Inactivation of the Glucocorticoid Receptor in Hepatocytes Leads to Fasting Hypoglycemia and Ameliorates Hyperglycemia in Streptozotocin-Induced Diabetes Mellitus

Abstract

Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia.

A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis

“…Therefore, serum levels of insulin were assessed. In line with the findings by Opherk et al (17), DEX treatment was indeed associated with a profound increase in serum insulin levels compared with PBS (Fig. 6), whereas the blood glucose levels in DBA-1 mice were hardly affected (data not shown).…”

“…However, in certain strains of mice, detecting a clear effect of GC on the regulation of blood glucose levels has not been trivial because of the compensatory actions of insulin. In fact, the blood serum insulin level was found to be a more reliable indicator of GR effects on glucose metabolism (17). Therefore, serum levels of insulin were assessed.…”

“…GC induce the transcriptional up-regulation of two rate-limiting enzymes involved in the gluconeogenesis, glucose-6-phosphatase (G6P), and phospho-enol pyruvate carboxykinase (PEPCK). By this specific pathway, the de novo synthesis of glucose is augmented (16,17). This increase in the glucose concentration results, via the ATP ϩ -sensitive K ϩ channel in the pancreatic ␤ cell, in an immediate secretion of insulin (18,19), which compensates the hyperglycemic state.…”

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

“…Pharmacological evidence further validates that selective inactivation of GR improves insulin resistance and obesity in these diabetic animals and patients with Cushing's syndrome (Okada et al 1992, Sartor & Cutler 1996, Watts et al 2005. Moreover, specific inactivation of hepatic GR reduces elevated glucose output and reduces hyperglycemia and insulin resistance in diabetic models (Opherk et al 2004). These findings substantiate the importance of GR in the pathogenesis of insulin resistance and obesity, thereby implicating GR as a potential target for the treatment of type 2 diabetes and obesity.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…These findings show the essential role of the glucocorticoid receptor in glucose metabolism in the liver, and offer new treatment approaches for diabetic hyperglycemia with glucocorticoid receptor antagonists. 65 Figure 2 Corticotropin cells from rat pituitary stained with an antibody against ACTH (a, b). During stress, CRH induces rapid marginalization of ACTH around cell membranes before release into the systemic circulation.…”