Diagnostic reproducibility of diabetes was substantial (ҝ-statistic = 0.74, 95%CI: 0.58-0.90) in 154 African descent individuals with 1 h-OGTTs performed 10 ± 7d (mean ± SD) apart. Diabetes was diagnosed in 34 individuals with 65%(22/34) detected at both visits (non-switchers) and 35%(12/34) at one visit (switchers). With insulin resistance greater in non-switchers, 1 h-OGTT reproducibility may be better if insulin resistance present.

G6PD deficiency (G6PD-D) variants are associated with lower hemoglobin A1c (HbA1c) concentrations, raising concerns about the diagnostic efficacy of HbA1c for abnormal glucose tolerance (Abnl-GT) in Africans, in whom risk of G6PD-D and Abnl-GT is high. G6PD-D is assessed using genotyping or an enzymatic assay, but because G6PD-D is X-linked, the enzymatic assay is necessary for determining status for women heterozygous for deficiency variants. We assessed: 1) ability of HbA1c to detect Abnl-GT by G6PD-D; 2) concordance of genotyping and enzymatic assay for G6PD-D in sub-Saharan Africans living in the US. 534 participants of the Africans in America study were included, with HbA1c ranging from 3.1-11.3%. Abnl-GT determined by HbA1c (≥5.7%) was compared to the diagnostic standard, the oral glucose tolerance test (fasting glucose≥100 mg/dL and/or 2h glucose≥140 mg/dL). G6PD-D status was determined by genotype (n = 263), enzymatic assay (n = 83), or both (n = 188). G6PD-D could not be determined for 13 women heterozygotes with only genotype data. In the remaining participants, HbA1c was 0.9% lower among those with G6PD-D (4.6 ± 0.5; range 3.1-5.6) compared to those with normal G6PD activity (5.5 ± 0.6; range 4.2-11.3; P < 0.001). Glucose concentrations did not differ between groups. HbA1c sensitivity and specificity for Abnl-GT were 0% (0/17) and 100% (37/37) among those with G6PD-D, and 50% (98/195) and 80% (217/272) among those with normal activity. After excluding women heterozygotes, concordance for G6PD-D detection by genotype and the enzymatic assay was 100%. G6PD-D was associated with ~0.9% lower HbA1c in this study, leading to a failure of HbA1c to identify Abnl-GT in these participants. Such a dramatic difference in a screening tool could have consequences in practice, including late diagnosis, undertreatment, and increased complications among those with G6PD-D. Additionally, the results for the enzymatic assay were perfectly concordant with the genotype results for G6PD-D. However, as genotype alone cannot predict G6PD-D in heterozygous women, the enzymatic assay was more informative.

The screening, diagnosis and management of gestational diabetes mellitus (GDM) have evolved over time. Similarly, continuous glucose monitoring (CGM) has advanced in parallel: from intermittent to real-time monitoring, shorter to longer wear-time and poor to increased precision. Thus, CGM has replaced multiple glucose fingerstick testing in type 1 diabetes mellitus (T1D), including pregnant women with T1D. Despite its advantages, the uptake of CGM in women with GDM remains limited. Doubts persist over its cost, accuracy and optimal utilisation, besides there is paucity of evidence supporting its use in both diagnosis and management. This review summarises the current clinical evidence, benefits and limitations of using CGM in pregnant women with GDM. Like T1D, only larger pointed studies and randomised controlled trials will clarify the value of CGM in GDM.

The evolutionarily conserved Hippo signaling pathway regulates organ size and tissue homeostasis. Yes-associated protein (YAP) functions as a transcriptional co-activator and is a critical downstream effector of the Hippo signaling pathway. Altered crosstalk with oncogenic signaling pathways contributes to YAP dysregulation in cancer. Kinase Suppressor of Ras 1 (KSR1) scaffolds the Ras cascade. Some of the functions of the Ras and Hippo pathways in regulating cellular processes are similar. Nevertheless, the potential intersection of Ras and Hippo signaling has not been explored. Here, we identify KSR1 as a previously unrecognized scaffold of the Hippo pathway. We demonstrate that KSR1 constitutively binds to YAP and MST1 and forms a complex with LATS1. Moreover, KSR1 modulates YAP protein levels and its transcriptional activity, at least in part through the RhoA/actin axis. Our findings provide insight into the role of KSR1 as a scaffold of the Hippo signaling that could yield novel therapeutics.

