Search

Perioperative hyperglycemia is common and is associated with significant morbidity. Although patient characteristics and surgery influence perioperative glucose metabolism, anesthetics have a significant impact. We hypothesized that mice that were obese and insulin-resistant would experience greater hyperglycemia in response to sevoflurane anesthesia compared with lean controls. We further hypothesized that sevoflurane-induced hyperglycemia would be attenuated by salsalate pre-treatment. Lean and obese male C57BL/6J mice were anesthetized with sevoflurane for 60 min with or without pre-treatment of 62.5 mg·kg−1 salsalate. Blood glucose, plasma insulin, and glucose uptake into different tissues were measured. Under sevoflurane anesthesia, obese mice had higher blood glucose compared to lean mice. Increases in blood glucose were attenuated with acute salsalate pre-treatment at 60 min under anesthesia in obese mice (mean ± standard error of the mean [SEM], delta blood glucose; vehicle 5.79 ± 1.09 vs salsalate 1.91 ± 1.32 mM; P = 0.04) but did not reach statistical significance in lean mice (delta blood glucose, vehicle 4.39 ± 0.55 vs salsalate 2.79 ± 0.71 mM; P = 0.10). This effect was independent of changes in insulin but associated with an approx. 1.7-fold increase in glucose uptake into brown adipose tissue (vehicle 45.28 ± 4.57 vs salsalate 76.89 ± 12.23 µmol·g−1 tissue·hr−1; P < 0.001). These data show that salsalate can reduce sevoflurane-induced hyperglycemia in mice. This indicates that salsalate may represent a new class of therapeutics that, in addition to its anti-inflammatory and analgesic properties, may be useful to reduce perioperative hyperglycemia.

Salsalate, an ester formed by 2 salicylic acid molecules, has beneficial effect against metabolic disorders in clinical trials and in animal studies. This study focused on the mechanistic aspects of salsalate activity against non-alcoholic fatty liver disease (NAFLD). Using high-fat diet (HFD) fed mice, we showed that salsalate treatment decreased body-weight gains, reduced white adipose tissue mass and improved glycaemic control. Mice in salsalate-treated group also had reduced obese adipose tissue and hepatic macrophage infiltration and inflammation and adipogenesis gene expression. Histology analysis revealed predominant decreases in hepatosteatosis, including both macrovesicular and microvesicular steatoses. The treatment reversed AMPK activity repression that was accompanied by reduced caspase-6 activity and cleavage. Enzymatic assay and cell culture studies showed that salsalate promoted AMPK activation by directly activating AMPK. This study links salsalate effect against metabolic disorders to its activity on reversion of AMPK repression in NAFLD mice and on suppression of adipogenic gene induction.

A strategic approach is urgently needed to curb the growing global epidemic of diabetes. In this study, we investigated the effects and mechanisms of salsalate (SAL), an anti-inflammatory drug with anti-diabetic properties, assessing its potential to prevent diabetes in Otsuka Long-Evans Tokushima Fatty rats (OLETF). All animals in our placebo group developed diabetes, whereas none in the SAL test group did so, and only 25% of SAL-treated rats displayed impaired glucose tolerance (IGT). SAL lowered levels of glucagon and raised levels of insulin in plasma, while improving both insulin sensitivity and β-cell function. The protective effect of SAL is likely due to diminished β-cell dedifferentiation, manifested as relative declines in Neurogenin 3+/insulin- cells and synaptophysin+/islet hormone- cells and increased expression of β-cell-specific transcription factor Foxo1. Both Notch1-siRNA and N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT; an indirect inhibitor of the Notch1 pathway) were shown to prevent β-cell dedifferentiation. Similar to DAPT, SAL effectively reduced β-cell dedifferentiation, significantly suppressing Notch1 pathway activation in INS-1 cells. The inhibitory role of SAL in β-cell dedifferentiation may thus be attributable to Notch1 pathway suppression.

Background: Multiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically. Method: In this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n=20 male/group) using dosages expected to yield clinically relevant drug levels. Findings: Compared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen

Background: Diabetes is a long-term condition that can be treated and controlled but do not yet have a cure; it could be induced by inflammation and the goal of managing it is to prevent additional co-morbidities and reduce glycemic fluctuations. There is a need to examine inflammatory activities in diabetes-related angiopathies and explore interventions that could reduce the risk for future outcome or ameliorate its effects to provide insights for improved care and management strategies.Method: The study was conducted in Embase (1946–2020), Ovid Medline (1950–2020), and PubMed databases (1960–2020) using the PICO framework. Primary studies (randomized controlled trials) on type 2 diabetes mellitus and inflammatory activities in diabetes-related angiopathies were included. Terms for the review were retrieved from the Cochrane library and from PROSPERO using its MeSH thesaurus qualifiers. Nine articles out of 454 total hits met the eligibility criteria. The quality assessment for the selected study was done using the Center for Evidence-Based Medicine Critical Appraisal Sheet.Results: Data analysis showed that elevated CRP, TNF-α, and IL-6 were the most commonly found inflammatory indicator in diabetes-related angiopathies, while increased IL-10 and soluble RAGE was an indicator for better outcome. Use of drugs such as salsalate, pioglitazone, simvastatin, and fenofibrate but not glimepiride or benfotiamine reported a significant decrease in inflammatory events. Regular exercise and consumption of dietary supplements such as ginger, hesperidin which have anti-inflammatory properties, and those containing prebiotic fibers (e.g., raspberries) revealed a consistent significant (p < 0.05) reduction in inflammatory activities.Conclusion: Inflammatory activities are implicated in diabetes-related angiopathies; regular exercise, the intake of healthy dietary supplements, and medications with anti-inflammatory properties could result in improved protective risk outcome for diabetes patients by suppressing inflammatory activities and elevating anti-inflammatory events.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions. Objectives: To describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. Methods: For 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative. Results: Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Conclusions: Neither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.

A safe and effective approach is needed to prevent and reduce the incidence of diabetes worldwide. The hypoglycemic efficacy of salicylic acid (salsalate, SAL), which has anti-inflammatory properties, has been empirically demonstrated in studies conducted at the Joslin Diabetes Center and elsewhere. Here, we investigated the potential role of SAL in preventing the onset of diabetes in Zucker diabetic fatty (ZDF) rats and attempted to elucidate its underlying mechanisms. ZDF and Zucker lean (ZL) rats were administered a high-fat diet with or without SAL intervention and their relative rates of diabetes were compared. Our results showed that all rats in the placebo group developed diabetes, whereas only 10% of the SAL-treated rats presented with impaired glucose tolerance (IGT). None of the latter progressed to diabetes. Relative to the untreated rats, SAL lowered plasma glucagon and insulin while improving insulin sensitivity and β-cell function. SAL may protect against hyperglycemia by increasing the microbial diversity, ameliorating gut dysbiosis, restoring intestinal epithelial cell connections, inhibiting endotoxin influx into the blood, and attenuating inflammation. Together, these findings suggest that SAL may be a candidate prophylactic therapy against diabetes. The protective role of SAL may be attributed to its ability to reduce intestinal inflammation and improve gut dysbiosis.

Pain is a serious adverse event which frequently accompanies hematopoietic stem cell transplantation (HSCT). The safety and efficacy of NSAIDS during HSCT is currently unknown. Salsalate is a platelet-sparing NSAID with a favorable toxicity profile compared with other NSAIDS. We report the safety and efficacy of salsalate for different types of pain during SCT.We conducted a retrospective study of SCT recipients empirically treated with salsalate for 48 h. Pain scores were assessed using the verbal rating scale for pain. A subset analysis of patients who received 7 days of salsalate during periods of pancytopenia, mucositis, and other end-organ toxicities is included.Sixty-four patients, 42 auto- and 22 allografts, were identified. Reason for use: vertebral-related pain (30%), musculoskeletal (30%), and cytokine inflammatory pain syndromes (24%). Median dose 1500 mg/day, number of treatment days = 5, started on day+5 post-HSCT. Pain resolved/improved to pain score 4 in 76% and stable in 15%. Forty-four patients (28-auto and 16 allografts) received 7-day salsalate. Median WBC and platelet nadir were 0.1 and 10,000 cells/ml respectively.pain was improved or eradicated in 64% and stable in 32%.LFT elevation (n = 2), elevated serum creatinine (n = 2), and minor bleed (n = 5-nose, gums, and urine). Salsalate discontinuation (n = 6): ineffective (n = 1), the liver (n = 1), the kidney (n = 1), 5 platelet transfusions (n = 1), and vomiting (n = 2). There was no treatment related mortality. Salsalate was well tolerated, safe, and beneficial for several different types of pain during HSCT.

High-fat diets (HFDs) and excess adiposity increase proinflammatory cytokines in the colon, altering gene expression in a manner that promotes the development of colorectal cancer (CRC). Thus, compounds that reduce this biochemical inflammation are potential chemopreventive agents. Curcumin (CUR), a dietary polyphenol, and salsalate (SAL), a non-steroidal anti-inflammatory drug, are both anti-inflammatories. We investigated the inhibitory effects of CUR with or without SAL on inflammatory cytokines and procarcinogenic signaling in azoxymethane (AOM)-treated A/J mice. A sub-tumorigenic AOM dose was chosen to produce a biochemical and molecular procarcinogenic colonic environment without tumors. Mice were fed either a HFD (60% of kilocalories) or low-fat diet (LFD) (10% of kilocalories). One HFD treatment group received 0.2% CUR in the diet; one received 0.2% CUR + 0.15% SAL; and one received 0.4% CUR + 0.3% SAL. The HFD mice developed 30% greater fat mass than the LFD mice (p0.05). The colonic concentrations of interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the HFD mice were decreased by 50-69% by the high-dose combination regimen (p0.015). Only the combination regimens significantly suppressed phosphorylation of protein kinase B (Akt) and nuclear factor-κB (NF-κB) p65 (p0.044). The combination of CUR and SAL reduces the concentration of proinflammatory cytokines and diminishes activation of Akt and NF-κB more effectively than CUR alone, providing a scientific basis for examining whether this combination mitigates the risk of CRC in obese individuals.

To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease.Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial.Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/mSalsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.

Intro NSAIDs are drugs of choice for the treatment musculo-skeletal pain and other inflammatory conditions. Salsalate is a platelet sparing NSAID with less gastric toxicity compared to aspirin. Using NSAIDs during HSCT is challenging as periods of profound pancytopenia and toxicity raise concerns about the safety of these agents. To date, the use of salsalate during HSCT has not been previously reported. Methods All HSCT recipients treated with salsalate for at least 7 days during the period of profound neutropenia and thrombocytopenia were included. Patients were monitored for kidney, liver (25% for > 2 days), hearing, emergence of GI/GU or other bleeding disorders, time to engraftment, drug toxicity or discontinuation. The Verbal Rating Scale for Pain (Severe: 7-10, Moderate: 4-6, Mild: 1-3) was used to grade pain before and after treatment. Results 44 (28 autologous and 16 allogeneic) stem cell recipients were identified. Female (24/44; 55%), Age -61(32-74); Dx: Myeloma (n=24), NHL (n=8), AML (n=5), Other(n=7). 8 patients were receiving NSAIDS prior to admission. 6 patients were admitted with baseline grade 3 CKD . Median WBC and platelet nadir while receiving salsalate was Table 1 show pain was improved or eradicated in 27/44 (64%) of patients, and stable in 15/44 (36%)- 9 of which were receiving NSAID PTA. All patients who experienced generalized body pain improved with salsalate. Change in kidney and liver function was infrequent ( Moderate doses of NSAID salsalate are well tolerated throughout the entire transplantation period in autologous and allogeneic recipients and may benefit patients with a variety of different types of pain, including growth factor, engraftment and cytokine release pain syndromes. Additional studies are needed to confirm these results.

Background Salsalate may offer many advantages over other non-steroidal antiinflammatory agents in patients taking warfarin, however a drug-drug interaction may occur which has not been reported in the medical literature or by the manufacturer of salsalate. Objective To report a case of warfarin potentiation associated with salsalate treatment, which resulted in bleeding. Method Clinical review of the course of a patient, who was stable on warfarin when salsalate therapy was added for chronic pain. Case report A patient taking stable doses of warfarin for over 1 year (with good control) was prescribed salsalate 3 g/day for pain in his knee and lower back. Approximately 1 month later he presents to the anticoagulation clinic with bruising and an International Normalized Ratio (INR) of 6.8. The patient had a good response to his salsalate therapy and wanted to continue it. The warfarin was held for 3 days and dose lowered by 50 %. His bruising then subsided and he had good control of his warfarin therapy with INRs ranging from 1.9 to 2.2 over the next 4 months. The patient was then lost to follow up. Conclusion This case illustrates a strong association between starting salsalate and subsequent potentiation of warfarin, which heretofore has not been reported in the medical literature.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Pharmacological manipulation of tau protein in Alzheimer’s disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer’s disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.

Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1–knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (∼1 mmol/L). Salsalate treatment increased VO2, lowered fasting glucose, improved glucose tolerance, and led to an ∼55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.

BACKGROUND AND PURPOSE: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH. EXPERIMENTAL APPROACH: Transgenic APOE*3Leiden.CETP mice were fed a high-fat and high-cholesterol diet with or without salsalate for 12 and 20 weeks. The effects on body weight, plasma biochemical variables, liver histology and hepatic gene expression were assessed. KEY RESULTS: Salsalate prevented weight gain, improved dyslipidemia and insulin resistance and ameliorated diet-induced NASH, as shown by decreased hepatic microvesicular and macrovesicular steatosis, reduced hepatic inflammation and reduced development of fibrosis. Salsalate affected lipid metabolism by increasing β-oxidation and decreasing lipogenesis, as shown by the activation of PPAR-α, PPAR-γ co-activator 1β, RXR-α and inhibition of genes controlled by the transcription factor MLXIPL/ChREBP. Inflammation was reduced by down-regulation of the NF-κB pathway, and fibrosis development was prevented by down-regulation of TGF-β signalling. CONCLUSIONS AND IMPLICATIONS: Salsalate exerted a preventive effect on the development of NASH and progression to fibrosis. These data suggest a clinical application of salsalate in preventing NASH. Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; aspartate aminotransferase, 9000-97-9; glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8; peroxisome proliferator activated receptor alpha, 147258-70-6; salsalate, 552-94-3

Background and Objective Although salsalate administration consistently lowers plasma triglyceride concentrations in patients with type II diabetes, prediabetes, and/or insulin resistance, changes in low-density lipoprotein cholesterol (LDL-C) concentrations have been inconsistent; varying from no change to a significant increase. To evaluate the clinical relevance of this discordance in more detail, we directly measured LDL-C and obtained a comprehensive assessment of changes in lipid, lipoprotein, and apoprotein concentrations associated with salsalate use in insulin-resistant individuals, overweight or obese, but without diabetes, using vertical auto profile method. Methods A single-blind, randomized, placebo-controlled study was performed in volunteers who were overweight or obese, without diabetes, and insulin resistant on the basis of their steady-state plasma glucose concentration during an insulin suppression test. Participants were randomized 2:1 to receive salsalate 3.5 g/d (n = 27) or placebo (n = 14) for 4 weeks. Comprehensive lipid, lipoprotein, and apoprotein analysis by vertical auto profile was obtained after an overnight fast, before and after study intervention. Results There was no change in directly measured LDL-C concentration in salsalate-treated individuals. However, salsalate administration was associated with various changes considered to decrease atherogenicity; including decreases in triglyceride and total very low–density lipoprotein cholesterol (VLDL-C) concentrations, a shift from small denser LDL lipoproteins toward larger, more buoyant LDL particles, decreases in VLDL 1+2 -C and LDL 4 -C, and nonsignificant decreases in non–high-density lipoprotein cholesterol and apolipoprotein B. No significant changes occurred in the placebo-treated group. Conclusions Atherogenicity of the lipid, lipoprotein, and apoprotein profile of insulin-resistant individuals who were overweight or obese improved significantly in association with salsalate treatment. The clinical importance of this finding awaits further study.

To elucidate whether increased insulin concentration after salsalate treatment (3 g/day for 7 days) is attributable to an increased insulin secretion rate (ISR) or to reduced metabolic clearance of endogenous insulin (MCI) during stepped glucose infusion (SGI). The analysis was performed in obese subjects who participated in a randomized double-blind, parallel, placebo-controlled clinical trial. A total of 27 participants (16 on salsalate, 11 on placebo) completed baseline and follow-up SGI. During SGI in the salsalate group, C-peptide concentrations were reduced by 11%, while plasma insulin concentrations were increased by 30%, corresponding to a 30% reduction in MCI (p

OBJECTIVE: This pilot study examined the effect of adjunctive salsalate on psychopathology and cognition in patients with schizophrenia. METHODS: This was a 12-week, open label trial of salsalate (1.5g, twice per day) in patients with schizophrenia. Psychopathology, cognition and daily function were assessed at baseline and week 12 using various rating scales. Blood levels of inflammatory markers including white blood cell count (WBC), high sensitivity C reactive protein (hsCRP) and interleukin-6 (IL-6) were also measured. RESULTS: Eight subjects completed the study. There was no significant change in any of the rating scales at week 12. However, there was a trend decrease in the Positive and Negative Syndrome Scale (PANSS) total score, and a trend improvement in the Brief University of California San Diego Performance-based Skills Assessment (UPSA-B) total score (58.3±11.4 versus 53.5±11.9, p = 0.072; 69.7±18.2 versus 79.1±15.9, p = 0.084 respectively). There was a trend improvement in quality of life as measured by the Quality of Life Scale (QLS) total score (74.0±20.8 versus 76.9±22.7, p = 0.080). There was a significant decrease in WBC count (6.8± 1.3 versus 6.0±1.2 th/mm3, p = 0.022). There was no change in levels of hsCRP or IL-6 over 12 weeks (p’s > 0.1). CONCLUSION: Salsalate may have positive therapeutic effect in patients with schizophrenia. Future studies to examine potential benefits of salsalate as an adjunctive treatment to improve clinical symptoms and daily function in patients with schizophrenia are warranted.

Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

It is a well-known clinical observation that inflammatory diseases are accompanied by metabolic implications such as hyperglycemia, insulin resistance and increased fatty acids. On the other hand, metabolic diseases have inflammatory implications. There is a chronic and low-grade state of inflammation in obesity and type 2 diabetes. Physiological insulin resistance during infection or inflammation re-distributes glucose and fatty acids to immune cells. On the basis of systemic and adipose tissue inflammation such as MCP-1/TLR-4-driven macrophage infiltration and pro-inflammatory polarization of these cells, this lecture will give a summary of anti-diabetic effects of anti-inflammatory drugs used in rheumatology. What is the evidence from clinical studies using anti-inflammatory approaches to treat patients with type 2 diabetes mellitus? Basically, TNF plays an important role in insulin resistance in rodents. Blocking TNF in rodents reverses obesity-related diabetes. There are no state of the art clinical studies showing convincing evidence of an anti-diabetic potential due to underpowered cohorts and short duration of the studies. Only one single study over 6 months showed a 10% improvement of fasting glucose levels in 40 prediabetic obese patients. Diacerein belongs to the chemical group of anthranoids. Although the mechanism of action is unknown, diacerein decreases the levels of TNF and of IL1b and has therefore been used in rheumatic diseases. Diacerein has potent effects on insulin secretion and glycemic control with a reduction of HBA1c level by 1.6%. IL-1 receptor antagonists such as anakinra (a recombinant human IL-1 receptor antagonist) have also been studied in diabetes. Anakinra was able to improve glycemia, inflammation and insulin secretion. Two additional studies in patients with impaired glucose tolerance or prediabetes demonstrated positive effects of anakinra on beta cell secretory capacity. Since anakinra requires daily injections and often causes adverse effects at the injection site, humanized antibodies against IL1b have been developed. Each of these antibodies had beneficial effects in patients with type 2 diabetes. However, studies were either underpowered or showed only little improvements of glycosylated HBA1c levels, probably due to low pre-study levels. Inhibition of the IKK/NFkB pathway might also be of benefit in insulin resistance. Salsalate improves insulin sensitivity, insulin secretion and glycemic control to a moderate extent of 0.4–0.5%. Salsalate also has effects in prediabetic patients and in drug-naive type 2 diabetic patients. There is upcoming evidence of potential benefical effects of CCR2 antagonism in diabetes. Obesity causes an increased flux of fatty acids into muscle and liver with an accumulation of DAG in these organs. DAG activates specific isoforms of protein kinases, that is PKC T in muscle and PKC E in the liver. These isoforms cause an inhibitory phosphorylation of IRS-1 and the insulin receptor itself leading to insulin resistance. Weight reduction by diet, physical activity and bariatric surgery remove ectopic fat and are able reverse diabetes. Most interestingly, PKC-isoform specific inhibitors such as FGF-21 might represent new drug targets. Finally, targeting ectopic fat is more close to the pathophysiology of diabetes than anti-inflammatory therapy. Disclosure of Interest None declared

There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD.The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists.The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.

