The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis.

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

Comparison of the Impact of Insulin Degludec U100 and Insulin Glargine U300 on Glycemic Variability and Oxidative Stress in Insulin-Naive Patients With Type 2 Diabetes Mellitus: Pilot Study for a Randomized Trial.

BACKGROUND: There is an ongoing discussion about possible differences between insulin degludec (IDeg-100) and glargine U300 (IGlar-300). There is little data and head-to-head comparison of IDeg-100 and IGlar-300 regarding their simultaneous impact on glycemic variability and oxidative stress in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: In our randomized, open-label, crossover study, we compared the impact of IDeg-100 and IGlar-300 on glycemic variability and oxidative stress in insulin-naive patients with T2DM. METHODS: We recruited a total of 25 adult patients with T2DM (7 females) whose diabetes was uncontrolled (HbA1c ≥7.5%) on two or more oral glucose-lowering drugs; a total of 22 completed the study. Mean age was 57.3 (SD 6.99) years and duration of diabetes was 9.94 (SD 5.01) years. After the washout period, they were randomized alternately to first receive either IDeg-100 or IGlar-300 along with metformin. Each insulin was administered for 12 weeks and then switched. At the beginning and end of each phase, biochemical and oxidative stress parameters were analyzed. On 3 consecutive days prior to each control point, patients performed a 7-point self-monitoring of blood glucose profile. Oxidative stress was assessed by measuring thiol groups and hydroperoxides (determination of reactive oxygen metabolites test) in serum. RESULTS: IGlar-300 reduced mean glucose by 0.02-0.13 mmol/L, and IDeg-100 reduced glucose by 0.10-0.16 mmol/L, with no significant difference. The reduction of the coefficient of glucose variation also did not show a statistically significant difference. IGlar-300 increased thiols by 0.08 µmol/L and IDeg-100 increased thiols by 0.15 µmol/L, with no significant difference (P=.07) between them. IGlar-300 reduced hydroperoxides by 0.040 CARR U and IDeg-100 increased hydroperoxides by 0.034 CARR U, but the difference was not significant (P=.12). CONCLUSIONS: The results of our study do not show a significant difference regarding glycemic variability between patients receiving either insulin IDeg-100 or IGlar-300, although IGlar-300 showed greater dispersion of data. No significant difference in oxidative stress was observed. In a larger study, doses of insulins should be higher to achieve significant impact on glycemic parameters and consequently on glycemic variability and oxidative stress. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04692415; https://clinicaltrials.gov/ct2/show/NCT04692415.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Effects of Olive Oil and Its Components on Intestinal Inflammation and Inflammatory Bowel Disease.

With the rising global burden of inflammatory bowel disease (IBD) and the rising costs of novel biological drugs, there is an increasing need for dietary approaches and functional foods that could modulate the course of IBD. The Mediterranean diet has proven to be efficacious in managing chronic inflammatory diseases, and recent studies have also shown its benefits in the setting of IBD. Since olive oil and its compounds have been shown to provide a considerable anti-inflammatory effect, in this review, we aim to discuss the latest evidence concerning the impact of olive oil and its bioactive compounds on IBD. Numerous preclinical studies have exhibited solid evidence on the mechanisms by which polyphenol-rich extra-virgin olive oil (EVOO) or specific polyphenols like hydroxytyrosol (HT) provide their anti-inflammatory, antioxidative, antitumour, and microbiota-modulation effects. Accordingly, several human studies that explored the effects of olive oil on patients with IBD further confirmed the evidence brought forward by preclinical studies. Nevertheless, there is a need for larger-scale, multicentric, randomized control trials that would finally elucidate olive oil's level of efficacy in modulating the course of IBD.

The differences between insulin glargine U300 and insulin degludec U100 in impact on the glycaemic variability, arterial stiffness and the lipid profiles in insulin naïve patients suffering from type two diabetes mellitus - outcomes from cross-over open-label randomized trial.