In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, Yes-associated protein 1 [YAP], Transcriptional coactivator with PDZ-binding motif [TAZ], and Hippo scaffold, Ras GTPase-activating-like protein IQGAP1 [IQGAP1], in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its cotranscriptional activity in melanoma and breast carcinoma cells. Importantly, our study highlights the potential therapeutic significance of targeting PANX1. Pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP levels in melanoma cells. Furthermore, our Clariom™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), β-galactoside binding protein and galectin-3 (LGALS3), that are affected in PANX1-deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment.

Introduction and Objective: Genetic association studies report lower A1C levels with G6PD deficiency (G6PD-D). A1C is used as a diagnostic test for abnormal glucose tolerance (AbnlGT), a summary term for diabetes and prediabetes. It is critical to assess the clinical impact of G6PD-D on the diagnostic efficacy of A1C in populations in whom deficiency variants are common and risk of AbnlGT is high, such as Africans. G6PD-D is X-linked and caused primarily by the G6PD A- haplotype in Africa. G6PD-D can be assessed by either genotyping or clinical assay. We determined: 1) the ability of A1C to detect AbnlGT by G6PD-D status; 2) concordance of genotyping and the clinical assay in 506 African-born Blacks enrolled in the Africans in America study (men: 61% (308/506). Methods: AbnlGT was diagnosed by the OGTT. G6PD-D was assessed by genotype only (n=263), genotype and assay (n=188) or assay only (n=55). G6PD-D clinical assay used qualitative visual fluorescence screening in whole blood. A1C ≥5.7% was the threshold for AbnlGT. Results: G6PD-D status was indeterminant in 13 women who were heterozygous for G6PD A- and did not have the assay. In the remaining 493 participants, AbnlGT occurred in 41% (201/493) and G6PD-D in 10% (51/493). G6PD-D prevalence in men and women were: 14% (43/308) v 4% (8/185) P<.001. A1C levels with and without G6PD-D were: 4.6 ± 0.5, (range 3.1 - 5.6) v 5.5 ± 0.6 (range 4.2 - 11.3), P<.001). With G6PD-D, A1C sensitivity and specificity for AbnlGT detection were: 0% (0/16) and 100% (35/35), resp. Without G6PD-D, A1C sensitivity and specificity were: 50% (93/185) and 79% (202/257), resp. Participants with both genotyping and the assay (n=188), concordance for G6PD-D detection was 100%. Conclusion: G6PD-D lowered A1C levels by 0.9%. These falsely low A1C levels could lead to late diagnosis of AbnlGT and complications. Overall, as the assay can detect deficiency in women heterozygous for G6PD A-, the assay for G6PD was more informative than genotyping. A.R. Bentley: None. K. Ntabadde: None. K. Balahali: None. K. Ekoru: None. C. DuBose: None. D.B. Sacks: Other Relationship; Sebia, Trinity. A.A. Adeyemo: None. C.N. Rotimi: None. A.E. Sumner: None.

The epithelial Na+ channel (ENaC), by mediating the flow of Na+ ions across biological membranes, plays a key role in the regulation of Na+ and water absorption in several human epithelia. IQGAP1 is a scaffold protein that mediates diverse cellular processes, including intracellular signaling and trafficking. In this study, we establish that IQGAP1 binds to ENaC and regulates its functions. We observed that IQGAP1 coresides with aquaporin 2 in ENaC-expressing principal cells of the distal nephron of mouse kidney. We showed that purified IQGAP1 pulls down the α-, β-, and γ-subunits of ENaC. We demonstrated that endogenous IQGAP1 coimmunoprecipitates with ENaC subunits in Madin-Darby canine kidney cell lysates. Functionally, coexpression of IQGAP1 with ENaC in Xenopus oocytes reduces ENaC surface abundance and amiloride-sensitive Na+ transport activity. Together, our data indicate that IQGAP1 binds to ENaC, which likely influences channel trafficking to regulate its cell surface abundance and Na+ transport function. More broadly, these observations suggest new physiological roles for IQGAP1 in Na+ and water absorption in epithelium.

