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Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming. • Interrupting glucagon signaling in zebrafish or mice results in delta and beta cell proliferation. • In a mouse transplantation model of interrupted glucagon signaling, human delta and beta cell proliferation increased. • Disrupting mTOR activation or targeting the arginine transporter SLC7A2 prevented delta and beta cell proliferation. • Interrupted glucagon signaling increased delta cell mass but not beta cell mass in healthy mice. [ABSTRACT FROM AUTHOR]

Interrupting glucagon signaling (IGS) elicits robust alpha cell proliferation in an amino acid-dependent manner in mouse and human pancreatic islets. To determine whether IGS triggers beta cell proliferation in mouse and human islets in vivo, we quantified the percentage of Ki67-positive beta cells in adult mouse and human islets after IGS. Wild type (WT) mouse islets transplanted into liver-specific glucagon receptor (GCGR) knockout (LKO) mice exhibited a 4.1-fold increase in beta cell proliferation (WT to LKO: 0.98±0.34%, WT to WT: 0.24±0.19%, P=0.008, n=8). Likewise, treatment of C57BL6 mice with an anti-GCGR monoclonal antibody (GCGR-Ab) elicited a 3.6-fold increase in beta cell proliferation (GCGR-Ab: 1.09±0.21%, control (CTR): 0.30±0.14%, P=0.004, n=10). Given that the cationic amino acid transporter, Slc7a2, is one of the most highly expressed amino acid transporters in pancreatic islets and required for IGS-induced alpha cell proliferation, we assessed GCGR-Ab-induced beta cell proliferation in adult mice with inactivation of Slc7a2. There was a 3.2-fold increase in beta cell proliferation in WT mice treated with GCGR-Ab (GCGR-Ab: 1.45±0.46%, CTR: 0.46±0.15%, P=0.001, n=10). Notably, this effect was absent in Slc7a2 knockout mice (GCGR-Ab: 0.35±0.35%, CTR: 0.41±0.28%, n=10), suggesting that GCGR antagonism induces beta cell proliferation in an amino acid-dependent manner in mice. Furthermore, transplanted human islets from normal donors (ages 10-55, n=8) into immunodeficient mice exhibited a 2.8-fold increase in beta cell proliferation (GCGR-Ab: 0.61±0.60%, CTR: 0.22±0.21%, P=0.05, n=8) following GCGR-Ab treatment. These data indicate that IGS stimulates beta cell proliferation in mouse and human islets and that in mouse islets, this is Slc7a2-dependent. Disclosure: K.C. Coate: None. E. Spears: None. C. Dai: None. S. Wisniewski: None. G. Poffenberger: None. L.D. Shultz: None. D.L. Greiner: None. D.J. Drucker: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics. Research Support; Self; Novo Nordisk Inc. H. Yan: Stock/Shareholder; Self; REMD Biotherapeutics Inc. K. Sloop: None. A.C. Powers: None. D. Dean: None. Funding: National Institutes of Health (DK117147) [ABSTRACT FROM AUTHOR]

Background: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Methods: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed. Results: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Conclusions: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy. [ABSTRACT FROM AUTHOR]

Introduction: The Alzheimer's Disease Composite Score (ADCOMS) is a tool developed to detect clinical progression and measure treatment effect in patients in early stages of Alzheimer's disease (AD). The psychometric properties of the ADCOMS have been established; however, the threshold for clinical meaningfulness has yet to be identified. Methods: Anchor-based, distribution-based, and ROC curve analyses were used to estimate clinically meaningful thresholds for change in ADCOMS for patients with mild cognitive impairment (MCI) and AD dementia. This study included data from three sources: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the National Alzheimer's Coordinating Center (NACC), and a legacy dataset that included data from four sources: the placebo group from three MCI trials and an earlier data cut from ADNI. Results were stratified by disease severity (MCI vs. dementia) and APOE ε4 carrier status. Results: A total of 5355 participants were included in the analysis. The ADCOMS was able to detect change for MCI and dementia patients who experienced a meaningful decline in cognition (as defined by the Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB]) between baseline and month 12. The following ADCOMS cut-offs were proposed: 0.05 for MCI and 0.10 for dementia. Conclusions: The ADCOMS was previously established as a valid and reliable tool for use in clinical trials for MCI due to AD and dementia populations. By defining thresholds for clinically meaningful change of ADCOMS, this work is an important step in interpreting clinical findings and estimates of treatment effects in early stage AD trials. [ABSTRACT FROM AUTHOR]

