration of Cleome arabica aqueous extract (CAAE) at a dose of 100 mg/kg on glycemia was performed in normal and diabetic rats. Additionally, histopathological structure of the liver, phytochemical screening and in vitro antioxidant activity were studied. Results: The acute toxicity test revealed that all treated rats survived, and no change in body weight was observed. The results demonstrated that CAAE exhibited a significant antihyperglycemic effect in diabetic rats. Furthermore, the plant extract ameliorated the liver histology in diabetic rats with a concomitant antioxidant activity. Conclusion: This study shows that Cleome arabica is partly safe, and its LD50 seems to be greater than 5000 mg/kg. Cleome Arabica has a favorable effect against diabetes, which could be due to the presence of numerous secondary metabolites and by the protection of hepatocytes.

Background: One of the widely spread disorders is Diabetes mellitus, especially type 2 (T2DM). T2DM is attributed to the change in life style and stress. A possible strategy to block dietary carbohydrate absorption is regulation of postprandial blood glucose level as well, the use of some natural plant extracts with inhibitory effect against carbohydrate digestive enzymes such as alpha- amylase and fewer side effects than synthetic drugs. This study was conducted to investigate the anti-diabetic effect of Cinnamon and Saussurea extract, individually, on blood glucose, lipid profile, insulin, interleukin1-beta and weight loss in diabetic rats treated with Streptozotocin (STZ). Methods: The experiment was performed on 60 Wistar male rats; the experimental study include 6 groups (10 rats each): (I) normal rats, (II) Streptozotocin- induced diabetic rats, (III) normal rats orally received (200 mg/kg/day) Saussurea ethanolic extract (SEE) for consecutive 4 weeks, (IV) normal rats orally received (100mg/kg/day) Cinnamon aqueous extract (CAE) for consecutive 4 weeks, (V) Streptozotocin –treated rats received SEE orally (200mg /kg/ day) for consecutive 4 weeks, and (VI) Streptozotocin –treated rats received CAE orally (100mg /kg/ day) for consecutive 4 weeks. Results: The results of the following study revealed that SEE has more anti-diabetic effect against Streptozotocin treatment than CAE due to the high α-amylase inhibition potential and higher phenolic content. Also, GC-MS analysis of SEE exhibited higher concentrations of phenolic compounds such as: dehydrocostus lactone, azuleno, eicosa-pentaenoic acid and linoelaidic acid that revealed anti-diabetic, anti-lipidemic and anti-inflammatory activities, while CAE showed the presence of cinnamic and quinic acids. Injection of STZ resulted in a decline in the insulin, high density lipoprotein and body weight values matched with the increase in glucose, total cholesterol, LDL-Cholesterol, triglycerides and interleukin1- β (IL-1β). The administration of extracts of SEE and CAE into STZ-treated rats separately resulted in a decline in the elevated levels of blood glucose, total cholesterol, triglycerides and improving serum HDL-Cholesterol and body weight. Conclusion: Both tested herbal extracts performed anti-diabetic effect that mainly could be mechanized via the α-amylase- inhibitory potentials due to the high phenolic and flavonoids content.

Aims: We aim to investigate curcumin interaction with p53-fibrinolytic system, smad dependent and independent pathways underlying their prime role during lung injury and fibrosis. Background: Curcumin, an active component of Curcuma longa plant, substantially modulates respiratory conditions. TGF-β1 plays a central role in lung remodeling by balancing extracellular matrix (ECM) production and degradation, which is a hallmark for alveolar EMT. However, the crosstalk of curcumin is not known yet with TGF- β1 mediated p53-Fibrinolytic system regulating alveolar EMT leading to IPF. In the present study, the potential molecular mechanism of curcumin in TGF-β1 mediated p53-fibrinolytic system in basal alveolar epithelial cells was explored. Objectives: To understand the potential molecular mechanism of curcumin in TGF-β1 mediated p53-fibrinolytic system in basal alveolar epithelial cells. Methods: Basal alveolar epithelial cells were treated with TGF- β1 to induce alveolar EMT and after 24 hrs curcumin was administered to study its anti-fibrotic effects. Molecular techniques like immunoblot, RT-PCR and immunofluorescence were performed to assess the anti-fibrotic role of curcumin on EMT markers, IL-17A, p53-smad interaction to investigate the anti-fibrotic role of curcumin. Results: The results indicated that TGF-β1-induced EMT in A549 cells exhibited altered expression of the IL-17A, p53-fibrinolytic markers and EMT markers at the mRNA and protein level. Intervention with curcumin attenuated alveolar EMT and inactivated TGF-β1 induced Smad/non Smad signaling pathways via blocking p53-fibrinolytic system. Conclusion: This study provides the first evidence of the dynamic response of curcumin on TGF- β1 mediated p53-fibrinolytic system during alveolar injury in vitro.