OBJECTIVE Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance. RESEARCH DESIGN AND METHODS This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment. RESULTS Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change −7% [95% CI −10 to −14] vs. 1% [−3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (−25% [−34 to −15] vs. −6% [−26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (−23% [−30 to −16] vs. 3% [−10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms. CONCLUSIONS Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion.

Inflammation has been implicated in development of the insulin resistance that leads to elevated blood sugar levels associated with type 2 diabetes. It is reported that salsalate, a common non-steroidal anti-inflammatory drug, has been shown to decrease blood glucose concentration in some clinical study. Recently, we found that bovine milk-derived α-lactalbumin had anti-inflammatory activity caused by inhibiting cyclooxygenase-2. In this study, we investigated the effects of chronic administration of α-lactalbumin on glucose tolerance in Goto-Kakizaki (GK) rats, a model of type 2 diabetes. After 10 weeks administration of the α-lactalbumin (300 mg/kg, twice a day), oral glucose tolerance tests revealed significant decrements of blood glucose levels after glucose loading. However, significant differences of insulin levels were not observed among three GK rats groups after glucose loading. α-Lactalbumin treatment enhanced high molecular weight form of adiponectin and suppressed prostaglandin E2 levels in plasma. These results suggest that α-lactalbumin effectively decreased blood glucose levels after glucose loading in GK rat, and the decrements may be due to enhancement of adiponectin.

OBJECTIVE To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We conducted an ancillary study to the National Institutes of Health–sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months. RESULTS A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/µL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI −0.86 to 2.25%]; P = 0.38) or NMD (−0.59% [95% CI −2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009). CONCLUSIONS Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.

Salicylates are among the oldest medicinal compounds known to humans, and have been used to reduce fever, pain, and inflammation. The major oral salicylates are aspirin and salsalate, both of which are rapidly metabolized to salicylate in vivo. Owing to its acetyl group, aspirin irreversibly inhibits cyclo-oxygenases and thus blocks platelet aggregation, whereas salsalate has been used for treatment of inflammatory diseases such as rheumatoid arthritis. Recently, beneficial effects of salicylates in type 2 diabetes and cancer have been proposed. This has led to renewed interest in understanding how these simple molecules have such diverse and multifaceted effects. Here we discuss the idea that AMP-activated protein kinase (AMPK) might mediate some effects of salicylate-based drugs, particularly by modulating cellular metabolism.

The AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy that appears to have arisen at an early stage during eukaryotic evolution. In 2001 it was shown to be activated by metformin, currently the major drug for treatment for type 2 diabetes. Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, as discussed below it now appears unlikely that AMPK is the sole target of the drug. AMPK is also activated by several natural plant products derived from traditional medicines, and the mechanisms by which they activate AMPK are discussed. One of these is salicylate, probably the oldest medicinal agent known to humankind. The salicylate prodrug salsalate has been shown to improve metabolic parameters in subjects with insulin resistance and prediabetes, and whether this might be mediated in part by AMPK is discussed. Interestingly, there is evidence that both metformin and aspirin provide some protection against development of cancer in humans, and whether AMPK might be involved in these effects is also discussed.

Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment.Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2).In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.ClinicalTrials.gov NCT00330733.Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Objective: Nearly two-third of the patients with type 2 diabetes have degrees of fatty liver; this may induce some side effects in them. This study aimed to find effect of salsalate on treatment of steatohepatitis and correlation of fatty liver with metabolic syndrome in the setting of impaired glucose metabolism. Methods: In a double-blind randomized trial within two distinct groups, i.e., recently diagnosed diabetics and prediabetic cases allocated in two arms of the intervention to receive 3 g salsalate or placebo. All cases underwent glucose and lipid level studies and liver ultrasound study. Findings: Out of 46 patients with diabetes, 34 (74%) had fatty liver in ultrasound; this ratio was 75% in 113 prediabetic cases. Relative frequency of fatty liver stages did not differ between diabetics and prediabetics. Within diabetics, mean aspartate aminotransferase (AST) level of fatty liver cases (23 ± 7 IU/dl) was higher than others (18 ± 3 IU/dl) (P < 0.05). Changes in transaminase levels following intervention did not significantly differ, comparing drug and placebo arms in two subgroups. Conclusion: According to the findings, if diabetes could be assumed as the logical consequence of prediabetic state, it seems that fatty liver did develop before this preliminary status. In this study, salsalate could not change biochemical markers of fatty liver significantly.

Recent studies [1,2] in insulin-resistant individuals without diabetes have been unable to confirm previous findings [3] that salsalate, a non-steroidal, anti-inflammatory salicylate derivative can enhance insulin sensitivity; however, failure to improve insulin sensitivity in overweight/obese, insulin-resistant individuals without diabetes should not necessarily lead to the conclusion that salsalate is without therapeutic potential in this population. Indeed, an argument can be made that administration of salsalate may be of unique benefit to such individuals; that is, those who are overweight/obese and insulin-resistant before gross decompensation of glucose tolerance, but at increased risk of Type 2 diabetes and cardiovascular disease. For example, in the two recent studies of overweight/obese, insulin-resistant individuals without diabetes, fasting plasma glucose concentration fell by 6% [1] and 7% [2] after salsalate treatment. In addition, fasting plasma triglyceride concentrations decreased by ~25% in both studies. This article is protected by copyright. All rights reserved.