From June 2013 to March 2015, in total 41 passive sampler deployments of 2 wk duration each were conducted at 17 sites in South Philadelphia, PA, with results for benzene discussed here. Complementary time-resolved measurements with lower cost prototype fenceline sensors and an open-path ultraviolet differential optical absorption spectrometer were also conducted. Minimum passive sampler benzene concentrations for each sampling period ranged from 0.08 ppbv to 0.65 ppbv, with a mean of 0.25 ppbv, and were negatively correlated with ambient temperature (–0.01 ppbv/°C,R2= 0.68). Co-deployed duplicate passive sampler pairs (N= 609) demonstrated good precision with an average and maximum percent difference of 1.5% and 34%, respectively. A group of passive samplers located within 50 m of a refinery fenceline had a study mean benzene concentration of 1.22 ppbv, whereas a group of samplers located in communities >1 km distant from facilities had a mean of 0.29 ppbv. The difference in the means of these groups was statistically significant at the 95% confidence level (p< 0.001). A decreasing gradient in benzene concentrations moving away from the facilities was observed, as was a significant period-to-period variation. The highest recorded 2-wk average benzene concentration for the fenceline group was 3.11 ppbv. During this period, time-resolved data from the prototype sensors and the open-path spectrometer detected a benzene signal from the west on one day in particular, with the highest 5-min path-averaged benzene concentration measured at 24 ppbv. Implications: Using a variation of EPA’s passive sampler refinery fenceline monitoring method, coupled with time-resolved measurements, a multiyear study in South Philadelphia informed benzene concentrations near facilities and in communities. The combination of measurement strategies can assist facilities in identification and mitigation of emissions from fugitive sources and improve information on air quality complex air sheds. [ABSTRACT FROM AUTHOR]

Background: High dietary sodium intake has been identified as a potential cause of asthma and airway hyperreactivity. This study was designed to test the hypothesis that dietary sodium intake is an independent determinant of the risk of hyperreactivity in the general population, and to assess the role of atopy in the association between these factors.Methods: Airway reactivity to methacholine, atopy, 24 hour urinary sodium excretion, and self-reported smoking and symptom history were measured in a random sample of 1702 adults aged 18-70 from an administrative district of Nottingham. Hyperreactivity was defined as a PD20FEV1 of 12.25 mumol or less, and atopy was defined quantitatively as the mean allergen skin weal response to Dermatophagoides pteronyssinus, cat fur, and grass pollen, and categorically as the occurrence of any allergen response 1 mm or greater than the saline control. Multiple logistic regression analysis was used to estimate the independent relative odds of hyperreactivity, atopy, or symptoms in relation to sodium excretion in all 1702 subjects, and multiple linear regression to assess the independent relation between sodium excretion and mean allergen skin weal diameter, and the PD20 value amongst hyperreactive subjects.Results: There was no relation between the relative odds of hyperreactivity to methacholine and 24 hour urinary sodium excretion, either before or after adjustment for age, smoking, allergen skin weal diameter, and sex, and similarly no relation if the analysis was restricted to men or women only. The relative odds of having at least one allergen skin test response 1 mm greater than the saline control were increased in relation to sodium excretion after adjustment for age, sex, and smoking by a ratio of 2.08 (95% CI 1.04 to 4.15) per log10 unit increase in sodium excretion, but there was no evidence of an association between sodium excretion and the occurrence of self-reported wheeze, hay fever, eczema, or asthma. There was no relation between 24 hour sodium excretion and the magnitude of the mean allergen skin weal response or the PD20 value.Conclusions: These findings do not support the hypothesis that a high dietary sodium intake is a risk factor for airway hyperreactivity or atopic disease in the general adult population. [ABSTRACT FROM AUTHOR]