Background: Serum ferritin concentrations are altered in hypothyroidism, but there is no available literature regarding the status of serum ferritin in anti-thyroid peroxidase (anti-TPO) positive hypothyroidism. The objectives of our study were to evaluate the titer of anti-TPO and serum ferritin in newly diagnosed hypothyroid patients and to find out any difference in serum ferritin concentration between antibody-positive and antibody-negative patients. Methods: A total of 143 subjects above the age of 18 years were recruited, and serum Thyroid Stimulating Hormone (TSH), free T3, free T4, anti-TPO, and ferritin were assayed by chemiluminescence method. According to their serum analysis findings, three groups were made as Group 1 of 49 subjects with hypothyroidism and anti-TPO positive, Group 2 of 47 subjects with hypothyroidism and anti-TPO negative, and Group 3 of 47 euthyroid and anti-TPO negative controls. Results: Kruskal Wallis H test was applied, and the difference in concentration of TSH, FT3, FT4, Ferritin, anti-TPO amongst the three groups was found to be significant. The relationship between anti-TPO levels and serum ferritin concentration was further studied by multinomial logistic regression. We have found that there is a significant difference between the concentrations of ferritin; hence, it is highly likely that those with a high level of anti-TPO antibody shall have a higher concentration of serum ferritin. Conclusion: Ferritin concentrations were decreased in anti-TPO negative hypothyroidism, but in the case of anti-TPO positive hypothyroidism the ferritin concentrations are raised. Hence, hypothyroidism should not always be considered as an iron deficiency state.

Aims: The etiopathogenesis of Rheumatoid Arthritis (RA) is not clearly understood. However, the role of the cytokines play an important part in this mechanism. We aimed to bring a new approach to the concept of 'remission' in patients with RA. Background: RA is a chronic, autoimmune, inflammatory disease that involves small joints in the form of symmetrical polyarthritis and progresses with exacerbations and remissions. Pain, swelling, tenderness and morning stiffness are typical of the joints involved. Although it is approached as primary joint disease, a wide variety of extra-articular involvements may also occur. It is an interesting pathophysiological process, the exact cause of which is still unknown, with many environmental, genetic and potentially undiscovered possible factors in a chaotic manner. Objective: In this cross-sectional study, sedimentation rate (ESR), C- Reactive protein (CRP), Tumor necrosis factor (TNF)-α, soluble-TNF-α receptor (TNF-R), Interleukin (IL)-1B and IL-10 were measured in three groups which were healthy volunteers, patients with RA in the active period, and patients with RA in remission. Disease activity score-28 (DAS-28) was calculated in active RA and RA in remission. Methods: This study included 20 healthy volunteers, 20 remission patients with RA and 20 active RA patients. Venous blood samples were collected from patients in both healthy and RA groups. Results: RA group consisted 43 (71.6%) female and 17 (28.4%) male. Control group consisted 11 (55%) female and 9 (45%) male. TNF-R was significantly high only in the active group according to the healthy group (p=0.002). IL-10 was significantly high in active RA, according to RA in remission (p=0.03). DAS-28 was significantly high in active RA, according to RA in remission (p=0.001). In the active RA group, ESR and TNF-R had a positive correlation (r:0.442; p=0.048). In the active RA group, there was also a positive correlation between TNF-R and CRP (r:0.621; p=0,003). Both healthy and active RA group had significant positive correlation between ESR and CRP (r: 0.481; p=0.032 and r: 0,697; p=0,001 respectively). Conclusion: TNF-R can be the main pathophysiological factor and a marker showing activation. TNF-R can be very important in revealing the effect of TNF on the disease and the value of this effect in the treatment and ensuring the follow-up of the disease with CRP instead of ESR in activation.

Background: Lupinus albus is a member of the Fabaceae family. As a natural or cultivated plant, Lupinus albus is distributed in Europe, the Balkans and Turkey, especially in Marmara and Aegean regions. The lupine is a nutritious and protective plant against diabetes. Objective: In the present study, the effects of Lupinus albus fruits on malondialdehyde (MDA), reduced glutathione (GSH), total protein, ADEK vitamins, and cholesterol values, which are the indicators of oxidative damage and antioxidant defense. In this regard, muscle, liver, renal, and brain tissues of STZ-induced type I diabetes rats were studied. Methods: The analyzes of ADEK vitamins and cholesterol levels in tissues were performed via Shimadzu HPLC device. The lipid peroxidation levels were measured at 532 nm in spectrophotometer. Determination of GSH was read at 412 nm against blank, and for the total protein levels Lowry method was applied. Results: According to the results obtained, it was determined that among the rats with induced type I diabetes, the group applied lupine fruit extract was found to have increased GSH level and decreased MDA levels in all the tissues. The protein values were increased in liver tissues but decreased in the other tissues. The level of vitamins was significantly increased in almost all the tissues in the diabetic group. Conclusion: In the present study, it was shown that the lupine reduced the devastating effects of type I diabetes by decreasing the fasting blood glucose and lipid peroxidation values and increasing the glutathione level in comparison to the diabetic group.

Objective: The stamen is a byproduct of saffron (Crocus sativus) flowers. Herein, its cardiovascular effects were evaluated on hypertension induced by angiotensin II (AngII) and NG-nitro-Larginine methyl ester (L-NAME), as well as baroreflex sensitivity (BRS). Methods: Rats were randomly divided into 10 groups: 1) control, 2) AngII (50 ng/kg, i.v.), 3) losartan (10 mg/kg, i.p.) + AngII, 4) L-NAME (10 mg/kg, i.v.), 5) sodium nitroprusside (SNP) (50 mg/kg, i.p.) + L-NAME, 6, 7) saffron stamen extract (SS) (100 and 200 mg/kg, i.p.) + AngII and 8, 9) SS (100 and 200 mg/kg) + L-NAME, and 10) SS (200 mg/kg) + phenylephrine (Phen, i.v.). The treated rats first received two doses of SS, 30 min after the injection of L-NAME, AngII, and Phen in separate groups. The cardiovascular parameters were recorded by the PowerLab apparatus via an angiocatheter inserted into the femoral artery. The maximal changes (Δ) of mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) in the treated groups were compared with those of the hypertensive and control groups. The changes in MAP and HR induced by Phen were used for BRS evaluation. Results: The SS extract did not significantly affect the basal cardiovascular parameters. The injection of AngII significantly increased the MAP and SBP (P<0.01-P<0.001) with no significant effect on the HR. The SS extract significantly attenuated the pressor effect induced by AngII (P<0.001). Increased MAP and SBP induced by L-NAME (P<0.001) were also significantly attenuated by the SS extract (P<0.01). The effect of SS extract on L-NAME was significantly higher than that of AngII (P<0.05). Moreover, BRS was significantly improved by the SS extract. Conclusion: Our findings provide evidence that the SS extract has anti-hypertensive effects that are probably mediated by an inhibitory effect on AngII, increasing nitric oxide production, or improving baroreflex sensitivity.

Background: One of the most common complications of pregnant women is gestational diabetes mellitus (GDM). Oxidative stress can play an important role in GDM. Objective: The aim of this study was to evaluate salivary antioxidants and oxidative stress markers in GDM. Methods: Twenty pregnant women with GDM and 20 healthy pregnant women with normal blood glucose test participated in this study. Five mL of unstimulated saliva samples were collected. Spectrophotometric assay was carried out for sialo-chemical analysis. Stata software was used for data analysis. Results: The GDM group exhibited no significant difference in salivary total antioxidant capacity and malondialdehyde compared to the healthy control group. All antioxidants markers, the uric acid, total antioxidant, peroxidase and catalase, decreased in GDM group that the difference of peroxidase and catalase was statistically significant. All of oxidative stress markers, the salivary malondialdehyde, total oxidative stress and total thiol, increased in GDM group. GDM group exhibited significantly higher salivary total oxidative stress levels. Conclusion: Catalase level was significantly lower and total oxidative stress was significantly higher. These two markers might have significant importance and might exhibit early changes compared to other factors in GDM. Some salivary antioxidants might have diagnostic, prognostic or therapeutic implications in GDM. Other studies with large sample size on salivary and blood samples need to be done to confirm these properties and salivary samples using instead of blood samples in GDM biomarkers changes.

