Greater Efficacy and Improved Endothelial Dysfunction in Untreated Type 2 Diabetes with Liraglutide versus Sitagliptin

Objective:The incretin hormone glucagon-like peptide 1 (GLP-1) and its analogs, including the glucagonlike peptide 1 receptor agonist liraglutide, use a simple once-daily regimen and can be easily introduced in the outpatient setting. We compared treatment with liraglutide monotherapy and dipeptidyl peptidase-4 (DPP-4) inhibitor monotherapy in patients with untreated type 2 diabetes( T2DM).Methods:This study included 40 outpatients with untreated T2DM who were randomized to receive liraglutide (0.9 mg/day, n=24) or DPP-4 inhibitors (n=16:sitagliptin, 50 mg/day) as initial treatment for 6 months. Glycemic control, urinalysis, blood pressure, body weight, lipid levels, vascular endothelial function, and inflammatory factors were assessed before and after treatment.Results:Significant improvement was observed in HbA1c and fasting blood glucose levels after treatment in both groups;improvements in the liraglutide group were significantly better than in the sitagliptin group. Only the liraglutide group demonstrated significant improvements in blood pressure, low-density lipoprotein cholesterol levels, urinary albumin excretion, flow-mediated dilatation, and high-sensitivity C-reactive protein levels. Linear regression analysis demonstrated a significant negative relation between change in flow-mediated dilatation and high-sensitivity C-reactive protein levels.Conclusion:Liraglutide provided significant glycemic control and improved blood pressure, lipid levels, endothelial function, and inflammatory factors in untreated T2DM. In addition to its impact on blood glucose levels, liraglutide may have beneficial effects on the cardiovascular system in patients with T2DM

Effect of Poly (ADP-ribose) Polymerase Inhibitors on Hypoadiponectinemia Caused by Chronic Blockade of Nitric Oxide Synthesis in Rats

Oxidant stress-induced activation of poly (ADP-ribose) polymerase (PARP) contributes to the pathogenesis of various cardiovascular diseases. Adiponectin is an adipocyte-derived anti-atherogenic protein. In the present study, we investigated the role of PARP in the development of hypoadiponectinemia caused by chronic blockade of nitric oxide synthesis with N^ω-nitro-L-arginine methyl ester (L-NAME) in rats. Decreased production of NO and increased production of O_2^- were observed in aortas from L-NAME-treated rats. Plasma adiponectin levels and adiponectin mRNA levels within adipose tissue were markedly decreased in L-NAME-treated rats. Concurrent administration of potent PARP inhibitors, INO-1001 or PJ34, with L-NAME did not restore plasma adiponectin levels or fat adiponectin mRNA levels. Thus, the cardiovascular protective effects of PARP inhibitors are not associated with adiponectin levels. Therefore, drugs which increase adiponectin levels may be beneficial alongside PARP inhibitors in the treatment of cardiovascular disease

HMG-CoA Reductase Inhibitors Suppress High Glucose-induced Excessive O2⁻ production in J-774 Cells

Statins (HMG-CoA reductase inhibitors) have so-called pleiotropic effects, which directly reduce neoinitial inflammation of atherosclerosis, and one possible mechanism is the attenuation of oxidative stress. Although an increase in oxidant stress is suggested to cause and aggravate arteriosclerosis in diabetes, the origin of oxidant stress and effects of statins on the oxidant stress in diabetes are not clearly delineated. We evaluated in this study the effect of high glucose on superoxide anion (O_2^-) production in the J-774 macrophage-like cell line, and the effect of various statins (cerivastatin, fluvastatin, and nisvastatin) on it. The basal and 12-O-tetradecanoylphor-bol 13-acetate (TPA)-stimulated O_2^- productions were measured by chemiluminescence (CL) amplified with a Cypridina luciferin analog. Both basal CL and TPA-stimulated CL (TPA-CL) in J-774 cells cultured with high glucose were apparently increased in dose and time dependent manners, and the increments were clearly suppressed by a NADPH oxidase inhibitor (diphenyleneiodonium chloride) or a protein kinase C inhibitor (GF-109803 X). Three statins significantly inhibited the high glucose-induced excessive O_2^- production in a dose dependent manner. Furthermore, co-incubation with mevalonic acid and the metabolites, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, partially prevented the statin-induced suppression of TPA-CL. These data suggest that in J-774 cells high glucose causes excessive O_2^- production through NADPH oxidase and protein kinase C pathways, and statins suppress the excessive O_2^- generation. This effect of statins could be, in part, dependent on the inhibition of synthesis of isoprenoid intermediates. Statins may be useful as a drug to prevent arteriosclerosis by inhibiting oxidative stress in poorly controlled diabetic patients