OBJECTIVE:We investigated the association between historic redlining and risk of gestational diabetes mellitus (GDM) and whether this relationship is mediated by maternal obesity and area-level deprivation. RESEARCH DESIGN AND METHODS:This retrospective study included 86,834 singleton pregnancies from Kaiser Permanente Southern California's health records (2008-2018). Redlining was assessed using digitized Home Owners' Loan Corporation (HOLC) maps, with patients' residential addresses geocoded and assigned HOLC grades (A, B, C, or D) based on their geographic location within HOLC-graded zones. For GDM case patients, exposure was assigned based on address at diagnosis date; for noncase patients, it was assigned based on address during the 24th to 28th gestational week. Health records were combined with area deprivation index (ADI) from 2011 to 2015 census data. Mixed-effect logistic regression models assessed associations between redlining and GDM, with mediation by BMI and ADI evaluated using inverse odds ratio weighting. Models were adjusted for maternal age, education, race and ethnicity, neighborhood-level income, and smoking status. RESULTS:Among the 10,134 (11.67%) GDM case patients, we found increased risk of GDM in B ("still desirable," adjusted odds ratio [aOR] 1.20, 95% CI 0.99-1.44), C-graded ("definitely declining," aOR 1.22, 95% CI 1.02-1.47), and D-graded ("hazardous," i.e., redlined, aOR 1.30, 95% CI 1.08-1.57) neighborhoods compared with the "best"-graded zone. Prepregnancy BMI and ADI mediated 44.2% and 64.5% of the increased GDM risk among mothers in redlined areas. CONCLUSIONS:Historic redlining is associated with an increased risk of GDM, mediated by maternal obesity and neighborhood deprivation. Future research is needed to explore the complex pathways linking redlining to pregnancy outcomes.

Early identification of high-risk women is critical for preventing gestational diabetes mellitus (GDM). We aimed to improve early prediction of GDM using multiple panels of cardiometabolic biomarkers assessed in early and mid-pregnancy, considering clinical accessibility. In a US study of 2802 pregnant individuals, we assessed 91 cardiometabolic biomarkers at 10–14 (random blood) and 15–26 (fasting) gestational weeks (GW) in 107 GDM cases and 214 controls. Candidate biomarkers were categorized by clinical accessibility from high to low: group I (clinically accessible tests like HbA1c, lipids), group II (clinically accessible biomarkers upon request like insulin-like growth factor (IGF) axis markers, adipokines), and group III (specialty lab-required targeted metabolomics: amino acids (AAs) and phospholipid fatty acids (FAs)). At each visit, we constructed a full model incorporating all candidate biomarkers and conventional predictors. We built alternative models utilizing different groups of biomarkers considering clinical accessibility. Variable selection was performed to retain variables with a p value < 0.10 for a parsimonious model. Model performance was evaluated by area under receiver operating characteristics curve (AUC), proportion of cases followed (PCF,

Introduction: An error grid compares measured versus reference glucose concentrations to assign clinical risk values to observed errors. Widely used error grids for blood glucose monitors (BGMs) have limited value because they do not also reflect clinical accuracy of continuous glucose monitors (CGMs). Methods: Diabetes Technology Society (DTS) convened 89 international experts in glucose monitoring to (1) smooth the borders of the Surveillance Error Grid (SEG) zones and create a user-friendly tool—the DTS Error Grid; (2) define five risk zones of clinical point accuracy (A-E) to be identical for BGMs and CGMs; (3) determine a relationship between DTS Error Grid percent in Zone A and mean absolute relative difference (MARD) from analyzing 22 BGM and nine CGM accuracy studies; and (4) create trend risk categories (1-5) for CGM trend accuracy. Results: The DTS Error Grid for point accuracy contains five risk zones (A-E) with straight-line borders that can be applied to both BGM and CGM accuracy data. In a data set combining point accuracy data from 18 BGMs, 2.6% of total data pairs equally moved from Zones A to B and vice versa (SEG compared with DTS Error Grid). For every 1% increase in percent data in Zone A, the MARD decreased by approximately 0.33%. We also created a DTS Trend Accuracy Matrix with five trend risk categories (1-5) for CGM-reported trend indicators compared with reference trends calculated from reference glucose. Conclusion: The DTS Error Grid combines contemporary clinician input regarding clinical point accuracy for BGMs and CGMs. The DTS Trend Accuracy Matrix assesses accuracy of CGM trend indicators.