Objective: The aim of the study was to determine the influence of maternal sodium valproate (SVP) on neonatal neuroendocrine (hypothalamic-pituitary-adrenal; HPA)-cytokines and oxido-inflammatory axes. Methods: Pregnant rats (Rattus norvegicus) were orally administered (by gavage) SVP (50 mg/kg) from gestation day (GD) 8 to lactation day (LD) 21. Results: The elevation in serum corticotropin-releasing hormone (CRH), corticosterone, and adrenocorticotropic hormone (ACTH) levels was highly significant at postnatal days (PNDs) 14 and 21 in both dams and neonates of the maternal SVP-treated group relative to those in the control group. However, hypercortisolism (cortisolemia) was highly significant in neonates at both PNDs 14 and 21, while in dams, it was not significantly increased at LD 14 but was at LD 21. This disruption caused adverse effects on maternal food consumption and maternal/neonatal body weight. The maternal SVP treatment resulted in higher levels of neonatal serum adrenaline, noradrenaline, neuropeptide Y (NPY), tumor necrosis factor-alpha (TNF-α), leptin, interleukins (IL-1β, IL-17, IL-4, IL-6 & IL-2), transforming growth factor-beta (TGF-β), and prostaglandin E2 (PGE2), and lower levels of neonatal serum growth hormone (GH), insulin growth factor-1 (IGF-1) and adiponectin at both PNDs. This administration also induced the oxidative stress in neonatal cerebrum and cerebellum at both tested PNDs via the production of free radicals (malondialdehyde; MDA & nitric oxide; NO) and reduction of antioxidant parameters (glutathione; GSH, superoxide dismutase; SOD & catalase; CAT). Conclusion: Maternal SVP treatment stimulated the neonatal stress-brain (HPA) axis, resulted in an oxido-inflammatory state, and disrupted the neuroendocrine-cytokines axis, and generally neonatal health.

Background: Activation of the Angiotensin II type 1 receptor (AT1R) has been implicated in the pathogenesis of the cardiovascular disease, while activation of Angiotensin II type 2 receptor (AT2R) leads to effects that are opposite to those mediated by AT1R. The interaction between female sex hormones and the renin-angiotensin system was proven to play an essential role in the pathological changes in the cardiovascular system. Objectives: To investigate the direct effect of estrogen and progesterone on arterial and cardiac AT1R and AT2R expression in vivo in male. Method: Male adult rats were assigned into four groups: Group 1 (control), group 2 (progesterone treated group; 10mg/kg), group 3 (estrogen treated group; 20μg/kg) and group 4 (progesterone; 10mg/kg + estrogen; 20μg/kg treated group). All treatments were administrated subcutaneously every second day for 21days. Results: Estrogen treatments increase the left ventricle (LV) protein expression of AT1R, and progesterone treatment decreased the LV protein expression of AT2R. In the aorta, estrogen treatment increased the mRNA expression levels of AT1R, while progesterone treatment increased the AT2R mRNA expression levels. Estrogen treatment decreases the LV and aortic endothelial nitric-oxide synthase (eNOS) mRNA levels while progesterone treatments decrease the LV eNOS mRNA levels but increase the aortic eNOS mRNA levels. The serum angiotensin II levels were increased by estrogen treatment only. Conclusion: Both estrogen and progesterone treatments appear to have a harmful effect on the male rat hearts, possibly by increasing the protein expression of AT1R (for estrogen), decrease the protein and mRNA expression of AT2R (for progesterone), and decrease the eNOS mRNA levels (for both). However, it seems that progesterone but not estrogen exerts a vascular protective effect in males.

Introduction: Primary hyperparathyroidism (PHPT) is rare in pregnancy. PHPT and hypercalcemia are associated with negative maternofetal outcomes. Therefore, an early diagnosis and adequate treatment are essential. Case Presentation: We described the case of a pregnant woman complaining of nausea, vomiting and weight loss. Diagnosis of gestational PHPT (GPHPT) was made based on elevated serum calcium and parathyroid hormone levels (3.4 mmol/L and 41.6 pmol/L). Neck ultrasound documented a nodule suggestive of enlarged parathyroid, whereas the abdomen ultrasound revealed renal microlithiasis. Conservative treatment was started with oral hydration and a low-calcium diet. Clinical and biochemical monitoring was weekly and multidisciplinary. Despite our suggestion, the patient refused parathyroidectomy in the second trimester. Additional intravenous fluid rehydration from the 15th to the 25th week of gestation ameliorated the symptoms rapidly, and reduced calcium levels progressively from the 23rd week. At week 40, the woman gave birth to a healthy girl. At month 8 postpartum, calcemia and PTH were still elevated, and accompanied by osteoporosis and nephrocalcinosis. Surgery was accepted, and a parathyroid adenoma was removed. Conclusion: In the absence of guidelines for GPHPT management, its treatment should be individualized. In our case, despite high calcium levels, conservative treatment with strict monitoring led to a positive outcome of pregnancy.

