allopurinol and Glucose-Intolerance

Topics: Adenosine Triphosphatases; Aldosterone; Allopurinol; Animals; Contraceptives, Oral, Combined; Female; Glucose Intolerance; Humans; Insulin Resistance; Levonorgestrel; Nitric Oxide; Plasminogen Activator Inhibitor 1; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Triglycerides; Valproic Acid

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Chemokine CCL2; Collagen; Diabetic Nephropathies; Febuxostat; Glucose Intolerance; Hyperglycemia; Hyperuricemia; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Obese; Oxidative Stress; Peptide Fragments; Uric Acid; Xanthine Oxidase

Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation.. Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity.. Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers.. Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Allopurinol; Anaerobiosis; Animals; Blood Glucose; Body Weight; Buffers; Cell Respiration; Cold Ischemia; Electron Transport; Fasting; Fatty Liver; Glucose Intolerance; Glutathione; Hydrogen-Ion Concentration; Insulin; Insulin Resistance; Liver; Male; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Liver; Organ Preservation Solutions; Oxidative Phosphorylation; Raffinose; Thinness