RNASeq of pituitary adenomas reveals dysfunctional metabolic, secretory and differentiation molecular pathways

Pituitary adenomas consist of a group of highly heterogeneous intracranial tumours with variable presentation, clinical prognosis and management. High throughput sequencing was used in order to try and identify common de-regulated pathways and characterize tumours according to specific molecular behaviour. RNA sequencing (RNAseq) was chosen since it provides not only information regarding the expression profile but also the mutational load of each specific tumour analysed. 58 locally resected tumours (36 non-functional tumours; 17 growth hormone-secreting; 3 prolactin-secreting; 2 Cushing’s) were stored in RNAlater (Qiagen, US) and RNA was extracted to purified. RNAseq was performed on all samples plus a control on the BGI-Seq500 platform (Beijing Genomics Ind., China). Bioinformatic analyses was also performed by BGI with additional analyses still being carried out. Preliminary data reveals a number of known and novel de-regulated pathways which characteristically differentiate between different tumour types such as hormone signalling and production pathways. However, novel metabolic pathways also appear to differ significantly, not only between controls and tumours but also between different tumour types with changes in lipid transport and glucose metabolism being observed. Additionally various hormone receptor signalling pathways were also found to be altered. Verification and additional bioinformatic analyses will be required to further delve into the vast data that is generated by this technique which has provided a wealth of information.peer-reviewe

Giant functional gonadotroph adenoma : case report

A 49 year old male, known to suffer from hypertension, was bein investigated for recurrent occipital headaches. An MR Brain showed a 2.4 cm×2.8 cm×4.2 cm sellar mass with suprasellar extension, optic chiasm compression, infrasellar extension with erosion into the sphenoidal sinus, lateral extension into the left sided cavernous sinus and further extension through the cavernous sinus into the parietal lobe. The tumour contained some cystic areas and moderately enhanced with contrast. Pituitary function tests results showed: FSH 17.3 U/l (0.1–11), LH: 15.1 U/l (0.8–7.6), Testosterone 7 nmol/l (4.4–26.5) whilst thyroid function tests, cortisol, GH, IGF1 and prolactin were normal. The patient complained of bilateral gynaecomastia, testicular swelling and tenderness, mild lethargy and occasional nausea in the mornings. He denied visual disturbances. An ultrasound testes confirmed testicular enlargement with a right testicular volume of 21 ml and left testicular volume of 29 ml. He underwent transsphenoidal surgery for removal of the giant macroadenoma in September 2018. Histology showed a pituitary adenoma with strong diffuse LH and patchy FSH expression. Ki67 proliferative index was low (less than 3%). Post operatively FSH was 8 U/l, LH 4.7 U/l, Testosterone 4.4 nmol/l. The rest of his pituitary function tests were normal. Gynaecomastia and testicular symptoms significantly improved post operatively. His post-operative MR scan showed a small residual tumour mainly in the left cavernous sinus.DISCUSSION: Functional gonadotropin secreting adenomas are a rare entity with only few published cases in middle aged males. They are difficult to diagnose as hormonal secretion is erratic. They rarely cause a clinical syndrome. Excess FSH secretion results in testicular enlargement due to the increase in length of the seminiferous tubules. LH and testosterone levels can be low, normal or high. First line treatment is surgical resection of the adenoma. Regular clinical, biochemical and radiological follow up must be ensured.peer-reviewe