BACKGROUND AND AIMS: Diabetes mellitus type two is one of the major cardiovascular risk factors. Treatment of diabetes can reduce this risk, but the treatment options differ a lot in their risk-reducing capabilities. We compared the impact of insulin degludec (IDeg-100) and insulin glargine U300 (IGlar-300) on cardiovascular risk parameters - glycaemic variability (GV), arterial stiffness and lipid parameters - in insulin naive patients with DMT2. METHODS: To 23 individuals who previously had uncontrolled DMT2 on two or more oral antidiabetic drugs, IGlar-300 and IDeg-100 were applied for 12 weeks and then switched in a cross over design manner. Prior and after of each insulin phase, we analysed biochemical parameters,7-point SMBG profile over three days and arterial stiffness which was assessed indirectly by measuring the augmentation index (AIx) on the principles of applanation tonometry. RESULTS: There were no significant differences between IGlar-300 and IDeg-100 regarding reduction of mean glucose values and coefficient of variation (CV). Both insulins insignificantly reduced AIx for standardised pulse of 75 beats/min and without differences between them. IGlar-300 and IDeg-100 reduced triglycerides and increased HDL with no significant difference between the two insulins. IGlar-300 increased the total cholesterol level and IDeg-100 decreased total cholesterol, but without statistically significant difference. IGlar-300 increased LDL level by 0.508 mmol/L and IDeg-100 decreased LDL by 0.217 mmol/L, with statistically significant difference (p = 0.0215). CONCLUSIONS: This study did not show significant difference between IGlar-300 and IDeg-100 regarding glycaemic parameters and augmentation index using the same dose of 0.2 IU/kg for both insulins, but it has revealed possible differences in impact on lipid profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04692415 . Retrospectively registered on December 31th 2020.

Surgical Treatment of Recurrent Metastatic Parathyroid Gland Carcinoma.

AIM: We present the case of a 48-year-old male patient who underwent surgery for a recurrent metastatic parathyroid gland carcinoma in the patient's right paratracheal space of the neck. The patient had undergone surgery for lower right parathyroid gland carcinoma 28 months earlier. RESULTS: The metastases were resected en bloc with an ipsilateral central neck dissection and with the removal of the enlarged lower left parathyroid gland. After exploration of the remnant parathyroid glands we noticed that lower left parathyroid gland was macroscopically enlarged so we decided to remove it to prevent possible hypercalcemia in future and to also prevent possible recurrence of cancer or development of a new primary, considering the identical embryological origin of the lower parathyroid glands and possibility of synchronous, multiple tumors, which generally follow the same embryological origin if they occur. The patient was also treated with radiation therapy after the surgery. CONCLUSION: With the present surgical approach to recurrent metastatic parathyroid gland carcinoma, we aimed to prevent the recurrence of cancer or development of new primary and prevent or delay hypercalcemia in the future with all severe adverse metabolic states associated with high serum calcium levels.

Hypoglycemia and Glucagon Utilization in Insulin-Treated Diabetic Patients.

BACKGROUND: First choice of therapy for severe hypoglycemia outside hospital environment is glucagon injection, an undertaught and underused remedy. Aim of this study was to investigate knowledge about glucagon therapy, possession rate and usage rate in insulin-treated diabetic patients, with special emphasis on history of hypoglycemia and severe hypoglycemia episodes. METHODS: In this cross-sectional study, 300 insulin-treated diabetic patients (146 males and 154 females, mean age 61.1±16.4 years) were recruited from comprehensive Diabetes Center in Croatia. Specialized self-administered, 13-item questionnaire regarding glucagon therapy and history of hypoglycemia was obtained from each patient, as well as data collected from medical history documentation. RESULTS: Experience of hypoglycemic episode was reported by 233 (77.7%), and severe hypoglycemia by 73 (24.3%) patients. Participants with experience of hypoglycemia have significantly longer diabetes duration (17.2±11.2 vs. 11.9±8.5 years, P<0.001) and lower BMI values (26.38±3.97 vs. 31.11±7.17 kg/m2, P<0.001). Knowledge about glucagon therapy had 55.3% patients, 44.7% obtained it from the pharmacy, while glucagon was used in 35.6% cases of severe hypoglycemia. Glucagon knowledge was better in patients that attended at least one diabetes lecture (P=0.038), while educational level showed no statistical significance (P=0.286). Main significant positive predictor of glucagon knowledge was history of severe hypoglycemia (OR 4.71, 95% CI 1.38 - 16.02, P=0.013). CONCLUSIONS: Glucagon therapy was underused in treating severe hypoglycemia. It is highly important to emphasize value of quality education as one of the fundamentals of good diabetes management.

