Impact Of Gain-Of-Function Mutations In The Low-Density Lipoprotein Receptor Related Protein 5 (lrp5) On Glucose And Lipid Homeostasis

IMPACT OF GAIN-OF-FUNCTION MUTATIONS IN THE LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 5 (LRP5) ON GLUCOSE AND LIPID HOMEOSTASIS. Dinah Foer, Meiling Zhu, Christine Simpson, Grace Lee, Rebecca Sullivan, and Karl L. Insogna. Section of Endocrinology, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT. Investigations in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis. However, the data in human studies is far from consensus. While LRP5 has been shown to be critical to Wnt signaling, the molecular mechanism for the effect on metabolism is unknown. We hypothesize that a high bone mass (HBM) mutation in LRP5 will lead to improved glucose and lipid homeostasis. We aim to measure the impact of these mutated receptors on human glucose and lipid metabolism and to investigate the pathway(s) by which Wnt may affect glucose metabolism in vitro. Eleven subjects with HBM-causing LRP5 mutations were matched by gender, age, and body mass index (BMI) to 22 unrelated control subjects. Hemoglobin A1c (HbA1c), estimated average glucose (eAG), HOMA-B, HOMA-IR, and lipid panel were analyzed. An oral glucose tolerance test and 1HMRS study of liver and skeletal muscle were performed on a subset of affected patients. Primary hepatocytes and HepG2 cells were treated in vitro with Wnt3a, and PEPCK-C mRNA expression was measured by QPCR. INS-1 cells and human pancreatic islet beta-cells were assayed for glucose-stimulated insulin secretion using an ELISA technique. Statistical differences were analyzed using the unpaired Student t-test and one-way ANOVA. There were no statistically significant differences between affected and control populations for HbA1c, eAG, insulin, HOMA-B and HOMA-IR. Differences in total cholesterol, triglycerides, and HDL, were not significant. However, LDL levels were significantly lower in affected subjects (p=0.04). Wnt did not effect PEPCK-C expression. Wnt did not significantly effect glucose-stimulated insulin secretion in INS-1 cells and human islets. In summary, this is the first investigation on the metabolic consequences of LRP5 mutations in human kindreds with HBM-causing mutations. Our data does not support the hypothesis that LRP5 improves glucose metabolism in these individuals. The data does suggest that there may be a specific, beneficial effect of LRP5 on LDL cholesterol, however additional studies need to be done to confirm the effect and elucidate the mechanism

Asthma Exacerbations in Type 2 Diabetics with Asthma on Glucagon-like Peptide-1 Receptor Agonists

Rationale: Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes mellitus and obesity. GLP-1R agonists reduce airway inflammation and hyperresponsiveness in preclinical models. Objectives: To compare rates of asthma exacerbations and symptoms between type 2 diabetic adults with asthma prescribed GLP-1R agonists and those prescribed sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas or basal insulin for diabetes treatment intensification. Methods: Electronic health records-based new-user, active comparator, retrospective cohort study of patients with type 2 diabetes and asthma newly prescribed GLP-1R agonists or comparator drugs, January 2000-March 2018. Primary outcome was asthma exacerbations; secondary outcome was encounters for asthma symptoms. Propensity scores were calculated for GLP-1R agonist and non-GLP-1R agonist use. Zero-inflated Poisson regression models included adjustment for multiple covariates. Measurements and Main Results: Patients initiating GLP-1R agonists (n=448), SGLT-2 inhibitors (n=112), DPP-4 inhibitors (n=435), sulfonylureas (n=2,253) or basal insulin (n=2,692), were identified. At six months, asthma exacerbation counts were lower in persons initiating GLP-1R agonists (reference) compared to SGLT-2 inhibitors (incidence rate ratio [IRR], 2.98 [95% CI, 1.30 to 6.80]), DPP-4 inhibitors (IRR, 2.45 [95% CI, 1.54 to 3.89]), sulfonylureas (IRR, 1.83 [95% CI, 1.20 to 2.77]) and basal insulin (IRR, 2.58 [95% CI, 1.72 to 3.88]). Encounters for asthma symptoms were also lower among GLP-1R agonist users. Conclusions: Adult asthmatics prescribed GLP-1R agonists for type 2 diabetes had lower counts of asthma exacerbations compared to other drugs initiated for treatment intensification. GLP-1R agonists may represent a novel treatment for asthma associated with metabolic dysfunction

Key use cases for artificial intelligence to reduce the frequency of adverse drug events: a scoping review

Adverse drug events (ADEs) represent one of the most prevalent types of health-care-related harm, and there is substantial room for improvement in the way that they are currently predicted and detected. We conducted a scoping review to identify key use cases in which artificial intelligence (AI) could be leveraged to reduce the frequency of ADEs. We focused on modern machine learning techniques and natural language processing. 78 articles were included in the scoping review. Studies were heterogeneous and applied various AI techniques covering a wide range of medications and ADEs. We identified several key use cases in which AI could contribute to reducing the frequency and consequences of ADEs, through prediction to prevent ADEs and early detection to mitigate the effects. Most studies (73 [94%] of 78) assessed technical algorithm performance, and few studies evaluated the use of AI in clinical settings. Most articles (58 [74%] of 78) were published within the past 5 years, highlighting an emerging area of study. Availability of new types of data, such as genetic information, and access to unstructured clinical notes might further advance the field

COVID-19 infection in patients with mast cell disorders including mastocytosis does not impact mast cell activation symptoms

SARS-CoV-2 is a novel coronavirus responsible for the clinical syndrome COVID-19. This virus was initially recognized in December 2019 in Wuhan, China and has since spread leading to a global pandemic. Mast cells (MCs) are tissue resident innate immune cells that play a pathobiologic role in a range of diseases, such as asthma, rhinitis and food allergy and MC activation disorders. MC activation leads to the release of inflammatory mediators, including tryptase and several cytokines such as interleukin (IL)-6. MCs are often active participants in propagation of inflammation during viral infection.(1) Reports of serious COVID-19 infections have identified IL-6, TNF and IL-1β as hallmarks of cytokine storm leading to severe outcomes.(2) MCs are a source of IL-6 and other proinflammatory mediators, leading to the possibility of MCs directly contributing to the severity of SARS-CoV-2 infection. However, studies involving allergic asthma, a disease associated with increased lung MC numbers and activation, have not shown an increased risk for severe outcomes.(3) Thus, the role of MCs in SARS-CoV-2 infection remains unknown.Peer reviewe

Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs

International audienc