Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic Islets Desensitized to Sulfonylureas

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at β-cell KATP channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucosedependence and sensitivity to metabolic inhibitors of the interaction between NAT and KATP channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT

Glucose-dependent and Glucose-sensitizing Insulinotropic Effect of Nateglinide: Comparison to Sulfonylureas and Repaglinide

Nateglinide, a novel D-phenylalanine derivative, stimulates insulin release via closure of KATP channels in pancreatic β-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS) in vitro from isolated rat islets. The EC50 of nateglinide to stimulate insulin secretion was 14 μM in the presence of 3mM glucose and was reduced by 6-fold in 8mM glucose and by 16-fold in 16mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (~2x EC50 in the presence of 8mM glucose) nateglinide and repaglinide shifted the EC50s for GSIS to the left by 1.7mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of the EC50. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemia in vivo

Importance of early insulin secretion. Comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes

WSTĘP. Badanie przeprowadzono w celu porównania wpływu nateglinidu, gliburydu i placebo na poposiłkowe zwyżki glikemii oraz wydzielanie insuliny u chorych na cukrzycę typu 2 leczonych uprzednio dietą. MATERIAŁ I METODY. Badanie przeprowadzono metodą podwójnie ślepej próby, z udziałem grupy kontrolnej. Randomizacją objęto 152 chorych z kilku ośrodków. Otrzymywali oni przez 8 tygodni nateglinid (120 mg przed posiłkiem 3 razy dziennie, n = 51) lub gliburyd (5 mg 4 razy dziennie, po 2 tygodniach dawkę zwiększano do 10 mg 4 razy dziennie, n = 50) lub placebo (n = 51). Tydzień przed rozpoczęciem badania oraz po 8 tygodniach leczenia wykonywano oznaczenie profilu glikemii, insulinemii oraz stężenia peptydu C po prowokacji w postaci pokarmów płynnych. Tydzień przed badaniem oraz po 7 tygodniach terapii na podstawie 19 pomiarów określano dzienny profil glikemii i insulinemii. Chorzy spożywali w ciągu tego okresu 3 posiłki stałe. WYNIKI. Po spożyciu pokarmów płynnych nateglinid skuteczniej zmniejszał przyrostowe pole pod krzywą (AUC, area under the curve) dla glukozy niż gliburyd (D = -4,94 vs. -2,71 mmol &#8226; h/l, p < 0,05), zaś gliburyd skuteczniej niż nateglinid obniżał stężenie glukozy w osoczu na czczo (D = -2,9 vs. -1,0 mmol/l, p < 0,001). Natomiast wzrost stężenia peptydu C wywołany przez gliburyd był większy niż w przypadku nateglinidu (D = +1,83 vs. +0,95 nmol &#8226; h/p < 0,01) i jedynie gliburyd zwiększał stężenie insuliny na czczo. Po prowokacji w formie pokarmów stałych zarówno nateglinid, jak i gliburyd zapewniały podobną całkowitą kontrolę glikemii (D 12-h AUC przyrostowe = -13,2 vs. -15,3 mmol &#8226; h/l), lecz AUC dla insuliny w przypadku nateglinidu było wyraźnie mniejsze niż w przypadku gliburydu (D 12-h AUC = +866 vs. +1702 pmol &#8226; h/l, p = 0,01). WNIOSKI. Badanie to wykazało, że nateglinid wybiórczo zwiększał wczesne wydzielanie insuliny i zapewniał lepszą kontrolę glikemii w czasie spożywania posiłków niż gliburyd, powodując jednocześnie mniejszą całkowitą ekspozycję na insulinę niż gliburyd.INTRODUCTION. This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS. This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks &#8212; 1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured. RESULTS. During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide (D = &#8211;4.94 vs. &#8211;2.71 mmol &#8226; h/l, p < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide (D = &#8211;2.9 vs. &#8211;1.0 mmol/l, respectively, p < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide (D = +1.83 vs. +0.95 nmol &#8226; h/l, p < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control (D 12-h incremental AUC = &#8211;13.2 vs. &#8211;15.3 mmol &#8226; h/l), but the insulin AUCinduced by nateglinide was significantly less than that induced by glyburide (D 12-h AUC = +866 vs. +1,702 pmol &#8226; h/l, p = 0.01). CONCLUSIONS. This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Re-establishing the ‘outsiders’: English press coverage of the 2015 FIFA Women’s World Cup

In 2015, the England Women’s national football team finished third at the Women’s World Cup in Canada. Alongside the establishment of the Women’s Super League in 2011, the success of the women’s team posed a striking contrast to the recent failures of the England men’s team and in doing so presented a timely opportunity to examine the negotiation of hegemonic discourses on gender, sport and football. Drawing upon an ‘established-outsider’ approach, this article examines how, in newspaper coverage of the England women’s team, gendered constructions revealed processes of alteration, assimilation and resistance. Rather than suggesting that ‘established’ discourses assume a normative connection between masculinity and football, the findings reveal how gendered ‘boundaries’ were both challenged and protected in newspaper coverage. Despite their success, the discursive positioning of the women’s team as ‘outsiders’, served to (re)establish men’s football as superior, culturally salient and ‘better’ than the women’s team/game. Accordingly, we contend that attempts to build and, in many instances, rediscover the history of women’s football, can be used to challenge established cultural representations that draw exclusively from the history of the men’s game. In such instances, the 2015 Women’s World Cup provides a historical moment from which the women’s game can be relocated in a context of popular culture

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

cited By 0Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.Peer reviewe

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers