salicylates and Diabetes-Mellitus--Type-2

There is conflicting evidence regarding the efficacy of high dose salicylates in improving cardiometabolic risk in healthy and type 2 diabetes patients. We aimed to determine whether treatment with salicylates at an anti-inflammatory dose (≥1g daily) would improve cardiometabolic risk in healthy individuals and type 2 diabetes patients, compared to placebo.. Medline, Medline-in-process, Embase, and all EBM databases were searched for studies published up to December 2016. Twenty-eight articles from 24 studies comprising 1591 participants were included. Two reviewers independently assessed the risk of bias and extracted data from included studies. Meta-analyses using random-effects model were used to analyze the data.. High dose salicylates (≥3g/d) decreased fasting glucose (MD -0.4mmol/l, 95% CI -0.54, -0.27) and glucose area under the curve (MD -0.41mmol/l, 95% CI -0.81, -0.01). Salicylates (≥3g/d) also increased fasting insulin (MD 2.4 μU/ml, 95% CI 0.3, 4.4), 2-h insulin (MD 25.4 μU/ml, 95% CI 8.2, 42.6), insulin secretion (MD 79.2, 95% CI 35, 123) but decreased fasting C-peptide (MD -0.11nmol/l, 95% CI -0.2, -0.04), insulin clearance (MD -0.26l/min, 95% CI -0.36, -0.16) and triglycerides (MD -0.36mmol/l, 95% CI -0.51, -0.21) and increased total adiponectin (MD 1.97μg/ml, 95% CI 0.99, 2.95). A lower salicylate dose (1-2.9g) did not change any cardiometabolic parameters (p>0.1). No significant difference was observed between those receiving salicylates and placebo following withdrawal due to adverse events.. High dose salicylates appear to improve cardiometabolic risk factors in healthy individuals and type 2 diabetes patients.. CRD42015029826.

Topics: Anti-Inflammatory Agents; Cardiovascular System; Diabetes Mellitus, Type 2; Humans; Metabolism; Randomized Controlled Trials as Topic; Risk Factors; Salicylates

The incidence of complex noncommunicable diseases has strongly increased over the last several decades in the US, Europe and other parts of the world that have adopted a western lifestyle (M. Ezzati, E. Riboli, Science- 2012, 337, 1482-1487; S. Smyth, A. Heron, Nat. Med.- 2006, 12, 75). Despite considerable investment in the development of new types of drugs, options for the treatment of many common diseases remain inadequate. If current trends prevail, the rising incidence of disorders such as obesity and type 2 diabetes mellitus (T2DM) will soon result in an unsustainable burden on society (World Health Organization Technical Report Series- 2000, 894, i-xii, 1-253). Given the difficulty of treating fully developed complex disorders, new strategies for early intervention and prevention of common diseases are of great interest. Dietary natural products with beneficial effects, such as the recently described antidiabetic and lipid-lowering amorfrutins, could pave the way for efficiently treating and preventing metabolic and other complex diseases (C. Weidner, et al. Proc. Natl. Acad. Sci. USA- 2012, 109, 7257-7262).

Topics: Biological Products; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Obesity; PPAR gamma; Salicylates

Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barré syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Farnesol; Humans; Protein Binding; ras Proteins; Salicylates

The aim of this study was to assess the effects and safety of salicylates on type 2 diabetes mellitus (T2DM). We searched six databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CBM, CNKI and VIP) for all randomized controlled trials (RCTs) and self-control studies which investigated the effects of salicylates on T2DM. We included 34 RCTs and 17 self-control studies involving 13 464 patients with T2DM. It was demonstrated that salicylates had obvious effects on several parameters for patients with T2DM. (1) Any dose of salicylates could significantly reduce HbA1c level [mean difference (MD) -0.39%; 95% CI -0.47 to -0.32] in RCTs, but only high doses of salicylates (≥3000 mg/day) could effectively reduce fasting plasma glucose (FPG) level [standardized mean difference (SMD) -1.05; 95% CI -1.47 to -0.62] for patients with T2DM in both RCTs and self-control studies. Furthermore, high doses of salicylates could also increase plasma fasting insulin level (MD 12.20 mU/L; 95% CI 3.33 to 21.07); (2) In both RCTs and self-control studies, high doses of salicylates could significantly reduce plasma triglycerides concentration. The results for RCTs were MD -0.44 mmol/L, 95% CI -0.71 to -0.18, and those for self-control studies were 227±29 mg/dL (pre-treatment) and 117±8 mg/dL (post-treatment) (P=0.009); (3) All trials which reported cardiovascular events were RCTs using low doses (<1000 mg/day) of salicylates, and it was revealed that aspirin could significantly reduce the risk of myocardial infarction (OR 0.73; 95% CI 0.57 to 0.92); (4) Two RCTs and two self-control studies with ≥3000 mg/day salicylates reported adverse effects, and the overall effects were mild, and tinnitus occurred most frequently. No evidence of gastrointestinal bleeding was found in all these studies. In conclusion, from our systematic review, the anti-diabetic effect of salicylates is in a dose-dependent manner. High doses of salicylates may have beneficial effects on reducing FPG, HbA1c level and increasing fasting insulin concentration, and may also have some positive effects on lipidemia and inflammation-associated parameters for patients with T2DM, without serious adverse effects.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus, Type 2; Humans; Incidence; Randomized Controlled Trials as Topic; Risk Factors; Salicylates; Survival Rate; Treatment Outcome

