Effect of Hyperglycemia and Hyperlipidemia on the Expression of 11β-Hydroxysteroid-Dehydrogenase and Glucocorticoid Receptor in Insulin Sensitive Tissues
Type 2 diabetes mellitus is characterized by inadequate insulin secretion and impaired insulin action. Once diabetes mellitus is established, hyperglycemia and hyperlipidemia further impair β-cell function and insulin sensitivity. Increasing evidence in humans and experimental animals suggests that altered tissue cortisol metabolism may additionally promote insulin resistance. Of key importance for the tissue cortisol metabolism is the pre-receptor enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) with its two isoforms (11β-HSD1 and 11β-HSD2). 11β-HSD1 converts the inactive cortisone to cortisol and 11β-HSD2 converts cortisol to cortisone.
The aim of this study was to determine if exposure of cats to high glucose and lipid levels has an influence on the expression of 11β-HSD1, 11β-HSD2 and glucocorticoid receptor (GR) and by this mean on the tissue cortisol metabolism. Eleven cats were infused for 10 days through the jugular vein with glucose (n=5) or lipids (n=6) to clamp their blood concentrations at the level found in untreated feline diabetes (450-540 mg/dl for glucose and 265-620 mg/dl for triglycerides). Ten control cats were infused with saline (n=5) or received no infusion (n=5). At the end of the 10 day period blood samples to measure cortisol and tissue biopsies from omental and subcutaneous adipose tissue, liver and muscle to measure mRNA expression for 11β-HSD1, 11β-HSD2 and GR by real-time PCR were collected.
Lipid infused cats showed significantly higher 11β-HSD1 mRNA expression in omental and subcutaneous adipose tissue than all other cats, significantly lower 11β-HSD2 mRNA expression in omental adipose tissue than all other cats, significantly lower 11β-HSD2 mRNA expression in liver than control cats, significantly lower GR mRNA expression in omental adipose tissue than all other cats and significantly lower GR mRNA expression in subcutaneous adipose tissue than saline and glucose infused cats. Glucose infused cats showed significantly lower 11β-HSD2 mRNA expression in liver than control cats. Saline infused cats showed significantly higher GR mRNA expression in omental fat and significantly higher cortisol blood levels compared to untreated cats. In summary, two-week lipid infusion leads to higher 11β-HSD1 expression and lower GR expression in adipose tissue and lower 11β-HSD2 expression in omental adipose tissue and liver.
Up-regulation of 11β-HSD1 and down-regulation of 11β-HSD2 is expected to result in increased tissue cortisol concentrations. Down-regulation of GR possibly represents a self-protective mechanism of the tissue against increased tissue cortisol levels. In conclusion, these results indicate that hyperlipidemia has a profound effect on the 11β-HSD expression and support the connection between hyperlipidemia, tissue cortisol metabolism and insulin sensitivity.