Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

Defining and supporting high-quality telehealth for patients with opioid use disorder: The promise and potential pitfalls of telehealth expansion.

Many patients with opioid use disorders do not receive evidence-based treatment. The COVID-19 pandemic expanded the use of telehealth for prescribing medications for opioid use disorder (OUD). The uptake of telehealth has been variable, and this uneven expansion has created natural experiments to test assumptions and answer key questions about what improves outcomes for patients with OUD. Many current quality of care measures are not patient centered and do not focus on the practical questions that clinicians face. What criteria should be met before prescribing buprenorphine? Are physical exams necessary? Does the frequency and type of drug testing predict clinical outcomes? Are short check-in visits by phone or video better than less frequent in-person visits? Answering these questions can help define the essential components of high-quality care for patients with OUD. Defining the features of high-quality care can help create guardrails that will help protect our patients from potentially exploitive and ineffective care. Telehealth will likely end up being one additional tool to deliver care, but the scientific questions that can be answered during this period of rapid change can help answer some of the fundamental questions about providing high-quality care-and that will help all our patients, no matter how care is delivered.

Effects of obesity and diabesity on heart rhythm in the Zucker rat.

Obesity and type 2 diabetes mellitus are risk factors for hypertension, coronary heart disease, cardiac arrhythmias including atrial fibrillation, heart failure and sudden cardiac death. The effects of obesity and diabesity on heart rhythm were investigated in the Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) compared to the Zucker lean (ZL) control rat. In vivo biotelemetry techniques were used to assess the electrocardiogram and other cardiac and metabolic parameters. ZDF rats were characterized by age-dependent elevations in fasting and non-fasting blood glucose, glucose intolerance and weight gain and ZF rats were characterized by smaller elevations in fasting and non-fasting blood glucose and greater weight gain compared to ZL rats. Heart rate (HR) was progressively reduced in ZDF, ZF and ZL rats. At 195 days (6.5 months) of age there were significant differences in HR between ZDF (265 ± 8 bpm, n = 10), ZF (336 ± 9 bpm, n = 10) and ZL (336 ± 10 bpm, n = 10) rats and significant differences in HRV between ZDF (22 ± 1 bpm, n = 10), ZF (27 ± 1 bpm, n = 10) and ZL (31 ± 1 bpm, n = 10) rats. Power spectral analysis revealed no significant (P > 0.05) differences in HRV at low frequencies, reduced HRV at high frequencies and increased sympathovagal balance in ZDF compared to ZF and ZL rats. HR was reduced by ageing and additionally reduced by diabesity in the absence of changes in physical activity and body temperature. Reductions in HRV associated with altered sympathovagal drive might partly underlie disturbed HR in the ZDF rat. Possible explanations for reduced HR and future mechanistic studies are discussed.

Mechanisms underlying electro-mechanical dysfunction in the Zucker diabetic fatty rat heart: a model of obesity and type 2 diabetes.

Diabetes mellitus (DM) is a major and worsening global health problem, currently affecting over 450 million people and reducing their quality of life. Type 2 diabetes mellitus (T2DM) accounts for more than 90% of DM and the global epidemic of obesity, which largely explains the dramatic increase in the incidence and prevalence of T2DM in the past 20 years. Obesity is a major risk factor for DM which is a major cause of morbidity and mortality in diabetic patients. The electro-mechanical function of the heart is frequently compromised in diabetic patients. The aim of this review is to discuss the pathophysiology of electro-mechanical dysfunction in the diabetic heart and in particular, the Zucker diabetic fatty (ZDF) rat heart, a well-studied model of T2DM and obesity.

Genome accessibility is widely preserved and locally modulated during mitosis.

Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that such mitotically retained molecular signatures could provide transcriptional memory through mitosis. To understand the role of chromatin structure in mitotic memory, we performed the first genome-wide comparison of DNase I sensitivity of chromatin in mitosis and interphase, using a murine erythroblast model. Despite chromosome condensation during mitosis visible by microscopy, the landscape of chromatin accessibility at the macromolecular level is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly DNase hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility more strongly, whereas distal regulatory elements tend to lose accessibility. Large domains of DNA hypomethylation mark a subset of promoters that retain accessibility during mitosis and across many cell types in interphase. Erythroid transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but has little influence on mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis, but are modulated at the level of individual genes and regulatory elements.

Curcumin Acts as a Positive Allosteric Modulator of α7-Nicotinic Acetylcholine Receptors and Reverses Nociception in Mouse Models of Inflammatory Pain.

Effects of curcumin, a major ingredient of turmeric, were tested on the function of the α7-subunit of the human nicotinic acetylcholine (α7-nACh) receptor expressed in Xenopus oocytes and on nociception in mouse models of tonic and visceral pain. Curcumin caused a significant potentiation of currents induced by acetylcholine (ACh; 100 µM) with an EC50 value of 0.2 µM. The effect of curcumin was not dependent on the activation of G-proteins and protein kinases and did not involve Ca2+-dependent Cl- channels expressed endogenously in oocytes. Importantly, the extent of curcumin potentiation was enhanced significantly by decreasing ACh concentrations. Curcumin did not alter specific binding of [125I]α-bungarotoxin. In addition, curcumin attenuated nociceptive behavior in both tonic and visceral pain models without affecting motor and locomotor activity and without producing tolerance. Pharmacological and genetic approaches revealed that the antinociceptive effect of curcumin was mediated by α7-nACh receptors. Curcumin potentiated the antinociceptive effects of the α7-nACh receptor agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU282987). Collectively, our results indicate that curcumin is a positive allosteric modulator of α7-nACh receptor and reverses nociception in mouse models of tonic and visceral pain.

Defining toxicological tipping points in neuronal network development.

Measuring electrical activity of neural networks by microelectrode array (MEA) has recently shown promise for screening level assessments of chemical toxicity on network development and function. Important aspects of interneuronal communication can be quantified from a single MEA recording, including individual firing rates, coordinated bursting, and measures of network synchrony, providing rich datasets to evaluate chemical effects. Further, multiple recordings can be made from the same network, including during the formation of these networks in vitro. The ability to perform multiple recording sessions over the in vitro development of network activity may provide further insight into developmental effects of neurotoxicants. In the current study, a recently described MEA-based screen of 86 compounds in primary rat cortical cultures over 12 days in vitro was revisited to establish a framework that integrates all available primary measures of electrical activity from MEA recordings into a composite metric for deviation from normal activity (total scalar perturbation). Examining scalar perturbations over time and increasing concentration of compound allowed for definition of critical concentrations or "tipping points" at which the neural networks switched from recovery to non-recovery trajectories for 42 compounds. These tipping point concentrations occurred at predominantly lower concentrations than those causing overt cell viability loss or disrupting individual network parameters, suggesting tipping points may be a more sensitive measure of network functional loss. Comparing tipping points for six compounds with plasma concentrations known to cause developmental neurotoxicity in vivo demonstrated strong concordance and suggests there is potential for using tipping points for chemical prioritization.

Cell shortening and calcium dynamics in epicardial and endocardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