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Anti-Bacterial Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Protein Serine-Threonine Kinases; Salicylates

Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states.. Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates.. The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Inflammation; Insulin Resistance; Obesity; Salicylates

The incidence of type 2 diabetes is increasing at an alarming rate throughout the world. This is in large part due to the increase in obesity and the aging of the population. Therefore, new medications to combat type 2 diabetes are needed. Salicylates have been used as analgesics and antiinflammatory agents for several decades. Incidentally, in some studies it was noted that high-dose salicylate treatment reduced blood glucose concentrations. Recently, inflammation has been strongly associated with insulin resistance and diabetes. Some studies show that salsalate, which is a nonacetylated form of salicylate, reduces blood glucose concentrations in patients with type 2 diabetes, as well as in insulin-resistant patients without diabetes. Postulated mechanisms include the inhibition of nuclear factor NF-kappa-B. Discussed in this review are the efficacy, safety and mechanisms of salsalate relevant to the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; NF-kappa B; Salicylates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Bone Remodeling; Diabetes Mellitus, Type 2; Humans; Inflammation; Osteocalcin; Salicylates; Treatment Outcome

OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine [measured as furosine]) and AGE levels (glyoxal and methylglyoxal hydroimidazolones [G-(1)H, MG-(1)H], carboxymethyllysine [CML], carboxyethyllysine [CEL], pentosidine) were measured in patient serum samples. RESULTS Forty-eight weeks of salsalate treatment lowered levels of HbA1c and serum furosine (P < 0.001) and CML compared with placebo. The AGEs CEL and G-(1)H and MG-(1)H levels were unchanged, whereas pentosidine levels increased more than twofold (P < 0.001). Among salsalate users, increases in adiponectin levels were associated with lower HbA1c levels during follow-up (P < 0.001). Changes in renal and inflammation factor levels were not associated with changes in levels of early or late glycation factors. Pentosidine level changes were unrelated to changes in levels of renal function, inflammation, or cytokines. CONCLUSIONS Salsalate therapy was associated with a reduction in early but not late glycation end products. There was a paradoxical increase in serum pentosidine levels suggestive of an increase in oxidative stress or decreased clearance of pentosidine precursor.

Topics: Adiponectin; Adult; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Lysine; Male; Middle Aged; Pyruvaldehyde; Salicylates

Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM).. To assess 1-year efficacy and safety of salsalate in T2DM.. Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643).. 3 private practices and 18 academic centers in the United States.. Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes.. 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146).. Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures.. The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged.. Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM.. Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Kidney; Male; Middle Aged; Salicylates; Single-Blind Method; Young Adult

To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).. 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.. 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/m(2)), 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).. 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.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Brachial Artery; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Inflammation; Male; Middle Aged; Regional Blood Flow; Salicylates; Single-Blind Method; Time Factors; Treatment Outcome; Ultrasonography; Vasodilation

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-naïve 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 naïve patients with T2DM. The optimal duration of treatment with salsalate and sustainability of its effect requires further study (IRCT138709011465N1).

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Salicylates

Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies.. To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes.. Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678). 3 private practices and 14 universities in the United States.. Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (< or = 225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks.. After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy.. Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes.. Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline (P = 0.009). Mean HbA1c changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated.. The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time.. Salsalate lowers HbA1c levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation.. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Topics: Adolescent; Adult; Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastrointestinal Diseases; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Prodrugs; Salicylates; Tinnitus; Young Adult

Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF-kappaB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes.. In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose-limiting tinnitus occurred only at the higher dose. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects.. These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF-kappaB as a therapeutic approach in type 2 diabetes.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Calorimetry; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Male; NF-kappa B; Placebos; Salicylates

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.