An observational, multicentre study on different insulin glargine U100 titration algorithms used in patients with type 2 diabetes in daily medical practice in Adriatic countries: The ADRESA study.

AIMS: To compare the effectiveness of different titration algorithms for insulin glargine U100 used in everyday practice to achieve glycaemic targets in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 526 patients (278 in Slovenia, 248 in Croatia) with T2DM (aged ≥ 18 years) and treated with insulin glargine prior to inclusion were enrolled. Patients self-titrated insulin glargine according to physicians' guidance. RESULTS: Among the 524 patients included in the final analysis, the titration algorithm from the LANMET study was used most commonly (n = 368, 70.5% patients), followed by the Treat-To-Target (TTT) algorithm (n = 117, 22.4%). At the end of the study (6 months), 179 (34.3%) patients reached HbA1c ≤ 7%. There was no significant difference in the proportion of patients who reached their target HbA1c between the different algorithms at 6 months (35.6% using LANMET, 30.7% with TTT, and 32.4% with other algorithms; p = 0.611). HbA1c levels were more significantly reduced in patients using the TTT algorithm compared to LANMET (-2.31%, vs. -1.57%; p < 0.05). The proportion of patients with reported symptomatic hypoglycaemia did not differ significantly between the algorithms. CONCLUSIONS: Continuous titration of insulin glargine U100 is a safe and efficient option for T2DM management, regardless of the titration algorithm applied.

Prediabetes awareness among Southeastern European physicians.

AIMS/INTRODUCTION: Prediabetes (PD) represents a transitional state where the glucose levels are higher than normal, but not enough for diabetes mellitus diagnosis. As there is a growing number of the population with PD, its early detection and treatment could prevent the development of diabetes mellitus and its complications. We aimed to assess the overall knowledge of PD among medical professionals of different varieties. MATERIALS AND METHODS: A questionnaire-based study addressing PD and type 2 diabetes mellitus knowledge among Southeastern European general practitioners, postgraduates, physicians and superior specialists was carried out. RESULTS: A total of 397 physicians completed the questionnaire. The total rate of correct answers from diabetologists, non-diabetologist internists, residents and general practitioners was 69, 56.1, 54 and 53%, respectively. Questions related to the PD definition achieved a total of 46.6% correct answers. Correct responses considering the numerical definition of impaired fasting glucose and impaired glucose tolerance were 46.3 and 46.8%, respectively. Younger physicians had better knowledge of numerical values regarding PD and type 2 diabetes mellitus criteria (P < 0.001). CONCLUSIONS: The present results show that overall knowledge of PD is poor among Southeastern European physicians, which necessitates adequate educational programs on PD in this region.

[CROATIAN GUIDELINES FOR THE PHARMACOTHERAPY OF TYPE 2 DIABETES]. / HRVATSKE SMJERNICE ZA FARMAKOLOSKO LIJECENJE SECERNE BOLESTI TIPA 2.

INTRODUCTION: The Croatian Association for Diabetes and Metabolic Disorders of the Croatian Medical Association has issued in 2011 the first national guidelines for the nutrition, education, self-control, and pharmacotherapy of diabetes type 2. According to the increased number of available medicines and new evidence related to the effectiveness and safety of medicines already involved in the therapy there was a need for update of the existing guidelines for the pharmacotherapy of type 2 diabetes in the Republic of Croatia. PARTICIPANTS: as co-authors of the Guidelines there are listed all members of the Croatian Association for Diabetes and Metabolic Diseases, as well as other representatives of professional societies within the Croatian Medical Association, who have contributed with comments and suggestions to the development of the Guidelines. EVIDENCE: These guidelines are evidence-based, according to the GRADE system (eng. Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendations. CONCLUSIONS: An individual patient approach based on physiological principles in blood glucose control is essential for diabetes' patients management. Glycemic targets and selection of the pharmacological agents should be tailored to the patient, taking into account the age, duration of disease, life expectancy, risk of hypoglyce- mia, comorbidities, developed vascular and other complications as well as other factors. Because of all this, is of national interest to have a practical, rational and applicable guidelines for the pharmacotherapy of type 2 diabetes.