Outcomes of surgically treated nonfunctioning pituitary adenomas

INTRODUCTION: The sequelae of surgically treated non-functioning pituitary adenomas (NFPA) is an important area of study to help plan management. The aim was to study all Maltese patients who had a surgically treated NFPA and analyse the results of surgery, risk factors for tumour recurrence/regrowth and the role of postoperative radiotherapy.MATERIALS AND METHODS: One hundred and seventy-five patients were identified as having a NFPA of whom 77 had underwent pituitary surgery. Detailed analysis of these patients was done including their demographic details, surgical details, post-surgical management, regrowth and recurrence patterns.RESULTS: 63.6% of patients presented with visual field defects, 40.3% had headaches at presentation and 87.0% had chiasmal compression by their NFPA. Residual tumour postoperatively was evident in 67.5% of patients while 29.9% of patients had immediate postoperative radiotherapy. Recurrence /regrowth was documented in 18.2% of patients within a median time of 3.2 (IQR: 1.6–5.6) years. Factors that were found to be statistically significantly associated with a higher rate of regrowth using Kaplan-Meier estimates were the presence of residual tumour (P=0.036), presence of cavernous sinus invasion (P=0.034) and the lack of postoperative radiotherapy (P=0.004). Independent risk factors for tumour regrowth using multivariate Cox hazard analysis were absence of post-op radiotherapy (P=0.010) and cavernous sinus invasion (P=0.020).CONCLUSION: By studying this cohort of patients we were able to characterise better the outcomes of NFPA management and outline risk factors which can effect prognosis.peer-reviewe

Hypercalcaemia due to ovarian small cell carcinoma of the hypercalcaemic type (SCCOHT)

BACKGROUND: Hypercalcaemia is commonly encountered during clinical practice. SCCOHT is a rare ovarian malignancy typically found in young women. In two thirds of patients, it causes a paraneoplastic hypercalcaemia which is usually asymptomatic.CASE REPORT: A thirty-seven-year-old lady, presented to casualty with a one -week history of worsening nausea, vomiting, anorexia, abdominal pain, polydipsia, and polyuria. On examination all clinical parameters were within normal range. Her abdomen was distended but soft. Blood investigations revealed a corrected calcium level of 3.9 mmol/l. She was started on intravenous normal saline at one litre every six hours as acute management for hypercalcaemia. Additional tests revealed a PTH of <5 (15–65 pg/ml), a PTHrP of 5.7 ( <1.5 pmol/l), a 25-hydroxyvitamin D level of 17 (30–100 ng/ml) and normal renal function. The combination of a low PTH together with a high parathyroid hormone related protein (PTHrP) suggests humoral hypercalcaemia of malignancy. A computed tomography scan of the abdomen showed a large, hypodense, soft tissue pelvic mass arising from the left ovary. A magnetic resonance scan of the pelvis confirmed an 18×12×5 cm mass arising from left tubo-ovarian region with areas of internal cystic change, internal necrosis, prominent venous drainage, and a peripheral enhancement pattern A bone scan showed no evidence of abnormal foci of increased tracer uptake throughout the skeletal system. Despite three days of continuous fluid replacement her serum calcium remained high. She received one dose of the intravenous bisphosphonate Zoledronic acid 4 mg which reduced her calcium to 2.38 mmol/l after 48 h reaching a nadir of 1.94 mmol/l within five days. She underwent a bilateral salpingo-oopherectomy and total abdominal hysterectomy. Histology showed a left SCCOHT with sheets of small, uniform, hyperchromatic cells together with a single cystic pseudofollicle; very typical for SCCOHT. She is receiving Cisplatin/Etoposide combination chemotherapy to be followed by pelvic radiotherapy. A repeat CT scan after 3 cycles showed no distant metastases. Her calcium levels have since remained normal, repeat PTHrP and PTH levels have normalised.CONCLUSION: SCCOHT was initially reported in 1979 by Scully. Fewer than 500 cases have been reported worldwide. Abdominal pain is the most frequent symptom at 68%. At surgery 50% of patients have extra ovarian spread. It has a high rate of recurrence and overall survival is less than 10%. A combination of surgery, chemotherapy ± stem cell transplant and radiotherapy produce the best results.peer-reviewe