Background and purpose: Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)g agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARg are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARg activation in a non-genetic insulin-resistant animal model. Experimental approach: Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg·kg -1 ) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARg, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3b phosphorylation were assesed in rat liver. Key results: Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-a and markers of neutrophil infiltration. Diet-induced PPARg expression was unaffected by the pioglitazone treatment.
Conclusion and implications:Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.
OBJECTIVE-There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3 (GSK-3). Here, we investigate the role of GSK-3 inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes.
RESEARCH DESIGN AND METHODS-Ratswith streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2-12 IU/kg i.v.) or the selective GSK-3 inhibitor TDZD-8 (0.2-3 mg/kg i.v.) was administered during reperfusion.RESULTS-Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3 in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drugtreated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-B was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-␣; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression.CONCLUSIONS-Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3 contributes to the protective effect of insulin independently of any effects on blood glucose. Diabetes 58:235-242, 2009 E pidemiological studies have shown that diabetes is a leading risk factor for ischemic cerebrovascular diseases (1). Animal and human studies demonstrate that insulin reduces brain damage evoked by ischemia/reperfusion (I/R) injury (2,3). Glycemic control by insulin may be involved in this protective effect, but the molecular mechanisms underlying the protective effects of insulin are debated and still poorly understood (4). One important pharmacological effect of insulin is its ability to inhibit the activity of the glycogen synthase kinase (GSK)-3, a serine/threonine kinase that was originally identified for its key role in glucose metabolism (5). More recently, GSK-3 has emerged as a key regulatory switch in the modulation of neurodegeneration and inflammation (6,7). There are two mammalian isoforms of GSK-3: GSK-3␣ and GSK-3. GSK-3 is highly expressed in the central nervous system (8). Unlike most kinases, GSK-3 is constitutively active in cells and can be inactivated by phosphorylation at Ser9 (9). Binding of insulin to its receptor activates phosphatidylinositol 3-kinase, leading to the subsequent activation of protein kinase B/Akt, and the inactivation of GSK-3 by phosphorylation on the regulatory Ser-9. This contributes to the insulin-induce...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.