NEW FINDINGS: What is the central question of this study? To investigate haemodynamic dysfunction in the type 2 diabetic Goto-Kakizaki (GK) rat, we measured shortening and Ca2+ transport in ventricular myocytes from epicardial (EPI) and endocardial (ENDO) regions. What is the main finding and its importance? EPI and ENDO GK myocytes displayed similar hypertrophy. Time to peak (TPK) and time to half (THALF) relaxation were prolonged in EPI GK myocytes. TPK Ca2+ transient was prolonged and THALF decay of the Ca2+ transient was shortened in EPI GK myocytes. Amplitude of shortening, Ca2+ transient and sarcoplasmic reticulum Ca2+ were unaltered in EPI and ENDO myocytes from Goto-Kakizaki compared with control rats. We demostrated regional differences in shortening and Ca2+ transport in Goto-Kakizaki rats. ABSTRACT: Diabetic cardiomyopathy is considered to be one of the major diabetes-associated complications, and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca2+ transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared with control EPI-CON and ENDO-CON myocytes. Time to peak shortening was prolonged in EPI-GK compared with EPI-CON and in ENDO-CON compared with EPI-CON myocytes. Time to half-relaxation of shortening and time to peak Ca2+ transient were prolonged in EPI-GK compared with EPI-CON myocytes. Time to half-decay of the Ca2+ transient was prolonged in EPI-CON compared with EPI-GK and in EPI-CON compared with ENDO-CON myocytes. The amplitude of shortening and the Ca2+ transient were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Sarcoplasmic reticulum Ca2+ and myofilament sensitivity to Ca2+ were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Regional differences in Ca2+ signalling in healthy and diabetic myocytes might account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca2+ transient in EPI and ENDO myocytes from diabetic and control hearts.

Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca2+ homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca2+ in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca2+ transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca2+ currents and Ca2+ transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca2+ current was unaltered, the voltage dependence of the Ca2+ transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca2+ current and Ca2+ transient were unaltered. THALF decay of L-type Ca2+ current was unaltered; however, THALF decay of the Ca2+ transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca2+ current was unaltered; however, the voltage dependence of the Ca2+ transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca2+ transport in the GK diabetic rat hearts.

Mandatory Reporting of Fatal and Nonfatal Opioid Overdoses in a Rural Public Health Department.

In 2016, Clallam County became the first county in Washington State to mandate reporting of fatal and nonfatal opioid overdoses. This reporting improved our understanding of opioid overdoses in the community and allowed us to provide harm reduction and case management services after nonfatal overdoses. By using the Washington State Prescription Monitoring Program, we have been able to notify health care providers when their patients have experienced a fatal or nonfatal opioid overdose to help better guide their prescribing practices.

Computer-Based Driving in Dementia Decision Tool With Mail Support: Cluster Randomized Controlled Trial.

BACKGROUND: Physicians often find significant challenges in assessing automobile driving in persons with mild cognitive impairment and mild dementia and deciding when to report to transportation administrators. Care must be taken to balance the safety of patients and other road users with potential negative effects of issuing such reports. OBJECTIVE: The aim of this study was to assess whether a computer-based Driving in Dementia Decision Tool (DD-DT) increased appropriate reporting of patients with mild dementia or mild cognitive impairment to transportation administrators. METHODS: The study used a parallel-group cluster nonblinded randomized controlled trial design to test a multifaceted knowledge translation intervention. The intervention included a computer-based decision support system activated by the physician-user, which provides a recommendation about whether to report patients with mild dementia or mild cognitive impairment to transportation administrators, based on an algorithm derived from earlier work. The intervention also included a mailed educational package and Web-based specialized reporting forms. Specialists and family physicians with expertise in dementia or care of the elderly were stratified by sex and randomized to either use the DD-DT or a control version of the tool that required identical data input as the intervention group, but instead generated a generic reminder about the reporting legislation in Ontario, Canada. The trial ran from September 9, 2014 to January 29, 2016, and the primary outcome was the number of reports made to the transportation administrators concordant with the algorithm. RESULTS: A total of 69 participating physicians were randomized, and 36 of these used the DD-DT; 20 of the 35 randomized to the intervention group used DD-DT with 114 patients, and 16 of the 34 randomized to the control group used it with 103 patients. The proportion of all assessed patients reported to the transportation administrators concordant with recommendation did not differ between the intervention and the control groups (50% vs 49%; Z=-0.19, P=.85). Two variables predicted algorithm-based reporting-caregiver concern (odds ratio [OR]=5.8, 95% CI 2.5-13.6, P<.001) and abnormal clock drawing (OR 6.1, 95% CI 3.1-11.8, P<.001). CONCLUSIONS: On the basis of this quantitative analysis, in-office abnormal clock drawing and expressions of concern about driving from caregivers substantially influenced physicians to report patients with mild dementia or mild cognitive impairment to transportation administrators, but the DD-DT tool itself did not increase such reports among these expert physicians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02036099; https://clinicaltrials.gov/ct2/show/NCT02036099 (Archived by WebCite at http://www.webcitation.org/6zGMF1ky8).

