Folate deprivation induces cell cycle arrest at G0/G1 phase and apoptosis in hippocampal neuron cells through down-regulation of IGF-1 signaling pathway

Folate deficiency contributes to impaired adult hippocampal neurogenesis, yet the mechanisms remain unclear. Here we use HT-22 hippocampal neuron cells as model to investigate the effect of folate deprivation (FD) on cell proliferation and apoptosis, and to elucidate the underlying mechanism. FD caused cell cycle arrest at G0/G1 phase and increased the rate of apoptosis, which was associated with disrupted expression of folate transport and methyl transfer genes. FOLR1 and SLC46A1 were (P < 0.01) down-regulated, while SLC19A1 was up-regulated (P < 0.01) in FD group. FD cells exhibited significantly (P < 0.05) higher protein content of BHMT, MAT2b and DNMT3a, as well as increased SAM/SAH concentrations and global DNA hypermethylation. The expression of the total and all the 3 classes of IGF-1 mRNA variants was significantly (P < 0.01) down-regulated and IGF-1 concentration was decreased (P < 0.05) in the culture media. IGF-1 signaling pathway was also compromised with diminished activation (P < 0.05) of STAT3, AKT and mTOR. CpG hypermethylation was detected in the promoter regions of IGF-1 and FOLR1 genes, while higher SLC19A1 mRNA corresponded to hypomethylation of its promoter. IGF-1 supplementation in FD media significantly abolished FD-induced decrease in cell viability. However, IGF-1 had limited effect in rescuing the cell phenotype when added 24 h after FD. Taken together, down-regulation of IGF-1 expression and signaling is involved in FD-induced cell cycle arrest and apoptosis in HT-22 hippocampal neuron cells, which is associated with an abnormal activation of methyl transfer pathway and hypermethylation of IGF-1 gene promoter.     

The effects of EGF and IGF-1 on FSH-mediated in vitro maturation of domestic cat oocytes derived from follicular and luteal stages

The objective of this study was to evaluate the influence of epidermal growth factor (EGF) and insulin like growth factor-I (IGF-1) on the in vitro maturation of cat oocytes recovered from follicular and luteal stage ovaries. Oocytes from follicular (n = 580) and luteal (n = 209) stages were harvested and divided into four groups, which were cultured in FSH-mediated maturation medium supplemented with: (1) EGF alone (25 ng/mL); (2) IGF-1 alone (100 ng/mL); (3) EGF + IGF-1 (25 ng/mL EGF + 100 ng/mL IGF-I); or (4) no growth factor (control). The proportion of follicular stage oocytes reaching the metaphase II stage was significantly higher than that of oocytes obtained at the luteal stage in both control and study groups (p < 0.001). The percentages of oocytes reaching the metaphase II stage during the follicular period were 62.6% in control; 70.9% in EGF; 72.8% in IGF-1, and 78.1% in EGF + IGF-1 groups, whereas the respective values for gametes collected from luteal stage ovaries were 12.5%, 17.5%, 12.5%, and 16.9%. Additionally, the differences between the study and control groups were significant in the case of follicular stage oocytes. Finally, supplementing the maturation medium with EGF and/or IGF-1 significantly enhanced the meiotic maturation of oocytes recovered from follicular stage ovaries. The present study also demonstrated that the combination of EGF and IGF-I provides an additional or synergic effect on meiotic maturation of oocytes recovered from the follicular stage.     

