salicylates and Hyperglycemia

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

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. 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. 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.. RéSUMé: OBJECTIF: L’hyperglycémie périopératoire est fréquente et est associée à une morbidité significative. Bien que les caractéristiques propres au patient et à la chirurgie influencent le métabolisme périopératoire du glucose, les anesthésiques ont un impact significatif. Nous avons émis l’hypothèse que l’hyperglycémie en réponse à une anesthésie à base de sévoflurane serait plus prononcée chez des souris obèses et insulino-résistantes que chez des souris témoins maigres. Nous avons en outre émis l’hypothèse que l’hyperglycémie induite par le sévoflurane serait atténuée par un prétraitement au salsalate. MéTHODE: Des souris mâles C57BL/6J maigres et obèses ont été anesthésiées avec du sévoflurane pendant 60 min avec ou sans prétraitement de 62,5 mg·kg

Topics: Animals; Blood Glucose; Glucose; Hyperglycemia; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Salicylates; Sevoflurane

Sixteen novel orsellinic esters (

Topics: Animals; Blood Glucose; Depsides; Glycoside Hydrolase Inhibitors; Hyperglycemia; Hypoglycemic Agents; Male; Molecular Docking Simulation; Rats; Rats, Wistar; Resorcinols; Saccharomyces cerevisiae; Salicylates; Structure-Activity Relationship; Sucrose

To evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs).. We compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D(2), ex vivo thromboxane B(2) (TXB(2)) levels and plasma pharmacokinetics.. ST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T(max) values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB(2) generation was suppressed at 15 min and complete suppression of TXB(2) was sustained at 24h (p<0.01 vs niacin). ST0702 suppressed PGD(2) exposure eightfold (p = 0.012) compared to niacin over the first 24h.. This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB(2) and PGD(2) increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.

Topics: Animals; Apolipoproteins B; Aspirin; Blood Glucose; Chemistry, Pharmaceutical; Cholesterol, LDL; Cyclooxygenase Inhibitors; Hyperglycemia; Hypolipidemic Agents; Isosorbide; Lipid Metabolism; Lipids; Macaca fascicularis; Models, Biological; Niacin; Postprandial Period; Prodrugs; Prostaglandin D2; Salicylates; Thromboxane B2; Triglycerides

Advanced glycation end products (AGE) have been implicated in the pathogenesis of diabetic complications. The purpose of this study was to examine the novel coumarin-aspirin compound XLF-III-43 in the inhibition of AGE formation in diabetic nephropathy. In vitro analysis showed XLF-III-43 in a dose-dependent manner decreased glucose induced formation of glycation adducts on albumin and inhibited AGE-lysozyme crosslinking. The streptozotocin-induced diabetic rats were used to investigate the beneficial effects of XLF-III-43 treatment on diabetic nephropathy. Administration of XLF-III-43 significantly decreased (P<0.05) blood urea nitrogen and urinary albumin excretion. Moreover, XLF-III-43 ameliorated kidney hypertrophy, mesangial expansion and glomerulosclerosis in diabetic rats relative to untreated model group. These data correlated with decreased both AGE and downstream markers of AGE stress (TGF-beta1, CTGF, fibronectin and collagen IV fibrolysis) in kidneys of diabetic rats. These data support further development of XLF-III-43 for prevention of nephropathy via inhibition of AGE formation consequent to chronic hyperglycemia.

Topics: Animals; Body Weight; Coumarins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Gene Expression Regulation; Glycation End Products, Advanced; Hyperglycemia; Hypertension; Kidney; Rats; Rats, Sprague-Dawley; Salicylates

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Disease Models, Animal; Fasting; Glucose Tolerance Test; Hyperglycemia; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Salicylates; Stilbenes; Structure-Activity Relationship; Styrenes; Weight Gain

Topics: Acidosis; Alkalosis; Alkalosis, Respiratory; Animals; Aspirin; Child; Child, Preschool; Dehydration; Fever; Humans; Hyperglycemia; Infant; Papio; Poisoning; Salicylates

Topics: Acidosis; Aged; Blood Urea Nitrogen; Bradycardia; Catheterization; Female; Heart Failure; Hepatic Encephalopathy; Humans; Hyperglycemia; Kidney Failure, Chronic; Male; Methanol; Middle Aged; Peritoneal Dialysis; Pyelonephritis; Salicylates

Topics: Aspirin; Child; Coma; Diabetic Coma; Diagnosis; Diagnosis, Differential; Humans; Hyperglycemia; Infant; Parent-Child Relations; Parents; Poisoning; Salicylates; Toxicology; Urine

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Hyperglycemia; Rheumatic Fever; Salicylates

Topics: Animals; Cortisone; Glycosuria; Hyperglycemia; Rats; Salicylates