Natural Negative Allosteric Modulators of 5-HT3 Receptors.

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.

Microbiota modulate transcription in the intestinal epithelium without remodeling the accessible chromatin landscape.

Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine, but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis-regulatory regions (CRRs) characterized by nucleosome-depleted accessible chromatin. We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin accessibility. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome-depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is preprogrammed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs.

Development of a decision-making tool for reporting drivers with mild dementia and mild cognitive impairment to transportation administrators.

BACKGROUND: Driving in persons with dementia poses risks that must be counterbalanced with the importance of the care for autonomy and mobility. Physicians often find substantial challenges in the assessment and reporting of driving safety for persons with dementia. This paper describes a driving in dementia decision tool (DD-DT) developed to aid physicians in deciding when to report older drivers with either mild dementia or mild cognitive impairment to local transportation administrators. METHODS: A multi-faceted, computerized decision support tool was developed, using a systematic literature and guideline review, expert opinion from an earlier Delphi study, as well as qualitative interviews and focus groups with physicians, caregivers of former drivers with dementia, and transportation administrators. The tool integrates inputs from the physician-user about the patient's clinical and driving history as well as cognitive findings, and it produces a recommendation for reporting to transportation administrators. This recommendation is translated into a customized reporting form for the transportation authority, if applicable, and additional resources are provided for the patient and caregiver. CONCLUSIONS: An innovative approach was needed to develop the DD-DT. The literature and guideline review confirmed the algorithm derived from the earlier Delphi study, and barriers identified in the qualitative research were incorporated into the design of the tool.

A patient's experience in dementia care: Using the "lived experience" to improve care.

OBJECTIVE: To give FPs an understanding of the "lived experience" of dementia via the words of a person with dementia (PWD)- Faye Forbes, a 64-year-old Anglican priest with Alzheimer disease who provides her perspectives on living with dementia-and to use these thoughts to improve care and outcomes. SOURCES OF INFORMATION: Ovid MEDLINE was searched from January 2005 to February 2015 using subject headings for dementia, caregiver, perspectives, and quality of health care. Articles geared toward FPs were selected. Relevant review articles and original research articles were used when appropriate and if they were applicable to PWDs and their caregivers. MAIN MESSAGE: There are several frameworks that organize the main experiences described by patients and caregivers. We used a review of the qualitative literature to provide the framework to summarize Faye's experience under the following headings: seeking a diagnosis, accessing supports and services, information needs, disease management, and communication and attitudes. CONCLUSION: Physicians should consider these themes when developing a management plan for PWDs. Trying to understand the experiences and perspectives of PWDs and their caregivers is important in providing optimal care.

Explicit DNase sequence bias modeling enables high-resolution transcription factor footprint detection.

DNaseI footprinting is an established assay for identifying transcription factor (TF)-DNA interactions with single base pair resolution. High-throughput DNase-seq assays have recently been used to detect in vivo DNase footprints across the genome. Multiple computational approaches have been developed to identify DNase-seq footprints as predictors of TF binding. However, recent studies have pointed to a substantial cleavage bias of DNase and its negative impact on predictive performance of footprinting. To assess the potential for using DNase-seq to identify individual binding sites, we performed DNase-seq on deproteinized genomic DNA and determined sequence cleavage bias. This allowed us to build bias corrected and TF-specific footprint models. The predictive performance of these models demonstrated that predicted footprints corresponded to high-confidence TF-DNA interactions. DNase-seq footprints were absent under a fraction of ChIP-seq peaks, which we show to be indicative of weaker binding, indirect TF-DNA interactions or possible ChIP artifacts. The modeling approach was also able to detect variation in the consensus motifs that TFs bind to. Finally, cell type specific footprints were detected within DNase hypersensitive sites that are present in multiple cell types, further supporting that footprints can identify changes in TF binding that are not detectable using other strategies.