A Subcutaneous Octreotide Hydrogel Implant for the Treatment of Acromegaly

ObjectiveTo evaluate the pharmacokinetics, efficacy, and safety of a subcutaneous octreotide hydrogel implant in patients with acromegaly.MethodsIn 2 phase II open-label randomized studies, patients aged ≥ 18 years with confirmed acromegaly and octreotide responsiveness received one or two 52 mg hydrated implants (52 mg study) or a hydrated or nonhy drated 84 mg implant (84 mg study) inserted subcutane ously in the upper arm. Implants were removed after 6 months. The 84 mg study assessed pharmacokinetics in patients with undetectable baseline octreotide concentra tions. Both studies assessed efficacy (serum growth hor mone [GH], insulin-like growth factor 1 [IGF-1]) and safety (adverse events, physical examination, clinical chemistry).ResultsEleven patients received 1 (n = 5) or 2 (n = 6) 52 mg implants; 34 received a hydrated (n = 17 [safety]; n = 16 [efficacy analysis]) or nonhydrated (n = 17) 84 mg implant. With the nonhydrated versus hydrated 84 mg implant, mean maximum serum concen tration (C_max) and mean area under the drug concentration versus time curve from time 0 to 6 months were decreased (P = 0.002 and P = 0.03, respectively) and mean time to C_max was increased (P = 0.002). In both studies, IGF-1 and GH declined in month 1 and were significantly suppressed during the 6-month treatment versus baseline (P < 0.001). With the 52 mg and 84 mg implants, respectively, 3 of 11 patients (27%) and 17 of 33 patients (52%) achieved IGF-1 normalization and 8 of 11 patients (73%) and 13 of 33 patients (39%) exhibited GH < 2.5 ng/mL; 9 of 11 patients (82%) and 11 of 34 patients (32%) experienced treatment related adverse events, which were mainly gastrointestinal.ConclusionOctreotide hydrogel implants were well tolerated and maintained stable octreotide release and sup pression of IGF-1 and GH over 6 months. (Endocr Pract. 2012;18:870-881)     

Medical Treatment Landscape for Active Acromegaly in A Pituitary Center in Israel

Objective: To evaluate current real-life experience with medical treatment for active acromegaly in a large cohort.Methods: Data on demographic parameters, blood tests, imaging studies, and treatments were extracted from the medical records.Results: The cohort included 87 patients (43 male) with active acromegaly. The mean age at diagnosis was 40.2 ± 11.4 years, and the mean duration of follow-up was 7.9 ± 5.8 years. Seventy patients presented with a macroadenoma. Mean baseline insulin growth factor 1 (IGF-1) (n = 67) was 3.2 ± 1.9 × upper limit of normal (ULN). Surgery and radiotherapy were performed in 75 and 10 patients, respectively. Currently, 38 subjects receive somatostatin analogues, pegvisomant as a monotherapy is given to 8 patients, pasireotide is given to 17 patients, cabegoline to 4 patients, estrogen to 2 females, and SSAs combined with pegvisomant to 10 patients. Eight patients are not being actively treated, including 4 following radiotherapy. Good biochemical control (IGF-1 <1.3 × ULN) was achieved in 76 patients (87%), and 11 patients (13%) are currently uncontrolled (IGF-1 >1.3 × ULN). Seventy-eight percent of controlled patients are being given 1 medication; 11% are on combination therapy; 4 patients are well controlled after radiotherapy and 2 are partially controlled without any treatment. The main adverse effects of treatment were diabetes mellitus in 7 patients (on pasireotide) and symptomatic cholelithiasis in 5 patients.Conclusion: Active acromegaly can be controlled medically in most patients, with a low rate of adverse effects. This study displays the characteristic variety of treatment options available for active acromegaly.     

Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide

ObjectiveTo evaluate expression of somatostatin receptor subtypes 2 and 5 (SSTR 2 and 5) by RT/PCR and immunohistochemistry (IHC) in GH-secreting adenomas, seeking correlations with response to octreotide.MethodsSSTR2 and 5 expression was tested by IHC (n = 37), RT/PCR (n = 36) or both (n = 13) in GH-secreting adenomas from 60 patients with acromegaly who had undergone pituitary surgery; 36 had been treated preoperatively with octreotide LAR for 3–6 months, and were categorized as responders (achievement of GH <2.5 ng/mL and a normal age-adjusted IGF-1), partial responders (GH and IGF-1 reduction >50% and >30%, respectively) or non-responders. IHC was performed on a tissue microarray using specific antibodies directed to the carboxyl terminus of SSTR2 and 5.ResultsSSTR5 was the predominantly expressed receptor subtype by both IHC and RT/PCR in all tumors tested, regardless of whether they came from octreotide-naïve, octreotide-responsive, or octreotide-resistant patients. Immunostaining was concentrated in the cytoplasm. Neither SSTR2 nor SSTR5 expression correlated with baseline or post-octreotide GH or IGF-1 levels or tumor volume by either method. The agreement rate between RT/PCR and IHC was 77% in all 13 adenomas in which both methods were used.ConclusionExpression of these receptors does not guarantee an adequate response to somatostatin analogs; other functional aspects of this interaction, such as receptor homo- and heterodimerization, and the resulting signaling cascade, probably play a role in determining whether a patient will respond or not to these agents.     

IGF-1 concentrations after weaning in young sows fed different pre-mating diets are positively associated with piglet mean birth weight at subsequent farrowing

Pre-mating diets can influence piglet birth weight and within-litter birth weight variation and thereby piglet survival and development. The major objective of this study was to evaluate the litter characteristics of young sows whose pre-mating diets received different supplementation. The supplements included a top-dressing of 200 g, consisting of either wheat (CON) or wheat plus microfibrillated cellulose, _L-carnitine or _L-arginine at one of two supplementation levels (low and high) in late lactation and during the weaning-to-oestrus interval (WEI). The second objective was to investigate the role of body condition loss and IGF-1 concentration during the WEI for subsequent litter characteristics. In total, sows after their first (N = 41) and second (N = 15) lactation were used. One week before weaning, the sows were allocated to the seven treatments based on the number of piglets and BW loss from farrowing until 1 week before weaning. Pre-mating diets did not affect litter characteristics at subsequent farrowing. However, at subsequent farrowing, sows after their first lactation had a lower total number of piglets born per litter (18.3 v. 20.3), higher mean piglet birth weight (1 365 v. 1 253 g), lower CV of birth weight (20.0 v. 26.1%) and lower percentage of piglets < 1 000 g (11.5 v. 24.4%) than sows after their second lactation. Litter weight at second parturition was positively related to IGF-1 during the WEI after first lactation (P < 0.04). Within parity, piglet mean birth weight was positively related to IGF-1 at oestrus (P < 0.02). Surprisingly, within parity, a higher relative loin muscle depth loss during previous lactation was related to lower CV and SD of birth weight (P < 0.05, for both). In conclusion, pre-mating diets did not affect litter characteristics at subsequent birth. However, a higher IGF-1 concentration during the WEI was positively associated with subsequent litter weight and piglet mean birth weight. Further studies should elucidate the role of IGF-1 during the WEI for subsequent litter characteristics and dietary interventions to stimulate IGF-1.     

Beneficial effects of oral chromium picolinate supplementation on glycemic control in patients with type 2 diabetes: A randomized clinical study

BackgroundChromium is an essential mineral that contributes to normal glucose function and lipid metabolism. This study evaluated the effect of chromium picolinate (CrPic) supplementation in patients with type 2 diabetes mellitus (T2DM).MethodsA four month controlled, single blind, randomized trial was performed with 71 patients with poorly controlled (hemoglobin A1c [HbA1c] > 7%) T2DM divided into 2 groups: Control (n = 39, using placebo), and supplemented (n = 32, using 600 μg/day CrPic). All patients received nutritional guidance according to the American Diabetes Association (ADA), and kept using prescribed medications. Fasting and postprandial glucose, HbA1c, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and serum ferritin were evaluated.ResultsCrPic supplementation significantly reduced the fasting glucose concentration (−31.0 mg/dL supplemented group; −14.0 mg/dL control group; p < 0.05, post- vs. pre-treatment, in each group) and postprandial glucose concentration (−37.0 mg/dL in the supplemented group; −11.5 mg/dL in the control group; p < 0.05). HbA1c values were also significantly reduced in both groups (p < 0.001, comparing post- vs. pre-treatment groups). Post-treatment HbA1c values in supplemented patients were significantly lower than those of control patients. HbA1c lowering in the supplemented group (−1.90), and in the control group (−1.00), was also significant, comparing pre- and post-treatment values, for each group (p < 0.001 and p < 0.05, respectively). CrPic increased serum chromium concentrations (p < 0.001), when comparing the supplemented group before and after supplementation. No significant difference in lipid profile was observed in the supplemented group; however, total cholesterol, HDL-c and LDL-c were significantly lowered, comparing pre- and post-treatment period, in the control group (p < 0.05).ConclusionsCrPic supplementation had a beneficial effect on glycemic control in patients with poorly controlled T2DM, without affecting the lipid profile. Additional studies are necessary to investigate the effect of long-term CrPic supplementation.     