The Biomarkers for the Diagnosis of Heart Failure in Diabetes webinar was hosted by Diabetes Technology Society on September 20, 2023, with the objective to review current evidence and management practices of biomarker screening for heart failure in people with diabetes. The webinar discussed (1) the four stages of heart failure, (2) diabetes and heart failure, (3) natriuretic peptide and troponin for diagnosing heart failure in diabetes, (4) emerging composite and investigational biomarkers for diagnosing heart failure, and (5) prevention of heart failure progression. Experts in heart failure from the fields of clinical chemistry, cardiology, and diabetology presented data about the importance of screening for heart failure as an often-unnoticed complication of people with type 1 and type 2 diabetes.

BackgroundEpidemiological findings regarding the association of particulate matter ≤2.5 μm (PM2.5) exposure with hypertensive disorders in pregnancy (HDP) are inconsistent; evidence for HDP risk related to PM2.5 components, mixture effects, and windows of susceptibility is limited. We aimed to investigate the relationships between HDP and exposure to PM2.5 during pregnancy.Methods and findingsA large retrospective cohort study was conducted among mothers with singleton pregnancies in Kaiser Permanente Southern California from 2008 to 2017. HDP were defined by International Classification of Diseases-9/10 (ICD-9/10) diagnostic codes and were classified into 2 subcategories based on the severity of HDP: gestational hypertension (GH) and preeclampsia and eclampsia (PE-E). Monthly averages of PM2.5 total mass and its constituents (i.e., sulfate, nitrate, ammonium, organic matter, and black carbon) were estimated using outputs from a fine-resolution geoscience-derived model. Multilevel Cox proportional hazard models were used to fit single-pollutant models; quantile g-computation approach was applied to estimate the joint effect of PM2.5 constituents. The distributed lag model was applied to estimate the association between monthly PM2.5 exposure and HDP risk. This study included 386,361 participants (30.3 ± 6.1 years) with 4.8% (17,977/373,905) GH and 5.0% (19,381/386,361) PE-E cases, respectively. In single-pollutant models, we observed increased relative risks for PE-E associated with exposures to PM2.5 total mass [adjusted hazard ratio (HR) per interquartile range: 1.07, 95% confidence interval (CI) [1.04, 1.10] p < 0.001], black carbon [HR = 1.12 (95% CI [1.08, 1.16] p < 0.001)] and organic matter [HR = 1.06 (95% CI [1.03, 1.09] p < 0.001)], but not for GH. The population attributable fraction for PE-E corresponding to the standards of the US Environmental Protection Agency (9 μg/m3) was 6.37%. In multi-pollutant models, the PM2.5 mixture was associated with an increased relative risk of PE-E ([HR = 1.05 (95% CI [1.03, 1.07] p < 0.001)], simultaneous increase in PM2.5 constituents of interest by a quartile) and PM2.5 black carbon gave the greatest contribution of the overall mixture effects (71%) among all individual constituents. The susceptible window is the late first trimester and second trimester. Furthermore, the risks of PE-E associated with PM2.5 exposure were significantly higher among Hispanic and African American mothers and mothers who live in low- to middle-income neighborhoods (p < 0.05 for Cochran's Q test). Study limitations include potential exposure misclassification solely based on residential outdoor air pollution, misclassification of disease status defined by ICD codes, the date of diagnosis not reflecting the actual time of onset, and lack of information on potential covariates and unmeasured factors for HDP.ConclusionsOur findings add to the literature on associations between air pollution exposure and HDP. To our knowledge, this is the first study reporting that specific air pollution components, mixture effects, and susceptible windows of PM2.5 may affect GH and PE-E differently.

KSR1, a key scaffold protein for the MAPK pathway, facilitates ERK activation upon growth factor stimulation. We recently demonstrated that KSR1 binds the Ca 2+ -binding protein calmodulin (CaM), thereby providing an intersection between KSR1-mediated and Ca 2+ signaling. In this study, we set out to generate a KSR1 point mutant with reduced Ca 2+ /CaM binding in order to unravel the functional implications of their interaction. To do so, we solved the structural determinants of complex formation. Using purified fragments of KSR1, we showed that Ca 2+ /CaM binds to the CA3 domain of KSR1. We then used in silico molecular modeling to predict contact residues for binding. This approach identified two possible modes of interaction: (1) binding of extended Ca 2+ /CaM to a globular conformation of KSR1-CA3 via electrostatic interactions or (2) binding of collapsed Ca 2+ /CaM to α-helical KSR1-CA3 via hydrophobic interactions. Experimentally, site-directed mutagenesis of the predicted contact residues for the two binding models favored that where collapsed Ca 2+ /CaM binds to the α-helical conformation of KSR1-CA3. Importantly, replacing KSR1-Phe 355 with Asp reduces Ca 2+ /CaM binding by 76%. The KSR1-F 355 D mutation also significantly impairs the ability of EGF to activate ERK, which reveals that Ca 2+ /CaM binding promotes KSR1-mediated MAPK signaling. This work, by uncovering structural insight into the binding of KSR1 to Ca 2+ /CaM, identifies a KSR1 single-point mutant as a bioreagent to selectively study the crosstalk between Ca 2+ and KSR1-mediated signaling.

