GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes.

AIMS/HYPOTHESIS: We have previously shown that diabetes causes pericyte dysfunction, leading to loss of vascular integrity and vascular cognitive impairment and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), used in managing type 2 diabetes mellitus, improve the cognitive function of diabetic individuals beyond glycaemic control, yet the mechanism is not fully understood. In the present study, we hypothesise that GLP-1 RAs improve VCID by preventing diabetes-induced pericyte dysfunction. METHODS: Mice with streptozotocin-induced diabetes and non-diabetic control mice received either saline (NaCl 154 mmol/l) or exendin-4, a GLP-1 RA, through an osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularisation indices (vascular density, tortuosity and branching density). Cognitive function was evaluated with Barnes maze and Morris water maze. Human brain microvascular pericytes (HBMPCs), were grown in high glucose (25 mmol/l) and sodium palmitate (200 µmol/l) to mimic diabetic conditions. HBMPCs were treated with/without exendin-4 and assessed for nitrative and oxidative stress, and angiogenic and blood-brain barrier functions. RESULTS: Diabetic mice treated with exendin-4 showed a significant reduction in all cerebral pathological neovascularisation indices and an improved blood-brain barrier (p<0.05). The vascular protective effects were accompanied by significant improvement in the learning and memory functions of diabetic mice compared with control mice (p<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Diabetes increased GLP-1 receptor expression and receptor nitration in HBMPCs. Stimulation of HBMPCs with exendin-4 under diabetic conditions decreased diabetes-induced vascular inflammation and oxidative stress, and restored pericyte function (p<0.05). CONCLUSIONS/INTERPRETATION: This study provides novel evidence that brain pericytes express the GLP-1 receptor, which is nitrated under diabetic conditions. GLP-1 receptor activation improves brain pericyte function resulting in restoration of vascular integrity and BBB functions in diabetes. Furthermore, the GLP-1 RA exendin-4 alleviates diabetes-induced cognitive impairment in mice. Restoration of pericyte function in diabetes represents a novel therapeutic target for diabetes-induced cerebrovascular microangiopathy and VCID.

Inhibition and Allosteric Regulation of Monomeric Phosphoenolpyruvate Carboxykinase by 3-Mercaptopicolinic Acid.

For almost 40 years, it has been known that tryptophan metabolites and picolinic acid analogues act as inhibitors of gluconeogenesis. Early studies observed that 3-mercaptopicolinic acid (MPA) was a potent hypoglycemic agent via inhibition of glucose synthesis through the specific inhibition of phosphoenolpyruvate carboxykinase (PEPCK) in the gluconeogenesis pathway. Despite prior kinetic investigation, the mechanism of the inhibition by MPA is unclear. To clarify the mechanism of inhibition exerted by MPA on PEPCK, we have undertaken structural and kinetic studies. The kinetic data in concert with crystallographic structures of PEPCK in complex with MPA and the substrates for the reaction illustrate that PEPCK is inhibited by the binding of MPA at two discrete binding sites: one acting in a competitive fashion with PEP/OAA (∼10 µM) and the other acting at a previously unidentified allosteric site (Ki ∼ 150 µM). The structural studies suggest that binding of MPA to the allosteric pocket stabilizes an altered conformation of the nucleotide-binding site that in turn reduces the affinity of the enzyme for the nucleotide.

Dyskeratosis Congenita: A Case Report of a Patient With Coronary Artery Disease.

Clinical evidence demonstrates that patients with telomere biology disorders, such as dyskeratosis congenita, are more prone to coronary artery disease. We present the case of a 43-year-old female diagnosed with dyskeratosis congenita with critical cardiovascular disease. She underwent coronary artery bypass graft (CABG) with improvement of her cardiac function. Although this is a rare genetic disease, further studies are warranted to investigate the underlying pathophysiology of cardiovascular disease in patients with dyskeratosis congenita.

Case report: Hyperosmolar hyperglycemic syndrome secondary to PEG-asparaginase-induced hypertriglyceridemia and pancreatitis.

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (T-ALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreatitis and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase.

Integrating Data To Advance Research, Operations, And Client-Centered Services In California.

The value of using administrative records for operational and evaluation purposes has been well established in health and human services. However, these records typically reflect the reach of a single government agency or program and fail to capture the experiences of individuals as they engage with different agencies or programs over time. Thus, the potential for these data to improve everyday operations, coordinate services, develop targeted interventions, and advance the science behind broader social policies has yet to be fully realized. A first step toward realizing that potential is to transition from an agency-centered to a client- or person-centered organization of data. We systematically linked tens of millions of records across California's largest health and human services programs. Our results underscore how the integration of records can help shift discussions from the programs that administer services to the people who are served.

Creating value for communities: Los Angeles County's investment in Housing for Health.

With U.S. healthcare expenditures leading and social service spending trailing other developed nations, patients, caregivers, and employers are insisting on improved value in health and healthcare for communities. Yet, health systems struggle to understand how to best invest existing funding or savings to reach these goals. We share the experience of Los Angeles County's health system that has invested in housing through their Housing for Health Program (HFH) to address the needs of high cost populations within communities. The approach rested on four key program strategies including having partnerships with various housing facilities, a whole person approach with broad community-based resources, a local footprint in community health services, and a robust jail and prison transitions program. HFH also relied on three key implementation strategies including having dynamic funding sources, stakeholder alignment, and continuous improvement. This case report describes these program and implementation strategies plus challenges and lessons learned navigating homeless individuals through the regulations of various funding contracts, maintaining service provider capacity, maintaining local culture in implementation, and persistent gaps in affordable housing availability. Future policies can incentivize similar efforts and infrastructure to transfer healthcare dollars into public services to improve housing and value for communities.