The Role of the Liver in Glucocorticoid Induced Diabetes

Researchers have found a mechanism to explain how glucocorticoids, drugs used to treat inflammatory conditions such as asthma and arthritis, interact with the liver receptor protein peroxisome proliferator-activated receptor-alpha (PPAR-alpha) to cause serious side effects like diabetes and hypertension.

Investigators at Washington University School of Medicine (St. Louis, MO, USA; www.wustl.edu) used mice genetically engineered to lack both PPAR-alpha and LDLR (the receptor for low density lipoprotein) or only LDLR. These mice gave them the tools to study the effects of fatty acid metabolism on glucocorticoid activity.

In a study published July 6, 2003, in the online edition of Nature Medicine, the researchers report that mice lacking only LDLR had increased levels of insulin, fasting glucose, and leptin, all signs of diabetes. The animals also became less hypoglycemic when given insulin, suggesting that they were developing insulin resistance, the precursor to diabetes. Mice lacking both LDLR and PPAR-alpha showed no signs of diabetes. Treatment with the glucocorticoid dexamethasone increased blood pressure in mice that had PPAR-alpha but not LDLR. Treatment did not have an effect on blood pressure in mice lacking both PPAR-alpha and LDLR.

An adenovirus vector was used to replace PPAR-alpha in the liver of mice lacking both PPAR-alpha and LDLR. The animals developed the same symptoms of diabetes and hypertension when chronically treated with dexamethasone as mice with normal levels of PPAR-alpha throughout the body.

"The scientific community has not fully appreciated the potentially important role of the liver in these conditions,” said senior author Dr. Clay F. Semenkovich, professor of medicine and of cell biology and physiology at Washington University. "These results strongly suggest that the liver is the key to controlling blood pressure and glucose, and our preliminary evidence with human liver cells strongly suggests that the results in mice are relevant to human disease. We believe that diabetes, hypertension, and many other disorders of western civilization are related to metabolism of fatty acids, not just glucose metabolism. These results support that theory, because PPAR-alpha is activated by fatty acids and appears to be important in the development of these problems.”