Increased oxidative stress and mitochondrial dysfunction in zucker diabetic rat liver and brain.

BACKGROUND/AIMS: The Zucker diabetic fatty (ZDF, FA/FA) rat is a genetic model of type 2 diabetes, characterized by insulin resistance with progressive metabolic syndrome. We have previously demonstrated mitochondrial dysfunction and oxidative stress in the heart, kidneys and pancreas of ZDF rats. However, the precise molecular mechanism of disease progression is not clear. Our aim in the present study was to investigate oxidative stress and mitochondrial dysfunction in the liver and brain of ZDF rats. METHODS: In this study, we have measured mitochondrial oxidative stress, bioenergetics and redox homeostasis in the liver and brain of ZDF rats. RESULTS: Our results showed increased reactive oxygen species (ROS) production in the ZDF rat brain compared to the liver, while nitric oxide (NO) production was markedly increased both in the brain and liver. High levels of lipid and protein peroxidation were also observed in these tissues. Glutathione metabolism and mitochondrial respiratory functions were adversely affected in ZDF rats when compared to Zucker lean (ZL, +/FA) control rats. Reduced ATP synthesis was also observed in the liver and brain of ZDF rats. Western blot analysis confirmed altered expression of cytochrome P450 2E1, iNOS, p-JNK, and IκB-α confirming an increase in oxidative and metabolic stress in ZDF rat tissues. CONCLUSIONS: Our data shows that, like other tissues, ZDF rat liver and brain develop complications associated with redox homeostasis and mitochondrial dysfunction. These results, thus, might have implications in understanding the etiology and pathophysiology of diabesity which in turn, would help in managing the disease associated complications.

Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK) Rats.

BACKGROUND/AIM: Type 2 diabetes is the most common metabolic disorder, characterized by insulin resistance and pancreatic islet beta-cell failure. The most common complications associated with type 2 diabetes are hyperinsulinemia, hyperglycemia, hyperlipidemia, increased inflammatory and reduced insulin response. Aspirin (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with the prevention of diabetes, obesity and related cardiovascular disorders. Aspirin has been used in many clinical and experimental trials for the prevention of diabetes and associated complications. METHODS: In this study, five month old Goto-Kakizaki (GK) rats, which showed signs of mild hyperglycemia (fasting blood glucose 80-95 mg/dl vs 55-60 mg/dl Wistar control rats) were used. Two subgroups of GK and Wistar control rats were injected intraperitoneally with 100 mg aspirin/kg body weight/ day for 5 weeks. Animals were sacrificed and blood and tissues were collected after performing glucose tolerance (2 h post 2g IP glucose ingestion) tests in experimental and control groups. RESULTS: Aspirin caused a moderate decrease in hyperglycemia. However, we observed a significant improvement in glucose tolerance after ASA treatment in GK rats compared to the nondiabetic Wistar rats. Also, the ASA treated GK rats exhibited a significant decrease in insulinemia. ASA treatment also caused a marked reduction in the pro-inflammatory prostaglandin, PGE2, which was significantly higher in GK rats. On the other hand, no significant organ toxicity was observed after ASA treatment at this dose and time period. However, the total cholesterol and lipoprotein levels were significantly increased in GK rats, which decreased after ASA treatment. Immunofluorescence staining for insulin/glucagon secreting pancreatic cells showed improved beta-cell structural and functional integrity in ASA-treated rats which was also confirmed by SDS-PAGE and Western blot analysis. CONCLUSION: The improved glucose tolerance in ASA-treated GK rats may be associated with increased insulin responses due to the anti-inflammatory properties of ASA and enhanced nitric oxide (NO) level which facilitated insulin signaling and energy utilization in target tissues. These results may have implications in determining the therapeutic use of ASA in insulin-resistant type 2 diabetes.