Goto-Kakizaki (GK) rats represent a unique non-obese and lean model with manifestation of type 2 diabetes (T2DM) broadly mimicking the human T2DM development. Therefore, in addition to the use of GK rats to test the efficacy of drugs, it may represent a great tool to study the influence of altered physiological process and/or organ specific pathophysiological changes (i.e., liver, kidney, etc.) on the disposition of drugs. The objectives of the review were: (a) to compile the published pharmacokinetic data of several drugs, such as cephalexin, cyclosporine, exendin-4, gliclazide, grepafloxacin, rosuvastatin, salsalate, salicylic acid, and theophylline, in GK rats relative to normal rats; and (b) critically evaluate the possible role of physiologically altered processes on the pharmacokinetics of reviewed drugs. The drugs chosen for this review provided a spread of various physiological processes and represented reasonable pool of published data set to fulfil the objectives of the review. The use of GK rats for gathering pharmacokinetic data may aid in making decisions on candidate selection and/or anticipating clinical pharmacology-related issues to the aid drug development in the diabetes area. However, given the interplay and complexities of multiple pathways governing drug disposition, caution needs to be exercised in data interpretation.

Importance Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease. Objective To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque. Design, Setting, and Participants In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease. Interventions Salsalate (3.5 g/d) or placebo orally over 30 months. Main Outcomes and Measures The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy. Results Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, −1 mm3; 95% CI, −11 to 9 mm3;P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group. Conclusions and Relevance Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results. Trial Registration clinicaltrials.gov Identifier:NCT00624923

Aims. In this study a streptozotocin induced type 1 diabetes mouse model was used to assess the effectiveness of salsalate, menhaden oil, the combination of salsalate and menhaden oil, or resolvin D1 on neuropathic endpoints.Materials and Methods. Changes in body weight, blood glucose, serum markers for triglycerides, free fatty acids, cholesterol, and resolvin D1, motor and sensory nerve conduction velocities and thermal sensitivity were assessed, as well as performing in vivo confocal microscopy of subepithelial corneal nerves and immunohistochemistry of nerves in the cornea and foot pad.Results. Diabetic animals failed to gain weight and had elevated blood glucose levels. Diabetic mice had slowed nerve conduction velocity, reduced innervation of the foot pad and cornea subepithelial and epithelial layers, and reduced thermal sensitivity. Monotherapy treatment with salsalate, menhaden oil, and resolvin D1 reduced the pathological signs of diabetic neuropathy. The combination of salsalate and menhaden oil also reduced signs of pathology and generated elevated plasma levels of resolvin D1 compared to other groups.Conclusions. Additional studies are needed to determine whether the combination of salsalate and menhaden oil may be more efficacious than monotherapy alone for the treatment of diabetic peripheral neuropathy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of heterogeneous drugs largely known for their anti-inflammatory, antipyretic, and analgesic effects, which are met by means of the inhibition of the cyclooxygenase (COX) enzymes. Even when their use in patients with diabetes mellitus is limited due to relevant adverse events, some pharmacological and metabolic effects of NSAIDs have been further studied to be potentially beneficial in the prevention and/or treatment of diabetic subjects. Effects on endogenous glucose production, peripheral insulin resistance, pancreatic islet, and systemic inflammation and the insulin clearance have been reported. In this article, we overview the scientific literature of the last 5 years regarding the potential effects of NSAID treatment on diabetes prevention/treatment. The selected papers showed information in both humans and animal models. Furthermore, we included papers that suggest new areas for further investigation, and we discussed our own suggestions on this matter.

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targetingβ-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

To evaluate the effect of salsalate as an antiinflammatory agent on insulin resistance and glycemic control in persons with prediabetes.In this double-blind, placebo-controlled clinical trial, 66 persons who had prediabetes on the basis of the American Diabetes Association criteria were enrolled. They were randomly assigned to receive salsalate (3 g daily) or placebo for 12 weeks. Fasting plasma glucose (FPG) and insulin, glucose 2 hours after oral administration of 75 g of glucose, hemoglobin A1c, lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta-cell function were determined before and after treatment.Salsalate treatment reduced the FPG level from 5.86 ± 0.07 mmol/L to 5.20 ± 0.11 mmol/L and HOMA-IR from 4.2 ± 0.9 to 3.8 ± 0.3 (P = .01 for both changes). Homeostasis model assessment of beta-cell function increased in the salsalate-treatment group from 139.8 ± 11.0 to 189.4 ± 24.6 (P = .01). At the end of the study, FPG, HOMA-IR, and insulin levels were significantly different between salsalate and placebo groups (5.20 ± 0.11 mmol/L versus 5.53 ± 0.10 mmol/L, 3.8 ± 0.3 versus 4.4 ± 0.9, and 16.1 ± 1.9 μIU/mL versus 18.2 ± 2 μIU/mL, respectively; P.05 for all). There were no persistent complications after salsalate therapy.Treatment with salsalate can reduce insulin resistance and the FPG level in subjects with prediabetes. Determination of the long-term safety and efficacy of the use of salsalate necessitates further investigation.

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto-Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS-containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS-diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes.

Owing to the worldwide epidemic of obesity, and the popularity of diets rich in sugar and saturated fat, nonalcoholic fatty liver disease (NAFLD) is increasingly common; it is usually associated with insulin resistance, and may be considered a component of the metabolic syndrome. The pathologies which can complicate hepatic steatosis--steatohepatitis, cirrhosis, and hepatic cancer--appear to result from an interaction of hepatic lipid overload and hepatic oxidative stress. It is therefore proposed that comprehensive regimens which effectively target each of these precipitating factors should achieve the best therapeutic benefit in NAFLD. Appropriate weight loss, and a diet low in saturated fat, glycemic index, and added sugars, should decrease hepatic lipid load. Measures which enhance adipocyte insulin sensitivity--such as pioglitazone, astaxanthin, and spirulina--may also be helpful in this regard, as may agents that boost hepatocyte capacity for fatty acid oxidation, such as metformin, carnitine, hydroxycitrate, long-chain omega-3 fats, and glycine. Astaxanthin and spirulina appear to have considerable potential for controlling the oxidative stress associated with NAFLD - the former because it may help to prevent the mitochondrial damage that renders mitochondria a key source of superoxide in this syndrome, the latter because it is exceptionally rich in phycocyanobilin, a phytochemical inhibitor of NAPDH oxidase. Other antioxidants which show some promise in this syndrome include high-dose folate, lipoic acid, melatonin, N-acetylcysteine, vitamin E, and taurine. Finally, treatment with salsalate, an inhibitor of IkappaB kinase-beta, has potential for blunting the adverse impact of hepatic steatosis on oxidative stress and inflammation.

Chronic inflammation contributes to insulin resistance and type 2 diabetes mellitus (T2DM). We investigated whether treatment with salsalate, an anti-inflammatory medication, improves glycemia in a group of newly diagnosed drug-naive patients with T2DM. The study was a randomized, double-blind, placebo-controlled trial. Diagnosis of T2DM was made within 2 months of enrollment, and participants had not received any anti-glycemic agent. Sixty adults were randomized to receive salsalate (3 g/day) or placebo for 12 weeks. Fasting plasma glucose and insulin, glucose 2 h after 75 g oral glucose, HbA1C, lipid profile, HOMA-IR, and HOMA-B were determined before and after treatment. Salsalate reduced fasting glucose from 6.3 ± 0.2 mmol/l to 5.4 ± 0.2 mmol/l (P < 0.01) and TG from 1.9 ± 0.2 mmol/l to 1.5 ± 0.2 mmol/l (P < 0.03). Fasting insulin levels were increased in the salsalate group from 18.8 ± 1.6 to 21.6 ± 3.9, while they decreased in the placebo group. HbA1c rose in the placebo group from 6.2% ± 0.2 to 7.9% ± 1.1 mmol/mol, but decreased in the intervention group from 6.1% ± 0.5 to 5.6% ± 0.2 mmol/mol (P < 0.04 for between-group comparison). HOMA-IR did not change but HOMA-B increased ~1.7-fold (P = 0.06) in the salsalate group. The results show that salsalate is effective in improving glycemic control in newly diagnosed naive patients with T2DM. The optimal duration of treatment with salsalate and sustainability of its effect requires further study (IRCT138709011465N1).

Summary In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia–reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. IkappaB kinase-beta (IKKbeta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKKbeta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKKbeta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3–4.5 g daily); indeed, this is likely to be the mechanism responsible for salicylate’s utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.

Toxicity Index scores were computed from symptoms, laboratory abnormalities, and hospitalizations attributed to nonsteroidal antiinflammatory drug (NSAID) therapy in 2,747 patients with rheumatoid arthritis receiving 5,642 courses of 11 NSAIDs over 8,481 patient-years. Substantial differences in overall toxicity were found, the differences between drugs often being clinically significant (2-3 times as toxic) and highly statistically significant. The results strengthened after adjustment for differing patient characteristics, held generally across multiple ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data bank centers, and persisted after use of different techniques for the weighting of side effects. The most toxic side effects were experienced by patients taking indomethacin (mean +/- SEM score 3.99 +/- 0.58), tolmetin sodium (3.96 +/- 0.74), and meclofenamate sodium (3.86 +/- 0.66). Least toxic were coated or buffered aspirin (1.19 +/- 0.10), salsalate (1.28 +/- 0.34), and ibuprofen (1.94 +/- 0.43). The most toxic drugs were generally taken in the lowest relative doses. There are statistical differences in overall toxicity between different NSAIDs as used in rheumatoid arthritis, and these differences are both clinically and statistically significant.

In this 13-week, open-label, randomized study of the anti-inflammatory salsalate versus usual care, there were no significant improvements in flow-mediated dilation of the brachial artery, endothelial activation, inflammation or coagulation markers, homeostasis model assessment of insulin resistance or lipoproteins with salsalate or between groups in virologically suppressed, HIV-infected adults on antiretrovirals. Tinnitus and transaminitis occurred frequently in the salsalate group. Dose reduction due to toxicities encountered and low level of inflammation may explain these results.