The effect of adding zinc to vitamin A on IGF-1, bone age and linear growth in stunted children

A randomized, double-blind, placebo controlled trial of a single dose of 200,000 I.U. of vitamin A with daily zinc supplementation was conducted with children in Mojo village, Surabaya City. Children aged 48 to 60 months were randomized to receive a single dose of 200,000 I.U. of vitamin A plus zinc sulfate (n = 12) or a single dose of 200,000 I.U. of vitamin A (n = 12) plus placebo six days a week for six months. Children were evaluated weekly for nutrient intake and for IGF-1, C-reactive protein levels, gamma globulin levels, serum zinc, serum retinol, bone age and the index height for age at six months.At the end of the study, there was a significant increase in the serum retinol level (p < 0.03), serum zinc level (p < 0.03), IGF-1 hormone (p < 0.04) and Z-score height for age (p < 0.001), bone age (p < 0.01), and gamma globulin level (p < 0.04) and a significant decrease in the amount of infection/inflammation measured by CRP level (p < 0.001). There was also a significant correlation between CRP level and height for age (p < 0.01), and between gamma level and height for age (p < 0.01).These results suggest that combined vitamin A and zinc supplementation reduces the risk of infection and increases linear growth among children, and thus may play a key role in controlling infection and stunted growth for children under five years old.     

The effect of interleukins 27 and 35 and their role on mediating the action of insulin Like Growth Factor -1 on the inflammation and blood flow of chronically inflamed rat knee joint

IntroductionPrevious studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow.MethodMale rats were divided into two main groups of histopathology (n = 80) and blood flow (n = 72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1 + IL-27 antagonist, and IGF-1 + IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed.ResultsEndogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1 + IL-35 antagonist.ConclusionIL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF.     

Influence of premolar extraction or non-extraction orthodontic therapy on the angular changes of mandibular third molars

AimTo compare the angular changes of the third molars relative to the occlusal plane and to the second molar long axis in extraction group and compare these changes with a non extraction group.Materials and methodsThe study included pre and post treatment panoramic radiograph records of 90 subjects treated by first premolar extractions and 90 subjects who had been treated with non extraction orthodontic therapy (n = 90). Two angular variables were measured. Firstly, the angle between the long axis of the third molar and the occlusal plane (M3–OP) and secondly, the angle between the long axis of the third molar and the long axis of the second molar (M3–M2). Data were analyzed by paired and student’s t-test.ResultThe analyzed data to assess the changes in the third molar angulation from pretreatment to post treatment did not vary significantly in both the groups (p < 0.05). Both the groups showed decreased angular values. The M3–OP angular difference was (−7.3 ± 2.45) in extraction group as compared to (−5.85 ± 1.77) in non extraction group. The M3–M2 angular difference of (−4.26 ± 3.11) in extraction group and (−2.98 ± 1.74) in non-extraction group was observed.ConclusionExtraction of premolars did not demonstrate considerable changes on the angulation of the third molars. The factors other than premolar extractions may influence the angulation of the third molars.     

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

Comparison of Different Diagnostic Criteria for Gestational Diabetes Mellitus Based on the 75-G Oral Glucose Tolerance Test: A Cohort Study

ObjectiveTo compare the different diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the American Diabetes Association (ADA), World Health Organization (WHO), and Australian Diabetes in Pregnancy Society (ADIPS) in a 75-g, 2-hour oral glucose tolerance test (OGTT) and to investigate their effects on neonatal birth weight.MethodsHealthy pregnant women were enrolled in a cohort study to undergo a 75-g OGTT during 24 to 28 weeks of pregnancy and then followed up to delivery. ADA criteria and recommendations were used for the management of patients.ResultsAmong 670 pregnant women, GDM was diagnosed in 41 (6.1%), 81 (12.1%), and 126 (18.8%) on the basis of ADA, WHO, and ADIPS criteria, respectively. The kappa value was 0.38 (P < .0001) for the agreement between ADA and WHO criteria, 0.41 (P < .0001) for agreement between ADA and ADIPS criteria, and 0.64 (P < .0001) for agreement between WHO and ADIPS criteria. WHO-only “positive” women had significantly lower fasting plasma glucose (87.9 versus 102.2 mg/dL; P < .0001) and 1-hour plasma glucose levels (146.4 versus 200.5 mg/dL; P < .0001) but higher 2-hour plasma glucose levels (150.1 versus 109.1 mg/dL; P < .0001) than women diagnosed with GDM by only ADA criteria. The correlation coefficient between 1-hour glucose level and neonatal birth weight was 0.09 (P < .02). The adjusted odds ratio of macrosomia associated with GDM according to ADA criteria was 1.34 (95% confidence interval, 0.15 to 12).ConclusionThe frequency of occurrence of GDM was 6.1% in a 75-g OGTT based on ADA criteria, and there was fair agreement between ADA and WHO criteria, moderate agreement between ADA and ADIPS criteria, and strong agreement between WHO and ADIPS criteria. A modest correlation was found between the 1-hour serum glucose value and neonatal birth weight. (Endocr Pract. 2008;14:312-317)     

Surgical Reintervention in Acromegaly: is it Still worth trying?

Background and ObjectiveThere has not been a formal evaluation of how frequently and to what extent surgical reintervention in patients with persistently active acromegaly may achieve significant, albeit incomplete, reductions in growth hormone (GH) and insulinlike growth factor-I (IGF-I) levels. Of importance, recent studies suggest that the response to radiotherapy and pharmacotherapy is better with lower degrees of hypersomatotropism. The objective of this study was to evaluate the outcome of surgical reintervention in patients with active acromegaly at our institution between 1995 and 2005.MethodsWe retrospectively evaluated the outcome in 53 patients with active acromegaly (49 with macroadenomas) who underwent a second operation a mean of 24.1 ± 25.2 months after the first intervention. Basal and postglucose GH as well as IGF-I levels were analyzed at diagnosis and after the first and second pituitary procedures.ResultsBasal GH decreased in 38 patients (72%): to < 10 ng/mL in 17 and to < 2.5 ng/mL in 11. The mean IGF- I index and basal GH decreased significantly after surgical reintervention: 1.7 ± 0.4 to 1.4 ± 0.4 (P = .0001) and 13.0 ± 12.8 to 8.3 ± 11.3 ng/mL (P = .0001), respectively. Some decrement in IGF-I was observed after surgical reintervention in 30 patients (57%), being greater than 30% in 9 (17%). Only 5 patients (9%) achieved complete biochemical cure (normal IGF-I and a postglucose GH level of < 1 ng/mL). Reoperation achieved a significant decline in basal and postglucose GH levels as well as in IGF-I index only in patients with noninvasive macroadenomas.ConclusionPituitary surgical reintervention in patients with acromegaly results in a low percentage of biochemical cure. If a remnant of a noninvasive macroadenoma is visible and accessible, however, such a procedure may significantly reduce GH and IGF-I levels. (Endocr Pract. 2009;15:431-437)     

A Fraxinus excelsior L. seeds/fruits extract benefits glucose homeostasis and adiposity related markers in elderly overweight/obese subjects: A longitudinal,randomized, crossover,double-blind,placebo-controlled nutritional intervention study

PurposeThe aim of this study was to investigate the potential benefits of an extract obtained from seeds/fruits of an Oleaceae (Fraxinus excelsior L.) on glucose homeostasis and associated metabolic markers in non-diabetic overweight/obese subjects.Materials and methodsThis study was performed in 22 participants (50–80 years-old; BMI 31.0 kg/m²). The design was a longitudinal, randomized, crossover, double-blind, placebo-controlled 7-week nutritional intervention. The participants received daily 3 capsules each containing either 333 mg of an extract from Fraxinus excelsior L. seeds (Glucevia^®) or placebo capsules (control) in a random order for 3 weeks with 1 week of washout between treatments. Moreover, they followed a balanced covert energy-restricted diet (−15% energy). All variables were measured at the beginning and at the end of each period.ResultsCompared to baseline, the administration of 1 g of Glucevia^® for 3 weeks resulted in significantly lower incremental glucose area under the curve (−28.2%; p < 0.01), and significantly lower 2 h blood glucose values (−14%; p < 0.01) following an oral glucose tolerance test. No significant changes were found in the control group (−7.9% AUC, −1.6% 2 h blood glucose). Furthermore, significant differences were found between responses in the control and Glucevia^® groups with respect to serum fructosamine and plasma glucagon levels (p < 0.01 and p < 0.05, respectively). Interestingly, administration of Glucevia^® significantly increased the adiponectin:leptin ratio (p < 0.05) and decreased fat mass (p < 0.01) compared to control (p < 0.05).ConclusionThe administration of an extract from Fraxinus excelsior L. seeds/fruits in combination with a moderate hypocaloric diet may be beneficial in metabolic disturbances linked to impaired glucose tolerance, obesity, insulin resistance and inflammatory status, specifically in older adults.     

Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India

BackgroundInterleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer.Materials and methodsSingle nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (−174G>C; −572G>C, −596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software.ResultSignificantly higher number of smokers (p = 0.047), tobacco chewers (p = <0.001) and those with non-vegetarian food habits (p = 0.016) were seen in the case group. The distribution of genotypes at −174G>C locus differed significantly between cases and controls and the variant genotypes GC + CC were significantly rarer in the cases (p = 0.00073; OR = 0.52 95% CI 0.35–0.75). Variant genotypes (GC + CC) were more common in grade I than grade III tumors (p = 0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p = 0.0103), suggesting a protective effect. Genotype distribution at the other two loci (−572G>C and −596A>G) did not show association with bladder cancer.ConclusionsIL6 (−174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (−572G>C and −596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer.     

Cord blood nesfatin-1 in large for gestational age pregnancies

ObjectiveTo investigate possible alterations in cord blood levels of adipokine nesfatin-1 (secreted by adipose tissue and pancreatic β-cells and implicated in glucose metabolism and insulin resistance), as well as insulin, in large (LGA) and appropriate for gestational age (AGA) pregnancies, granted that these groups differ in body fat mass and metabolic/endocrine mechanisms.Materials and methodsCord blood nesfatin-1 and insulin concentrations were prospectively measured in 40 LGA (9 born from diabetic and 31 from non-diabetic mothers) and 20 AGA singleton full-term infants as well as their mothers.ResultsCord blood nesfatin-1 concentrations were significantly lower in LGA compared to AGA neonates (b = ?0.206, SE 0.07, p = 0.005). However, cord blood nesfatin-1 concentrations were elevated in infants born from mothers with gestational diabetes mellitus (GDM), compared to those born from non-diabetic mothers, after controlling for group (b = 0.190, SE 0.10, p = 0.05). Finally, cord blood nesfatin-1 concentrations were lower in cases of vaginal delivery (b = 0.11, SE 0.05, p = 0.042). Insulin levels were significantly elevated, as customized centiles increased (b = 0.004, SE = 0.002, p = 0.016). No significant correlation was found between insulin and nesfatin-1 in maternal and umbilical cord levels.ConclusionsIn this study nesfatin-1 levels are decreased in LGA compared to AGA fetuses. Fetal nesfatin-1 concentrations are higher in cases of GDM and cord blood nesfatin-1 concentrations are lower in cases of vaginal delivery.     

The anti-diabetic effects of GLP-1-gastrin dual agonist ZP3022 in ZDF rats

Aims/hypothesisCombination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats.MethodsZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions.ResultsZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2 ± 0.12 (high dose) vs. 7.9 ± 0.07% (vehicle), P < 0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31 ± 0.03 vs. 0.22 ± 0.02%, respectively, P < 0.05).ConclusionThese data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes.     

Significant Elevation of Growth Hormone Level Impacts Surgical Outcomes in Acromegaly

Objective: Transsphenoidal adenomectomy (TSA) is first-line treatment for acromegaly. Our aim was to determine the impact of pre-operative biochemical parameters on the outcomes of surgery.Methods: Retrospective case series of 79 consecutive acromegalics operated between 1994 and 2013. Inclusion criteria were: first TSA, pathology-confirmed growth hormone (GH) adenoma, and follow-up >3 months. Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) without adjuvant therapy during follow-up.Results: Median follow-up was 35.4 months (range, 3 to 187 months). Logistic regression analysis showed that the best model to predict long-term remission included the following pre-operative markers: GH, tumor diameter, and cavernous sinus invasion (CSI) (area under the curve, 0.933). A threshold GH of 40 ng/mL was associated with long-term remission (sensitivity, 97%; specificity, 42%). Group A (GH >40 ng/mL) comprised 19 patients (9 men); age, 43 ± 13 years; tumor diameter, 2.7 ± 1.0 cm; 73.7% with CSI; and pre-operative median GH, 77.8 ng/mL (interquartile range [IQR], 66.7 to 107.0 ng/mL). Three patients (15%) in group A achieved remission at 3 months, but 2 patients recurred during follow-up. Group B (GH ≤40 ng/mL) comprised 60 patients (25 men); age, 47 ± 13 years; tumor diameter, 1.6 ± 1.0 cm; 35% with CSI, preoperative median GH, 6.9 ng/mL (IQR, 3.4 to 16.9 ng/mL). Thirty-five patients (58%) in group B achieved remission at 3 months without recurrence during follow-up. Group A had larger tumors and a higher proportion of tumors with CSI (P<.05).Conclusion: Both GH and IGF-1 should be measured pre-operatively, as highly elevated GH levels negatively impact long-term surgical remission. This strategy allows early identification of patients who require adjuvant therapy and may decrease time to biochemical control.Abbreviations: AUC = area under the curve CSI = cavernous sinus invasion GH = growth hormone ICA = internal carotid artery IGF-1 = insulin-like growth factor 1 MRI = magnetic resonance imaging OGTT = oral glucose tolerance test POD2 = postoperative day 2 TSA = transsphenoidal adenomectomy     