Topics: Adult; Aged; Aspirin; Biomarkers; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Retrospective Studies; Salicylates; Thromboxane B2; von Willebrand Factor

Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure-activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Muscle Fibers, Skeletal; Palmitates; Salicylates; Signal Transduction; Structure-Activity Relationship

Previously, we reported that Mof was highly expressed in α-cells, and its knockdown led to ameliorated fasting blood glucose (FBG) and glucose tolerance in non-diabetic mice, attributed by reduced total α-cell but enhanced prohormone convertase (PC)1/3-positive α-cell mass. However, how Mof and histone 4 lysine 16 acetylation (H4K16ac) control α-cell and whether Mof inhibition improves glucose handling in type 2 diabetes (T2DM) mice remain unknown.. Mof overexpression and chromatin immunoprecipitation sequence (ChIP-seq) based on H4K16ac were applied to determine the effect of Mof on α-cell transcriptional factors and underlying mechanism. Then we administrated mg149 to α-TC1-6 cell line, wild type, db/db and diet-induced obesity (DIO) mice to observe the impact of Mof inhibition in vitro and in vivo. In vitro, western blotting and TUNEL staining were used to examine α-cell apoptosis and function. In vivo, glucose tolerance, hormone levels, islet population, α-cell ratio and the co-staining of glucagon and PC1/3 or PC2 were examined.. Mof activated α-cell-specific transcriptional network. ChIP-seq results indicated that H4K16ac targeted essential genes regulating α-cell differentiation and function. Mof activity inhibition in vitro caused impaired α-cell function and enhanced apoptosis. In vivo, it contributed to ameliorated glucose intolerance and islet dysfunction, characterized by decreased fasting glucagon and elevated post-challenge insulin levels in T2DM mice.. Mof regulates α-cell differentiation and function via acetylating H4K16ac and H4K16ac binding to Pax6 and Foxa2 promoters. Mof inhibition may be a potential interventional target for T2DM, which led to decreased α-cell ratio but increased PC1/3-positive α-cells.

Topics: Acetylation; Animals; Apoptosis; Cell Line; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Gene Regulatory Networks; Glucagon-Secreting Cells; Glucose Intolerance; Histone Acetyltransferases; Histones; Lysine; Mice, Inbred C57BL; Obesity; Proprotein Convertase 1; Salicylates

Topics: Adipose Tissue, White; Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Fatty Liver; Gene Expression; Gluconeogenesis; Glucose; Humans; Insulin; Lipid Metabolism; Liver; Male; Mice; Muscle, Skeletal; Obesity; Pyruvic Acid; Salicylates; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Thermogenesis

To compare rates and predictors of documented hypoglycaemia in type 2 diabetes patients treated with either basal insulin supported oral therapy (BOT), conventional therapy (CT) or supplementary insulin therapy (SIT) in primary care.. Data from 10,842 anonymous patients (mean age ± SD: 54 ± 8 yrs) on BOT, 2,407 subjects (56 ± 7 yrs) on CT, and 7,480 patients (52 ± 10 yrs) using SIT from 1,198 primary care practices were retrospectively analyzed (Disease Analyzer, Germany: 01/2005-07/2013). Stepwise logistic regression (≥1 documented hypoglycaemia: ICD code) was used to evaluate risk factors of hypoglycemia.. The unadjusted rates (95% CI) per 100 patient-years of documented hypoglycaemia were 1.01 (0.80-1.20) (BOT), 1.68 (1.10-2.30) (CT), and 1.61 (1.30-1.90) (SIT), respectively. The odds of having ≥1 hypoglycemia was increased for CT (OR; 95% CI: 1.71; 1.13-2.58) and SIT (1.55; 1.15-2.08) (reference: BOT). Previous hypoglycemia (OR: 11.24; 6.71-18.85), duration of insulin treatment (days) (1.06; 1.05-1.07), history of transient ischemic attack (TIA)/stroke (1.91; 1.04-3.50), and former salicylate prescriptions (1.44; 1.06-1.98) also showed an increased odds of having hypoglycemia. Higher age was associated with a slightly lower odds ratio (per year: 0.98; 0.97-0.99).. Insulin naïve type 2 diabetes patients in primary care, initiated with CT and SIT have an increased risk of hypoglycaemia compared to BOT, which is in line with previous randomized controlled trials. As hypoglycaemic events are associated with an increased mortality risk, this real-world finding is of clinical relevance.

