c-peptide and Reperfusion-Injury

High-fructose intake induces metabolic syndrome and cardiac dysfunction. Chronic intermittent hypobaric hypoxia (CIHH) preserves cardiac function during ischemia. We hypothesized that CIHH restores the impaired cardiac function in fructose-fed rats. Sprague-Dawley rats were randomly subject to treatment with fructose (10% fructose in drinking water for 6 weeks), CIHH (simulated 5000 m altitude, 6 h/day for 6 weeks in a hypobaric chamber), and CIHH plus fructose groups. In addition to an increase in blood pressure, fructose feeding caused elevated serum levels of glucose, fasting insulin and insulin C peptide, triglyceride, cholesterol, and mass ratio of heart to body. CIHH treatment decreased the arterial blood pressure, serum levels of biochemical markers, and cardiac hypertrophy in fructose-fed rats. Furthermore, CIHH treatment improved the recovery of left ventricular function after ischemia-reperfusion procedure (30 min global no-flow ischemia followed by 60 min of reperfusion) in rats with or without fructose feeding. In addition, CIHH treatment caused a significant increase in superoxide dismutase (SOD) activity and decrease in malondialdehyde level in cardiac myocardium experiencing ischemia-reperfusion in control and fructose-fed rats. Collectively, these data suggest that CIHH improve impaired cardiac function in fructose-fed rats through enhancing antioxidation in the myocardium.

Topics: Animal Feed; Animals; Antioxidants; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Fructose; Heart; Hypoxia; Insulin; Male; Malondialdehyde; Myocardium; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Triglycerides; Ventricular Function, Left

The function of peroxisome proliferator-activated receptor-gamma (PPARgamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPARgamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPARgamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPARgamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPARgamma, retinoid X receptor-alpha (RXRalpha), and PPARgamma/RXRalpha heterodimer expression was maintained. Accompanying the decrease in PPARgamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). This was associated with reduced interaction of PPARgamma and the coactivator, p300. To determine whether PPARgamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPARgamma agonists, rosiglitazone and connecting peptide. These treatments increased PPARgamma activation and reduced liver injury compared to untreated mice. Furthermore, PPARgamma-deficient mice had more liver injury after ischemia/reperfusion than their wild-type counterparts.. These data suggest that PPARgamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.

Topics: Animals; C-Peptide; E1A-Associated p300 Protein; Gene Expression Regulation; Hepatocytes; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Prostaglandin D2; Reperfusion Injury; Retinoid X Receptor alpha; Rosiglitazone; Thiazolidinediones

Neuronal apoptosis has been demonstrated to be a significant factor in neurological deficiencies associated with diabetes, and these deficiencies are exaggerated following ischemia. Diabetic rats have an increased basal level of apoptosis compared to non-diabetics and it has been previously demonstrated that infarct volumes were greater in diabetic animals following middle cerebral artery occlusion (MCAO) when compared to non-diabetics. In this study, we evaluated both the acute and chronic effects of insulin and/or C-peptide on CNS necrosis and apoptosis in non-diabetic and streptozotocin-induced diabetic rats following MCAO with reperfusion. Two brain areas, the sensori-motor cortex (layers-5 and 6) and the CA1 and CA3 sectors (pyramidal cell layers) of the hippocampus, were analyzed for apoptosis using TUNEL and Caspase-3 immunoreactivity. The chronic administration of a low maintenance concentration of insulin (2 U/kg), or the acute administration of insulin (2 U/kg) with or without C-peptide, did not alter the lesion volume or basal levels of apoptosis or the apoptotic levels in animals subjected to 2-h MCAO followed by 24-h reperfusion. However, both the acute or chronic administration of a high concentration of insulin (12 U/kg) significantly decreased lesion volume and apoptosis subsequent to 2-h MCAO followed by 24-h reperfusion. High dose insulin treatment also decreased the basal level of apoptosis. We conclude that in diabetic rats subjected to ischemia and reperfusion chronic insulin treatment decreased the basal apoptotic level, and both acute and chronic insulin decreased the MCAO-induced lesion volume and apoptosis. Maintenance insulin concentrations with or without C-peptide were without effect.

Topics: Animals; Apoptosis; Blood Glucose; Brain Ischemia; C-Peptide; Caspase 3; Caspases; Diabetes Mellitus, Experimental; Hypoglycemic Agents; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Insulin; Insulin Resistance; Male; Necrosis; Rats; Rats, Wistar; Reperfusion Injury

Pancreatitis remains to be a major complication following clinical pancreas transplantation. We performed orthogonal polarized spectral (OPS) imaging for direct in vivo visualization and quantification of human pancreatic microcirculation in six healthy donors for living donor liver transplantation and 13 patients undergoing simultaneous pancreas-kidney transplantation. We further determined the impact of microvascular dysfunction during early reperfusion on pancreatic graft injury. Exocrine and endocrine pancreatic impairment was determined by analysis of serum lipase, amylase and C-peptide levels. Compared to normal pancreas in liver donors (homogeneous acinar perfusion) functional capillary density (FCD) and capillary red blood flow velocity of reperfused grafts were significantly decreased. Elevated CRP concentrations on day 2 post-transplant and serum lipase and amylase levels determined on days 4-5 significantly correlated with microvascular dysfunction during the first 30 min of graft reperfusion. Post-transplant serum C-peptide also correlated significantly with pancreatic capillary perfusion. OPS imaging allows to intra-operatively assess physiologic pancreatic microcirculation and to determine microcirculatory impairment during early graft reperfusion. This impairment correlated with the manifestation of post-transplant dysfunction of both exocrine and endocrine pancreatic tissue. OPS imaging may be used clinically to determine the efficacy of interventions, aiming at attenuating microcirculatory impairment during the acute post-transplant reperfusion phase.

Topics: Adult; C-Peptide; Female; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Pancreas; Pancreas Transplantation; Reperfusion Injury; Time Factors; Tissue Donors