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It is well established that chronic glucocorticoid exposure causes hyperglycemia. While glucocorticoid receptor (GR) stimulates hepatic gluconeogenic gene transcription, additional mechanisms are activated by chronic glucocorticoid exposure to enhance gluconeogenesis. We found that chronic glucocorticoid treatment activated sphingosine-1-phosphate (S1P)-mediated signaling. Hepatic knockdown of hepatic S1P receptor 1 (S1PR1) had no effect on chronic glucocorticoid-induced glucose intolerance but elevated fasting plasma insulin levels. In contrast, hepatic S1PR3 knockdown exacerbated chronic glucocorticoid-induced glucose intolerance without affecting fasting plasma insulin levels. Finally, hepatic S1PR2 knockdown attenuated chronic glucocorticoid-induced glucose intolerance and reduced fasting plasma insulin levels. Here, we focused on dissecting the role of S1PR2 signaling in chronic glucocorticoid response on glucose homeostasis. We found that chronic glucocorticoid-induced hepatic gluconeogenesis, gluconeogenic gene expression, and GR recruitment to the glucocorticoid response elements (GREs) of gluconeogenic genes were all reduced in hepatic S1PR2 knockdown male mice. Hepatic S1PR2 knockdown also enhanced glucocorticoid suppression of RAR-related orphan receptor γ (RORγ) expression. Hepatic RORγ overexpression in hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, gluconeogenic gene expression, and GR recruitment to their GREs. Conversely, RORγ antagonist and the reduction of hepatic RORγ expression attenuated such glucocorticoid effects. Thus, chronic glucocorticoid exposure induces an S1PR2-RORγ axis to cooperate with GR to enhance hepatic gluconeogenesis. Overall, this work provides novel mechanisms of and pharmaceutical targets against steroid-induced hyperglycemia.Article highlights

Background: Neuropsychiatric symptoms affect the majority of dementia patients. Past studies report high rates of potentially inappropriate prescribing of psychotropic medications in this population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort by sex and race. Methods: We utilize Medicare claims and prescription fill records in a cohort of 100% Medicare North and South Carolina beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia and quantify diagnosis of anxiety, depression and psychosis using validated coding algorithms. We search Medicare claims for antianxiety, antidepressant and antipsychotic medications to determine prescriptions filled. Results: Anxiety and depression were diagnosed at higher rates in White patients; psychosis at higher rates in Black patients. (P <.001) Females were diagnosed with anxiety, depression and psychosis at higher rates than males (P <.001) and filled more antianxiety and antidepressant medications than males. (P <.001) Black and Other race patients filled more antipsychotic medications for anxiety, depression and psychosis than White patients. (P <.001) Antidepressants were prescribed at higher rates than antianxiety or antipsychotic medications across all patients and diagnoses. Of patients with no neuropsychiatric diagnosis, 11.4% were prescribed an antianxiety medication, 22.8% prescribed an antidepressant and 7.6% prescribed an antipsychotic. Conclusions: The high fill rate of antianxiety (benzodiazepine) medications in dementia patients, especially females is a concern. Patients are prescribed psychotropic medications at high rates. This practice may represent potentially inappropriate prescribing. Patient/caregiver education with innovative community outreach and care delivery models may help decrease medication use. [ABSTRACT FROM AUTHOR]

(1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-β and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3072 proteins in CSF samples of AD-biomarker positive mild cognitive impairment (MCI) participants (n = 38) and controls (n = 48), using the Explore panel of the Olink proximity extension assay (PEA). We performed group comparisons, association studies with diagnosis, age, and APOE ε4 status, overrepresentation analysis (ORA), and gene set enrichment analysis (GSEA) to determine differentially expressed proteins and dysregulated pathways. (3) Results: GSEA results demonstrated an enrichment of granulocyte-related and chemotactic pathways (core enrichment proteins: ITGB2, ITGAM, ICAM1, SELL, SELP, C5, IL1A). Moreover, some of the well-replicated, differentially expressed proteins in CSF included: ITGAM, ITGB2, C1QA, TREM2, GFAP, NEFL, MMP-10, and a novel tau-related marker, SCRN1. (4) Conclusion: Our results highlight the upregulation of neuroinflammatory pathways, especially chemotactic and granulocyte recruitment in CSF of early AD patients. [ABSTRACT FROM AUTHOR]

Introduction: Racial/ethnic disparities exist in many aspects of health care, but data on racial/ethnic disparities for neurodegenerative diseases (NDDs), such as dementia and Parkinson's disease (PD), are limited. Methods: We used North and South Carolina Medicare claims from 2013 to 2017 to evaluate disparities in incidence of NDDs and in health‐care utilization and outcomes for patients with NDDs. Results: Disparities in incidence of NDD between Black and White beneficiaries narrowed by 0.37 per 100 person‐years from 2014 to 2017. After thorough covariate adjustment, Black beneficiaries had a 4% higher risk of all‐cause hospitalization, spent 8% more days in skilled nursing facilities and 14% fewer days in hospice facilities, were 38% less likely to receive physical/occupational therapy services, were 8% less likely to receive dementia medications, and were 19% less likely to receive PD medications than White beneficiaries. Discussion: Effective system‐level approaches to promote health equity in NDD diagnosis, treatment, and outcomes are clearly needed. Highlights: Racial disparities in neurodegenerative disease incidence narrowed between 2014 and 2017.Black patients were less likely than White patients to receive hospice services.Black patients were less likely than White patients to receive physical therapy.Black patients were less likely than White patients to receive Alzheimer's disease or Parkinson's disease medications.There is a shortage of neurologists in counties with high dementia incidence. [ABSTRACT FROM AUTHOR]

Background: Aboriginal and Torres Strait Islander people have higher rates of diabetes and its complications than non‐Aboriginal people. Rumbalara Aboriginal Co‐operative is the major primary healthcare provider for Aboriginal people in the Greater Shepparton region. Aims: To evaluate the baseline metabolic parameters and presence of diabetes complications in people with type 2 diabetes attending Rumbalara Aboriginal Co‐operative in 2017 and compare it with other Aboriginal and Torres Strait Islander studies and Australian specialist diabetes services. Methods: Clinical and biochemical characteristics, including diabetes type, age, weight, body mass index (BMI), blood pressure, micro‐ and macrovascular complications, glycosylated haemoglobin (HbA1c), haemoglobin, renal function, lipid profile, urine albumin:creatinine ratio, diabetes medications, renin angiotensin system inhibition therapies, HMG‐CoA reductase inhibitors and antiplatelet agents, were determined. Results: One hundred and twenty‐six individuals had diabetes, 121 had type 2 diabetes. One hundred and thirteen identified as Aboriginal and/or Torres Strait Islander. Median age was 57.5 (48–68) years, median HbA1c was 7.8% (6.8–9.6) and median BMI was 33.4 kg/m2 (29–42.3). Compared with other Australian Aboriginal and Torres Strait Islander populations, this population was older and had more obesity, but with better glycaemia management. Compared with specialist diabetes services, this population was of similar age, with greater BMI but comparable HbA1c. Conclusions: Aboriginal people living with type 2 diabetes attending this regional Aboriginal health service have comparable glycaemic management to specialist diabetes services in Australia, managed largely by primary care physicians with limited access to specialist care for the past 5 years. [ABSTRACT FROM AUTHOR]