Purpose Use of non-steroidal anti-inflammatory drugs (NSAID) is associated with risk of acute kidney injury (AKI). Risk of AKI may vary with selectivity of the NSAID, but this has not been studied in a large cohort where AKI was assessed directly from laboratory data. The objective was to compare AKI risk between selective and non-selective NSAIDs using a laboratory-based definition of AKI. Methods We conducted a retrospective nested case-control study in the U.S. Department of Veterans Affairs health care system. From a cohort of 1 459 271 new NSAID users, we identified 22 824 cases of AKI (97% male; mean age: 63 years), and 336 734 matched controls between 2000 and 2006. AKI was defined as a creatinine increase of greater than 50%. Results We found higher risk of AKI in new users of any single NSAID (adjusted odds ratio = 1.82; 95%CI: 1.68, 1.98) compared to non-users without recent use. The risk of AKI varied among different NSAIDs with risk generally increasing with decrease in selectivity: rofecoxib (0.95; 0.64, 1.42), celecoxib (0.96; 0.63, 1.47), meloxicam (1.13; 0.63, 2.05), etodolac (1.31; 1.08, 1.59), diclofenac (1.11; 0.84, 1.48), piroxicam (1.53; 1.05, 2.23), salsalate (1.51; 1.22, 1.87), sulindac (1.61; 1.12, 2.30), ibuprofen (2.25, 2.04, 2.49), naproxen (1.72; 1.52, 1.95), high dose aspirin (3.64; 2.46, 5.37), indomethacin (1.94; 1.56, 2.42), keterolac (2.07; 1.78, 2.41). Those using multiple NSAIDs appeared to have higher risk (2.90; 2.62, 3.22). Conclusions This study provides evidence that risk of AKI may be lower with more selective agents than with naproxen or other non-selective NSAIDs. Copyright © 2009 John Wiley & Sons, Ltd.

Background—We tested the hypothesis that nuclear factor-κB (NF-κB) activity contributes to vascular endothelial dysfunction with aging and obesity in humans.Methods and Results—We conducted a randomized, double-blind, placebo-controlled crossover study in 14 nondiabetic overweight or obese (body mass index ≥25 kg/m2) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-κB activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8±1.1 mg/100 mL,P≤0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-κB and reduced total and nuclear expression of NF-κB in endothelial cells obtained from the subjects (allPPP=0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (r=−0.77,PPP=0.23). Salsalate reduced nitrotyrosine (P=0.06) and expression of NADPH oxidase p47phox(PConclusions—Our findings provide the first direct evidence that NF-κB, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese middle-aged and older humans.

OBJECTIVE—Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes. RESEARCH DESIGN AND METHODS—In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo. RESULTS—Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05). CONCLUSIONS—This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.

Evidence exists that interleukin (IL)-1β is involved in pancreatic β-cell damage, whereas TNF-α appears to be a key molecule in peripheral insulin resistance. Although increased plasma levels of IL-6 are seen in individuals with type 2 diabetes, mechanistic studies suggest that moderate acute elevations in IL-6, as provoked by exercise, exert anti-inflammatory effects by an inhibition of TNF-α and by stimulating IL-1 receptor antagonist (ra), thereby limiting IL-1β signaling. A number of medical treatments have anti-inflammatory effects. IL-1 antagonists have been tested in clinical studies and appear very promising. Also, there is a potential for anti-TNF-α strategies and salsalate has been shown to improve insulin sensitivity in clinical trials. Furthermore, the anti-inflammatory potential of statins, antagonists of the renin-angiotensin system, and glucose-lowering agents are discussed. While waiting for the outcome of long-term clinical pharmacological trials, it should be emphasized that physical activity represents a natural strong anti-inflammatory intervention with little or no side effects.

The balance of nitric oxide (NO) versus superoxide generation has a major role in the initiation and progression of endothelial dysfunction. Under conditions of high glucose, endothelial nitric oxide synthase (eNOS) functions as a chief source of superoxide rather than NO. In order to improve NO bioavailability within the vessel wall in type-1 diabetes, we investigated treatment strategies that improve eNOS phosphorylation and NO-dependent vasorelaxation. We evaluated methods to increase the eNOS activity by (1) feeding Ins2(Akita) spontaneously diabetic (type-1) mice with l-arginine in the presence of sepiapterin, a precursor of tetrahydrobiopterin; (2) preventing eNOS/NO deregulation by the inclusion of inhibitor kappa B kinase beta (IKKβ) inhibitor, salsalate, in the diet regimen in combination with l-arginine and sepiapterin; and (3) independently increasing eNOS expression to improve eNOS activity and associated NO production through generating Ins2(Akita) diabetic mice that overexpress human eNOS predominantly in vascular endothelial cells. Our results clearly demonstrated that diet supplementation with l-arginine, sepiapterin along with salsalate improved phosphorylation of eNOS and enhanced vasorelaxation of thoracic/abdominal aorta in type-1 diabetic mice. More interestingly, despite the overexpression of eNOS, the in-house generated transgenic eNOS-GFP (TgeNOS-GFP)-Ins2(Akita) cross mice showed an unanticipated effect of reduced eNOS phosphorylation and enhanced superoxide production. Our results demonstrate that enhancement of endogenous eNOS activity by nutritional modulation is more beneficial than increasing the endogenous expression of eNOS by gene therapy modalities.

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.