Background: Double pituitary adenomas (DA) are two morphologically and immunohystochemically different tumours in the same gland. They are rare, generally small adenomas and divided in: separated, when clearly recognizable before or during surgery, and contiguous, when diagnosed only in the following histopathological examination. Acromegaly and Cushing’s disease are the main prevalent clinical presentation. Objective: We described two cases of DA in a surgical series over 16 years in a single center. Methods: In September 2018, we diagnosed a DA in a man with acromegaly (case 1). In order to assess the presence of other cases of DA, we performed a retrospective analysis of the endonasal endoscopically operated sellar adenomas from January 2004 to December 2019. Results: 468 pituitary adenomas were found. A DA with a Pit-1 positive macroadenoma (GH-TSH- PRL positive) and an ACTH microadenoma clinically silent in an acromegalic woman was retrospectively found (case 2). Conclusion: Our analysis confirms that DA are rare (0.4% of the pituitary adenomas) and often associated with acromegaly. Their pre-operatively diagnosis is difficult but clinician’s awareness of DA can improve the diagnosis. The use of pituitary transcription factors could be useful in detecting DA.

Case Presentation: A two-year-old boy visited the doctor for hypokalemia and metabolic alkalosis. Laboratory examination revealed that urinary potassium excretion and serum aldosterone level were increased, with hyperthyroidism and thyroid-related antibodies positive at the same time. Genetic testing showed that there was a complex heterozygous mutation in the SLC12A3 gene, c.1077C>G (p.N359K) and c.1567G>A (p.A523?); the final diagnosis was Gitelman syndrome and autoimmune hyperthyroidism. Background: Gitelman syndrome is an autosomal recessive genetic disease caused by the inactivation of mutation of the SLC12A3 gene. The onset age is more than 6 years old; it is mainly manifested as low blood potassium, low blood sodium, low blood chlorine, metabolic alkalosis, increased urine potassium and urine chlorine excretion, and low urine calcium. Autoimmune hyperthyroidism manifests due to autoimmune disorders. The highest incidence rate in children is of Graves' disease, followed by chronic lymphocytic thyroiditis. Conclusion: Several cases of Gitelman syndrome with autoimmune hyperthyroidism have been reported, most of which were Asian adults, and the case we identified is the first reported case in children under 14 years with both Gitelman syndrome and autoimmune hyperthyroidism. At the same time, we carried out a high-precision clinical exosome analysis of the gene of this case and further explored the relationship between Gitelman syndrome and autoimmune hyperthyroidism from the perspective of the gene.This case suggests that even children under 6 years with hyperthyroidism and hypokalemia should be suspected of Gitelman syndrome to avoid misdiagnosis.

Background: Both exercise and metformin are used to control blood glucose levels in patients with type 2 diabetes mellitus (T2DM), while no previous studies have investigated the effect of resistance exercise combined with metformin versus aerobic exercise with metformin in T2DM patients. Objectives: This study was conducted to compare the effects of resistance exercise combined with metformin versus aerobic exercise with metformin in T2DM patients. Methods: A total of fifty-seven T2DM patients with a mean age of 46.2±8.3 years were randomized to three study groups; each group included nineteen patients. The first group conducted a resistance exercise program (REP, 50-60% of 1RM, for 40-50 min) combined with metformin, the second group conducted an aerobic exercise program (AEP, 50-70% maxHR, for 40-50 min) combined with metformin, and the third group received only metformin without exercise intervention (Met group). The study program was conducted thrice weekly for consecutive twelve weeks. Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), and maximal oxygen uptake (VO2max) were evaluated before and after study intervention. Results: Significant differences were reported after the 12-week intervention inter-groups in the outcome variables (p#130;0.05). FBG, HbA1c, HOMA-IR, and VO2max improved significantly in the REP group (p#130;0.001) and also in the AEP group (p=0.016, p=0.036, p=0.024, and p=0.019 respectively) while the Met group showed an only significant reduction in FBG (p=0.049), and non-significant changes in HbA1c, HOMA-IR, and VO2max (p#131;0.05). REP group achieved greater improvements than AEP group (FBG, p=0.034; HbA1c%, p=0.002; HOMA-IR, p#130;0.001; and VO2max, p=0.024). Conclusion: Both resistance and aerobic exercise programs combined with metformin are effective in controlling T2DM. Resistance exercise combined with metformin is more effective than aerobic exercise combined with metformin in the treatment of T2DM.