Patient-Led Versus Physician-Led Titration of Insulin Glargine in Patients with Uncontrolled Type 2 Diabetes: A Randomized Multinational Atlas Study

ObjectiveSelf-adjustment of insulin dose is commonly practiced in Western patients with type 2 diabetes but is usually not performed in Asian patients. This multinational, 24-week, randomized study compared patient-led with physician-led titration of once-daily insulin glargine in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering agents.MethodsPatient-led (n = 275) or physician-led (n = 277) subjects followed the same dose-titration algorithm guided by self-monitored fasting blood glucose (FBG; target, 110 mg/dL [6.1 mmol/L]). The primary endpoint was change in mean glycated hemoglobin (HbA_1c) at week 24 in the patient-led versus physician-led titration groups.ResultsPatient-led titration resulted in a significantly higher drop in HbA_1c value at 24 weeks when compared with physician-led titration (− 1.40% vs. − 1.25%; mean difference, − 0.15; 95% confidence interval, − 0.29 to 0.00; P = .043). Mean decrease in FBG was greatest in the patient-led group (− 2.85 mmol/L vs. − 2.48 mmol/L; P = .001). The improvements in HbA_1c and FBG were consistent across countries, with similar improvements in treatment satisfaction in both groups. Mean daily insulin dose was higher in the patient-led group (28.9 units vs. 22.2 units; P < .001). Target HbA_1c of < 7.0% without severe hypoglycemia was achieved in 40.0% and 32.9% in the patient-led and physician-led groups, respectively (P = .086). Severe hypoglycemia was not different in the 2 groups (0.7%), with an increase in nocturnal and symptomatic hypoglycemia in the patient-led arm.ConclusionPatient-led insulin glargine titration achieved near-target blood glucose levels in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering drugs, demonstrating that Asian patients can self-uptitrate insulin dose effectively when guided. (Endocr Pract. 2015;21:143-157)     

Role of monocyte chemoattractant protein-1 (MCP-1) as an immune-diagnostic biomarker in the pathogenesis of chronic periodontal disease

ObjectiveMonocyte chemoattractant protein-1 (MCP-1) is an important chemokine responsible for the initiation, regulation and mobilization of monocytes to the active sites of severe periodontal inflammation. The present study aims at evaluating the levels of MCP-1 in GCF, saliva and serum and to analyze the changes following phase I periodontal therapy. Assessment of possible correlations between levels of MCP-1 in the three biological fluids was also done.MethodsFifteen healthy and 30 patients of severe chronic periodontitis (diseased) participated in the study. Patients of the diseased group underwent scaling/root planing. Evaluation of PI, GI, PD, CAL and collection of samples of GCF, serum and saliva was done at baseline and 6 weeks following periodontal therapy. MCP-1 levels were quantified in all samples using ELISA.ResultsCompared to healthy controls, MCP-1 levels were statistically significantly higher in GCF (p < 0.001), saliva (p = 0.002) and serum (p < 0.001) in subjects with chronic periodontitis. Levels of MCP-1 in all the three fluids decreased significantly in patients after periodontal therapy (p < 0.001). There was a significant positive correlation between MCP-1 levels in GCF, saliva and serum in patients of chronic periodontitis both pre (r > 0.9) and post-treatment (r > 0.6).ConclusionsThe results suggest that levels of MCP-1 in GCF and saliva can be reliable indicators of severity of periodontal destruction and their serum levels reflect the systemic impact of this local inflammatory disease thereby strengthening the reciprocal oro-systemic association.