Self-monitoring of blood glucose in diabetes: from evidence to clinical reality in Central and Eastern Europe--recommendations from the international Central-Eastern European expert group.

Self-monitoring of blood glucose (SMBG) is universally considered to be an integral part of type 1 diabetes management and crucial for optimizing the safety and efficacy of complex insulin regimens. This extends to type 2 diabetes patients on intensive insulin therapy, and there is also a growing body of evidence suggesting that structured SMBG is beneficial for all type 2 diabetes patients, regardless of therapy. However, access to SMBG can be limited in many countries in Central and Eastern Europe. A consensus group of diabetes experts from 10 countries in this region (with overlapping historical, political, and social environments)--Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia, and Ukraine--was formed to discuss the role of SMBG across the spectrum of patients with diabetes. The group considered SMBG to be an essential tool that should be accessible to all patients with diabetes, including those with non-insulin-treated type 2 diabetes. The current article summarizes the evidence put forward by the consensus group and provides their recommendations for the appropriate use of SMBG as part of individualized patient management. The ultimate goal of these evidence-based recommendations is to help patients and providers in Central and Eastern Europe to make optimal use of SMBG in order to maximize the efficacy and safety of glucose-lowering therapies, to prevent complications, and to empower the patient to play a more active role in the management of their diabetes.

Impact of prostaglandin F2-alpha and tumor necrosis factor-alpha (TNF-alpha) on pain in patients undergoing thermal balloon endometrial ablation.

The primary objective of the study was to evaluate the correlation between prostaglandin F2-alpha and tumour necrosis factor-alpha concentration and that of pain experienced by patients undergoing thermal balloon ablation. Furthermore we evaluated the correlation between the endometrial and myometrial thicknesses and the degree of pain experienced by patients undergoing the procedure, and in addition the correlation between PGF2-alpha, TNF-alpha and endometrial and myometrial thicknesses. Single-arm cohort study (Canadian Task force classification II-2). In University Medical Centre Ljubljana, outpatient setting, 40 perimenopausal women with dysfunctional uterine bleeding (DUB), underwent endometrial thermal balloon ablation. The thickness of the endometrium and myometrium was measured prior to surgery using a transvaginal ultrasound that provided cross-sectional images. The degree of pain was rated using the visual analogue scale (VAS) and numeric rating scale (NRS) immediately and 60 minutes after the procedure. The concentration of PGF2-alpha and TNF-alpha in venous blood was measured prior to, at the end of and 60 minutes after the procedure. The results showed a positive correlation between the concentration of PGF2-alpha released during endometrial ablation and the endometrial and myometrial thickness (p > 0.01), including the reported degree of pain (p > 0.01). The concentration of TNF-alpha indicates a positive correlation with the level of pain (p > 0.05), but is not dependent on the thicknesses of the endometrium and myometrium. Endometrial thickness correlates to the degree of pain and the prostaglandin F2-alpha concentration. In clinical practice, performing the Gynecare ThermaChoice procedure immediately after menstruation or preoperative preparation of the endometrium using oral contraceptives enables this procedure to be performed in outpatient settings and can be considered a valuable treatment option for DUB.

Plasma nitrite concentration decreases after hyperoxia-induced oxidative stress in healthy humans.

The aim of this study was to measure plasma nitrite, the biochemical marker of endothelial nitric oxide ((•)NO) synthesis, before and after hyperoxia, in order to test the hypothesis that hyperoxia-induced vasoconstriction is a consequence of reduced bioavailability of (•)NO caused by elevated oxidative stress. Ten healthy men breathed 100% normobaric O(2) for 30 min between 15th and 45th min of the 1-h study protocol. Plasma nitrite and malondialdehyde (MDA), arterial stiffness (indicated by augmentation index, AIx) and arterial oxygen (P(tc)O(2)) pressure were measured at 1st, 15th, 45th and 60th minute of the study. Breathing of normobaric 100% oxygen during 30 min caused an increase in P(tc)O(2) (from 75 ± 2 to 412 ± 25 mm Hg), AIx (from -63 ± 4 to -51 ± 3%) and MDA (from 152 ± 13 to 218 ± 15 nm) values and a decrease in plasma nitrite (from 918 ± 58 to 773 ± 55 nm). During the 15-min recovery phase, plasma nitrite, AIx and MDA values remained altered. This study suggests that the underlying mechanism of hyperoxia-induced vasoconstriction may involve reduced (•)NO bioavailability caused by elevated and sustained oxidative stress.