INTRODUCTION:Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS:Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS:At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION:At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.

ImportanceThe associations of exposure to fine particulate matter (PM2.5) and its constituents with spontaneous preterm birth (sPTB) remain understudied. Identifying subpopulations at increased risk characterized by socioeconomic status and other environmental factors is critical for targeted interventions. ObjectiveTo examine associations of PM2.5 and its constituents with sPTB. Design, Setting, and ParticipantsThis population-based retrospective cohort study was conducted from 2008 to 2018 within a large integrated health care system, Kaiser Permanente Southern California. Singleton live births with recorded residential information of pregnant individuals during pregnancy were included. Data were analyzed from December 2023 to March 2024. ExposuresDaily total PM2.5 concentrations and monthly data on 5 PM2.5 constituents (sulfate, nitrate, ammonium, organic matter, and black carbon) in California were assessed, and mean exposures to these pollutants during pregnancy and by trimester were calculated. Exposures to total green space, trees, low-lying vegetation, and grass were estimated using street view images. Wildfire-related exposure was measured by the mean concentration of wildfire-specific PM2.5 during pregnancy. Additionally, the mean exposure to daily maximum temperature during pregnancy was calculated. Main Outcomes and MeasuresThe primary outcome was sPTB identified through a natural language processing algorithm. Discrete-time survival models were used to estimate associations of total PM2.5 concentration and its 5 constituents with sPTB. Interaction terms were used to examine the effect modification by race and ethnicity, educational attainment, household income, and exposures to green space, wildfire smoke, and temperature. ResultsAmong 409 037 births (mean [SD] age of mothers at delivery, 30.3 [5.8] years), there were positive associations of PM2.5, black carbon, nitrate, and sulfate with sPTB. Adjusted odds ratios (aORs) per IQR increase were 1.15 (95% CI, 1.12-1.18; P < .001) for PM2.5 (IQR, 2.76 mu g/m3), 1.15 (95% CI, 1.11-1.20; P < .001) for black carbon (IQR, 1.05 mu g/m3), 1.09 (95% CI, 1.06-1.13; P < .001) for nitrate (IQR, 0.93 mu g/m3), and 1.06 (95% CI, 1.03-1.09; P < .001) for sulfate (IQR, 0.40 mu g/m3) over the entire pregnancy. The second trimester was the most susceptible window; for example, aORs for total PM2.5 concentration were 1.07 (95% CI, 1.05-1.09; P < .001) in the first, 1.10 (95% CI, 1.08-1.12; P < .001) in the second, and 1.09 (95% CI, 1.07-1.11; P < .001) in the third trimester. Significantly higher aORs were observed among individuals with lower educational attainment (eg, less than college: aOR, 1.16; 95% CI, 1.12-1.21 vs college [>= 4 years]: aOR, 1.10; 95% CI, 1.06-1.14; P = .03) or income (<50th percentile: aOR, 1.17; 95% CI, 1.14-1.21 vs >= 50th percentile: aOR, 1.12; 95% CI, 1.09-1.16; P = .02) or who were exposed to limited green space (<50th percentile: aOR, 1.19; 95% CI, 1.15-1.23 vs >= 50th percentile: aOR, 1.12; 95% CI, 1.09-1.15; P = .003), more wildfire smoke (>= 50th percentile: aOR, 1.19; 95% CI, 1.16-1.23 vs <50th percentile: aOR, 1.13; 95% CI, 1.09-1.16; P = .009), or extreme heat (aOR, 1.51; 95% CI, 1.42-1.59 vs mild temperature: aOR, 1.11; 95% CI, 1.09-1.14; P < .001). Conclusions and RelevanceIn this study, exposures to PM2.5 and specific PM2.5 constituents during pregnancy were associated with increased odds of sPTB. Socioeconomic status and other environmental exposures modified this association.