scholarly journals The Heme Oxygenase System Abates Hyperglycemia in Zucker Diabetic Fatty Rats by Potentiating Insulin-Sensitizing Pathways

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2098-2108 ◽  
Author(s):  
Joseph Fomusi Ndisang ◽  
Nina lane ◽  
Ashok Jadhav
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Protein Kinase ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Antidiabetic Effect ◽  
Insulin Resistant ◽  
Aldolase B ◽  
Amp Activated Protein Kinase

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-κB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-κB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphastase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.

scholarly journals Up-Regulating the Hemeoxygenase System Enhances Insulin Sensitivity and Improves Glucose Metabolism in Insulin-Resistant Diabetes in Goto-Kakizaki Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2627-2636 ◽  
Author(s):  
Joseph Fomusi Ndisang ◽  
Ashok Jadhav
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Gastrocnemius Muscle ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Antidiabetic Effect ◽  
Insulin Resistant

Insulin-mediated signal transduction is positively correlated to adiponectin, adenosine monophosphate-activated protein kinase (AMPK), and glucose-transporter-4 (GLUT4) but negatively to oxidative/inflammatory mediators such as nuclear factor-κB, activating-protein (AP)-1, AP-2, and c-Jun-N-terminal-kinase. Although hemeoxygenase (HO) suppresses oxidative insults, its effects on insulin-sensitizing agents like AMPK and GLUT4 remains unclear and were investigated using Goto-Kakizaki rats (GK), a nonobese insulin-resistant type-2 diabetic model. HO was induced with hemin or inhibited with chromium mesoporphyrin (CrMP). The application of hemin to GK rats evoked a 3-month antidiabetic effect, whereas the HO-inhibitor, CrMP, exacerbated hyperglycemia and nullified insulin-signaling/glucose metabolism. Interestingly, the antidiabetic was accompanied by a paradoxical increase of insulin alongside the potentiation of insulin-sensitizing agents such as adiponectin, AMPK, and GLUT4 in the gastrocnemius muscle. Furthermore, hemin enhanced mediators/regulators of insulin signaling like cGMP and cAMP and suppressed oxidative insults by up-regulating HO-1, HO activity, superoxide dismutase, catalase, and the total antioxidant capacity in the gastrocnemius muscle. Accordingly, oxidative markers/mediators including nuclear factor-κB, AP-1, AP-2, c-Jun-N-terminal-kinase, and 8-isoprostane were abated, whereas CrMP annulled the cytoprotective and antidiabetic effects of hemin. Correspondingly, ip glucose tolerance, insulin tolerance, and homeostasis model assessment insulin resistance analyses revealed improved glucose tolerance, reduced insulin intolerance, enhanced insulin sensitivity, and reduced insulin resistance in hemin-treated GK rats. In contrast, CrMP, abolished the insulin-sensitizing effects and restored and/or exacerbated insulin resistance. Our study unveils a 3-month enduring antidiabetic effect of hemin and unmasks the synergistic interaction among the HO system, adiponectin, AMPK, and GLUT4 that could be explored to enhance insulin signaling and improve glucose metabolism in insulin-resistant diabetes.

Effect of genipin-1-β-d-gentiobioside on diabetic nephropathy in mice by activating AMP-activated protein kinase/silencing information regulator-related enzyme 1/ nuclear factor-κB pathway

2021 ◽  
Author(s):  
Fengtao Li ◽  
Lijun Song ◽  
Jing Chen ◽  
Yu Chen ◽  
Yongjun Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
Nuclear Factor Κb ◽  
Kidney Damage ◽  
Nuclear Factor ◽  
Related Enzyme ◽  
Amp Activated Protein Kinase ◽  
Related Proteins

Abstract Objectives Genipin-1-β-d-gentiobioside (GG) is a kind of compound extracted from Gardenia jasminoides Ellis. The chemical structure of GG is similar to that of geniposide and has antidiabetic effects. We aimed to investigate the efficacy of GG on diabetic nephropathy (DN) in vivo and in vitro experiments and explore its potential mechanism. Methods For high-fat diet/streptozotocin-induced DN mice used in our study, the general features of mice were analysed after GG treatment. Oxidative stress parameters and inflammatory factors were also measured by commercial kits. Kidney damage was assessed using hematoxylin and eosin (H&E), periodic acid-Schiff (PAS) and Masson staining, respectively. In vitro, podocyte injury was assessed by TUNEL and flow cytometric analyses. AMP-activated protein kinase/silencing information regulator related enzyme 1 (AMPK/SIRT1)/nuclear factor-κB (NF-κB) pathway-related proteins were detected by AMPK-siRNA intervention and western blotting. Key findings Treatment of GG could increase cell survival and attenuated kidney damage. Despite the presence of inflammatory and oxidative stress, when GG retained the expression of AMPK/SIRT1, it could be observed that the downstream NLRP3 inflammatory-related proteins were inhibited. Conclusions Results showed that the protective efficacy of GG on DN works together with hypoglycemia and suppressing oxidative stress and inflammation, which at least partly involved in APMK/SIRT1/NF-κB-dependent pathway.

Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase

2011 ◽  
Vol 435 (2) ◽  
pp. 463-474 ◽  
Author(s):  
Charlotte J. Green ◽  
Katherine Macrae ◽  
Sarah Fogarty ◽  
D. Grahame Hardie ◽  
Kei Sakamoto ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Transport ◽  
P38 Mapk ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Amp Activated Protein Kinase ◽  
Inflammatory Signalling

Sustained over-supply of saturated non-esterified ‘free’ fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-κB signalling axis and that AMPK can restrain the activity of this pro-inflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

scholarly journals PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

2015 ◽  
Vol 29 (4) ◽  
pp. 528-541 ◽  
Author(s):  
Jiali Liu ◽  
Huixia Li ◽  
Bo Zhou ◽  
Lin Xu ◽  
Xiaomin Kang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Hepatic Insulin Resistance ◽  
Causative Role ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

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