The metabolic syndrome is associated with high-normal urinary albumin excretion and retinopathy in normoalbuminuric type 1 diabetic patients.

Although metabolic syndrome was not extensively studied in type 1 diabetes, higher insulin resistance, the core feature of the syndrome was found to be associated with increased risk of developing microvascular complications. As diabetic nephropathy may progress to advanced lesion before microalbuminuria appears, we investigated the association of the metabolic syndrome and estimated glucose disposal rate (eGDR) with urinary albumin excretion (UAE), retinopathy and neuropathy in normoalbuminuric type 1 diabetic patients. Two hundred and 98 patients (UAE < 30 mg / 24 h at three occasions) were divided according to the IDF metabolic syndrome; eGDR (mg kg(-1) min(-1)) was calculated: 24.31-(12.22 x WHR) - (3.29 x HT) - (0.57 x HbA1c), (WHR = waist-to-hip ratio, HT = hypertension). Patients with (n = 99) compared to those without metabolic syndrome (N = 199) showed higher UAE (15.96 +/- 9.10; 13.48 +/- 8.36 mg /24 h), C-reactive protein (2.39 +/- 4.09;1.12 +/- 2.03 mg/L), prevalence of retinopathy (70.7; 55.27%) and polyneuropathy (80.8; 68.3%), and lower eGDR (5.75 +/- 1.74; 8.96 +/- 1.9), (p > 0.05). In patients with high-normal UAE, retinopathy and polyneuropathy eGDR was significantly lower compared with patients with low-normal UAE, and without retinopathy and polyneuropathy. In multiple regression analysis UAE and retinopathy were associated with diabetes duration (beta = -0.20, beta = -0.62), eGDR (beta = - 0.106; beta = -0.041), metabolic syndrome (beta = 0.49, beta = 0.28), (p > 0.05). In type 1 diabetic patients insulin resistance and IDF defined metabolic syndrome are associated with high-normal UAE, retinopathy and polyneuropathy. The predictive value of the metabolic syndrome for development of microalbuminuria and retinopathy needs to be assessed in further follow-up studies.

Comparison of acute effects of red wine, beer and vodka against hyperoxia-induced oxidative stress and increase in arterial stiffness in healthy humans.

OBJECTIVE: We determined and compared acute effects of different alcoholic beverages on oxygen-induced increase in oxidative stress plasma marker and arterial stiffness in healthy humans. METHODS: Ten males randomly consumed one of four tested beverages: red wine (RW), vodka, beer (0.32 g ethanol/kg body wt) and water as control. Every beverage was consumed once, a week apart, in a cross-over design. The volunteers breathed 100% normobaric O(2) between 60th and 90th min of 3h study protocol. Plasma lipid peroxides (LOOH) and uric acid (UA) concentration, blood alcohol concentration (BAC) and arterial stiffness (indicated by augmentation index, AIx) were measured before and 30, 60, 90, 120 and 180 min after beverage consumption. RESULTS: Intake of all alcoholic beverages caused a similar increase of BAC. The oxygen-induced elevation in AIx was similarly reduced in all three groups relative to the control (3.4 ± 1.3%, 5.4 ± 2.2% and 0.2 ± 1.6% vs. 13.7 ± 2.6% for red wine, vodka, beer and control, respectively, 60 min after intake). Exposure to oxygen resulted in increased plasma LOOH in all groups. However, in RW group this increase was lowest (1.1 ± 0.5) in comparison to the vodka (2.1 ± 0.5), beer (1.6±0.3) and control (2.5 ± 0.4µM/L H(2)O(2)). 60 min after intake of RW and beer plasma UA significantly increased (34 ± 4 and 15 ± 3) in contrast to vodka and control (-6 ± 2 and -8 ± 2µmol/L). CONCLUSION: All three alcoholic beverages provided similar protection against oxygen-induced increase in arterial stiffness, probably due to central vasodilatatory effect of alcohol itself, but only RW provided protection against oxygen-induced oxidative stress.