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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/E1029    most recent 90241.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Ndisang, J. F. Articles by Jadhav, A. Search for Related Content PubMed PubMed Citation Articles by Ndisang, J. F. Articles by Jadhav, A.

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Submitted 18 February 2008 ; accepted in final form 9 February 2009

In type 2 diabetes (T2D), postprandial and fasting hyperglycemia are important predictors of cardiovascular diseases; however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring antidiabetic effect of the heme oxygenase (HO) inducer hemin on Goto-Kakizaki rats (GK), a nonobese insulin-resistant T2D model. HO breaks down the heme-moiety-generating antioxidants (biliverdin/bilirubin and ferritin) and carbon monoxide, which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO activity and the HO-derived products. Chronically applied hemin (30 mg/kg ip) for a month reduced and maintained fasting glucose at physiological levels for 3 mo. Before therapy, glucose levels were 9.3 ± 0.3 mmol/l (n = 14). At 1, 2, and 3 mo posttherapy, we recorded 6.7 ± 0.13, 5.9 ± 0.2, and 7.2 ± 0.2 mmol/l, respectively. Hemin was also effective against postprandial hyperglycemia (14.6 ± 1.1 vs. 7.5 ± 0.4 mmol/l; n = 14; P < 0.01), and the effect remained sustained for 3 mo after therapy. The reduction of hyperglycemia was accompanied by enhanced HO-1, HO activity, and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total antioxidant capacity, and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-B, and activator protein-1 and -2 were abated. Furthermore, inhibitors of insulin signaling including soleus muscle glycogen synthase kinase-3 and JNK were reduced, while the insulin-sensitizing adipokine, adiponectin, alongside AMPK were increased. Correspondingly, hemin improved glucose tolerance, suppressed insulin intolerance, reduced insulin resistance, and overturned the inability of insulin to enhance glucose transporter 4, a protein required for glucose uptake. Hemin also upregulated HO-1/HO activity and cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-mo-enduring antidiabetic effect. The synergistic interaction among HO, adiponectin, and GLUT4 may be explored against insulin-resistant diabetes.

adiponectin; insulin resistance; oxidative stress; glucose transporter 4; glycogen synthase kinase-3; nuclear factor-B; activating protein-1; c-Jun NH₂-terminal kinase