Topics: Adult; Age Factors; Databases, Factual; Diabetes Mellitus, Type 2; Drug Prescriptions; Female; Germany; Humans; Hypoglycemia; Incidence; Insulin; Ischemic Attack, Transient; Male; Middle Aged; Primary Health Care; Recurrence; Risk Factors; Salicylates; Time Factors

PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARγ modulators (SPPARγMs) as safer alternatives to PPARγ full agonists.. This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARγMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARγ activation. Specifically, the in vivo glucose-lowering properties of the high-affinity SPPARγM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities.. The patent (WO2014177593 A1) under discussion proposes enriching functional food products or phytomedical extracts with safe licorice extracts, containing sufficient amounts of amorfrutins, with the ultimate goal of inhibiting the early development of disorders such as insulin resistance. Interestingly, some example compounds show anticancer properties in colon, prostate, and breast malignancies. However, further in vivo investigations of the claimed compounds for these specific indications will be necessary to definitively support their clinical applications.

Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Neoplasms; Patents as Topic; PPAR gamma; Salicylates

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Inflammation; Male; Salicylates; Vasodilation

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Inflammation; Male; Salicylates; Vasodilation

Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic fibrillar deposits has been postulated to be one of the main contributors to impaired insulin secretion and pancreatic β-cell death in approximately 90% of type 2 diabetic patients. So, compounds that prevent cytotoxic protein/polypeptide self-assembly and amyloidogenesis are considered as novel therapeutic agents against this disease. In this study, using thioflavin-T (ThT) and Anilinonaphthalene-8-sulfonic acid (ANS) fluorescence assays, transmission electron microscopy (TEM) and docking studies, we investigated whether EUK-8 and EUK-134, two salen derivatives with proven antioxidants activities, could interfere with the conversion of synthetic human amylin to its insoluble amyloid form. Spectroscopy and electron microscopy data indicated that incubation of human amylin with either EUK-8 or EUK-134 significantly inhibited amyloid formation at two molar ratios of 1:1 and 5:1 (drugs to protein). In addition, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay showed that treatment of SK-N-MC cells with the pre-formed fibrils in the presence of compounds at drug-to-protein molar ratios of 1:1 and 5:1, dramatically increased the viability of cells compared to the only fibrils formed-treated SK-N-MC cells. Docking results also demonstrated that the aromatic rings of EUK-8 and EUK-134 interact with the hydrophobic region (23-25) of IAPP via Van der Waals interactions. Based on these results and the proven antioxidant properties of these compounds, it could be concluded that these compounds might provide a novel approach to prevent islet amyloid deposition in β-cells and provide useful information for developing other novel compounds for the treatment of type 2 diabetes.

Topics: Amyloid; Anilino Naphthalenesulfonates; Antioxidants; Benzothiazoles; Cell Line, Tumor; Cell Survival; Diabetes Mellitus, Type 2; Ethylenediamines; Fluorescent Dyes; Humans; Islet Amyloid Polypeptide; Microscopy, Electron, Transmission; Molecular Docking Simulation; Neuroblastoma; Organometallic Compounds; Salicylates; Thiazoles

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Prediabetic State; Psychiatric Status Rating Scales; Salicylates; Schizophrenia; Triglycerides; Young Adult

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites.. Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B.. Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARβ/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention.. The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Salicylates

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Salicylates; Young Adult

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.

Topics: 3T3-L1 Cells; Animals; Biological Products; Blotting, Western; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Fabaceae; Gene Expression; Glycyrrhiza; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; PPAR gamma; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Salicylates

Topics: Animals; Biological Products; Diabetes Mellitus, Type 2; Fabaceae; Humans; Hypoglycemic Agents; Male; Salicylates

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.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Diabetes Mellitus, Type 2; Disease Models, Animal; Hydrolysis; Hypoglycemic Agents; Injections, Intravenous; Linear Models; Male; Metabolic Clearance Rate; Models, Biological; Nonlinear Dynamics; Rats; Rats, Wistar; Salicylates; Salicylic Acid

Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. It is also associated with increased inflammation. Ras inhibition downregulates inflammation in various experimental models. The aim of this study was to examine the effect of Ras inhibition on insulin sensitivity and glucose uptake, as well as its influence on type 2 diabetes development.. The effect of Ras inhibition on glucose uptake was examined both in vitro and in vivo. Ras was inhibited in cells transfected with a dominant-negative form of Ras or by 5-fluoro-farnesylthiosalicylic acid (F-FTS), a small-molecule Ras inhibitor. The involvement of IκB and NF-κB in Ras-inhibited glucose uptake was investigated by immunoblotting. High fat (HF)-induced diabetic mice were treated with F-FTS to test the effect of Ras inhibition on induction of hyperglycemia. Each of the Ras-inhibitory modes resulted in increased glucose uptake, whether in insulin-resistant C2C12 myotubes in vitro or in HF-induced diabetic mice in vivo. Ras inhibition also caused increased IκB expression accompanied by decreased expression of NF-κB . In fat-induced diabetic mice treated daily with F-FTS, both the incidence of hyperglycemia and the levels of serum insulin were significantly decreased.. Inhibition of Ras apparently induces a state of heightened insulin sensitization both in vitro and in vivo. Ras inhibition should therefore be considered as an approach worth testing for the treatment of type 2 diabetes.

Topics: Animals; Blotting, Western; Cell Line; Diabetes Mellitus, Type 2; Farnesol; Glucose; Insulin Resistance; Mice; Polymerase Chain Reaction; Proto-Oncogene Proteins p21(ras); Salicylates

Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and β-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 15 weeks with an upsurge of more than 100 mg/dl. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics by using a population method in S-ADAPT. Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and β-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on β-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. In addition, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Male; Models, Biological; Random Allocation; Rats; Rats, Inbred WKY; Salicylates; Sodium Salicylate; Software

Topics: Adolescent; Adult; Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Prodrugs; Salicylates; Young Adult

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Bone Density Conservation Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; Diabetes Mellitus, Type 2; Diphosphonates; Drug Therapy; Dyslipidemias; Enoxaparin; Fibrinolytic Agents; Fractures, Bone; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Imidazoles; Middle Aged; Neoplasm Staging; Pharmacy; Pyrazoles; Pyridones; Salicylates; Treatment Outcome; Venous Thromboembolism; Young Adult; Zoledronic Acid

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 2; Endocrinology; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Hypoglycemic Agents; Inflammation; Salicylates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Inflammation; Salicylates; Signal Transduction; Translational Research, Biomedical

Topics: Diabetes Mellitus, Type 2; Diagnosis, Differential; Drug Eruptions; Eczema; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Myocardial Infarction; Patch Tests; Platelet Aggregation Inhibitors; Salicylates

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Mice; Models, Biological; Phosphatidylinositol 3-Kinases; Phosphoproteins; Rats; Salicylates; Signal Transduction

A 70-year-old woman with type 2B diabetes mellitus was referred to the dermatology department because of inflammatory skin changes of unknown origin over the trunk and limbs. On admission follicular and parafollicular livid-red papulae with central crusts and reddened margins were noted over the lower legs and the lumbosacral region.. Further physical examination revealed no additional abnormalities. Erythrocyte sedimentation rate was 41/79 mm. The day-time blood-glucose profile was raised (10.2, 12.6 and 8.6 mmol/l), as was the glycosylated haemoglobin HbA1c (9.0%). Swabs from fresh lesions gave no evidence of fungal or bacterial infection. Biopsies revealed areas of widened epidermis with central ulceration filled with fibrin, granulocytes and collagen fibres.. The clinical and histological findings indicated an acquired reactive perforating collagenosis (dermatosis) which should be judged in relation to the long-standing diabetes mellitus. The cutaneous changes were covered with salicylate- and steroid-containing preparations, while individual lesions were excised or removed by curettage.. The condition of acquired reactive perforating collagenosis is, like Kyrle's disease (perforating follicular and parafollicular hyperkeratotic dermatosis), perforating serpiginous elastosis and perforating folliculitis classified among the perforating dermatoses. In the presence of renal failure and (or) diabetes mellitus these dermatoses must be thought of in the differential diagnosis, in addition to the more frequent pruriginous conditions, if there are corresponding skin changes.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents, Non-Steroidal; Curettage; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Salicylates; Skin; Skin Diseases

Topics: Administration, Topical; Aged; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Male; Psoriasis; Salicylates; Salicylic Acid

Topics: Acetazolamide; Acidosis, Lactic; Aged; Anorexia; Confusion; Coronary Disease; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Glaucoma; Humans; Joint Diseases; Male; Salicylates; Urinary Incontinence