Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and ß-cell protection.

Type 1 diabetes is due to destruction of pancreatic ß-cells. Lysine deacetylase inhibitors (KDACi) protect ß-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing ß-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1ß + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.

At home EEG monitoring technologies for people with epilepsy and intellectual disabilities: A scoping review.

BACKGROUND: Conducting electroencephalography in people with intellectual disabilities (PwID) can be challenging, but the high proportion of PwID who experience seizures make it an essential part of their care. To reduce hospital-based monitoring, interventions are being developed to enable high-quality EEG data to be collected at home. This scoping review aims to summarise the current state of remote EEG monitoring research, potential benefits and limitations of the interventions, and inclusion of PwID in this research. METHODS: The review was structured using the PRISMA extension for Scoping Reviews and the PICOS framework. Studies that evaluated a remote EEG monitoring intervention in adults with epilepsy were retrieved from the PubMed, MEDLINE, Embase, CINAHL, Web of Science, and ClinicalTrials.gov databases. A descriptive analysis provided an overview of the study and intervention characteristics, key results, strengths, and limitations. RESULTS: 34,127 studies were retrieved and 23 were included. Five types of remote EEG monitoring were identified. Common benefits included producing useful results of comparable quality to inpatient monitoring and patient experience. A common limitation was the challenge of capturing all seizures with a small number of localised electrodes. No randomised controlled trials were included, few studies reported sensitivity and specificity, and only three considered PwID. CONCLUSIONS: Overall, the studies demonstrated the feasibility of remote EEG interventions for out-of-hospital monitoring and their potential to improve data collection and quality of care for patients. Further research is needed on the effectiveness, benefits, and limitations of remote EEG monitoring compared to in-patient monitoring, especially for PwID.

Remote Electroencephalography Monitoring of Epilepsy in Adults: Protocol for a Scoping Review.

BACKGROUND: Electroencephalography (EEG) monitoring is a key tool in diagnosing and determining treatment for people with epilepsy; however, obtaining sufficient high-quality data can be a time-consuming, costly, and inconvenient process for patients and health care providers. Remote EEG monitoring has the potential to improve patient experience, data quality, and accessibility for people with intellectual or developmental disabilities. OBJECTIVE: The purpose of this scoping review is to provide an overview of the current research evidence and knowledge gaps regarding the use of remote EEG monitoring interventions for adults with epilepsy. METHODS: The PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) and Population, Intervention, Comparator, Outcome, and Study (PICOS) frameworks will be used to structure the review. Searches will be conducted in 6 databases (PubMed, MEDLINE, Embase, CINAHL, Web of Science, and ClinicalTrials.gov) for articles published in English that evaluate at least one out-of-hospital EEG monitoring intervention or device for adults with epilepsy. A descriptive analysis will be conducted to summarize the results; key themes and gaps in the literature will be discussed. RESULTS: Results will be included in the scoping review, which will be submitted for publication by April 2022. CONCLUSIONS: This scoping review will summarize the state of the field of remote EEG monitoring interventions for adults with epilepsy and provide an overview of the strengths, weaknesses, and gaps in the research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/33812.

The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro.

In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to ß-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized streptozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25-2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1ß plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors ß-cell survival during inflammatory conditions.

Hypoglycemia-Induced Changes in the Electroencephalogram: An Overview.

Hypoglycemia is defined by an abnormally low blood glucose level. The condition develops when rates of glucose entry into the systematic circulation are reduced relative to the glucose uptake by the tissues. A cardinal manifestation of hypoglycemia arises from inadequate supply of glucose to the brain, where glucose is the primary metabolic fuel. The brain is one of the first organs to be affected by hypoglycemia. Shortage of glucose in the brain, or neuroglycopenia, results in a gradual loss of cognitive functions causing slower reaction time, blurred speech, loss of consciousness, seizures, and ultimately death, as the hypoglycemia progresses. The electrical activity in the brain represents the metabolic state of the brain cells and can be measured by electroencephalography (EEG). An association between hypoglycemia and changes in the EEG has been demonstrated, although blood glucose levels alone do not seem to predict neuroglycopenia. This review provides an overview of the current literature regarding changes in the EEG during episodes of low blood glucose.

CRFR1 activation protects against cytokine-induced ß-cell death.

During the development of diabetes ß-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL1ß, which in vitro induce ß-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced ß-cell apoptosis, we evaluated the protective potential of CRFR activation in ß-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in ß-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells.

OBJECTIVE: Proinflammatory cytokines are cytotoxic to beta-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced beta-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in beta-cells. RESEARCH DESIGN AND METHODS: Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis factor-alpha). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively. RESULTS: We found that proinflammatory cytokines induced calcineurin-dependent dephosphorylation of Bad Ser136, mitochondrial stress, cytochrome c release, activation of caspase-9 and -3, and DNA fragmentation. Inhibition of Bad Ser136 dephosphorylation or Bax was found to inhibit cytokine-induced intrinsic proapoptotic signaling. CONCLUSIONS: Our findings demonstrate that the intrinsic mitochondrial apoptotic pathway contributes significantly to cytokine-induced beta-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis.