Regulation of Glucose Homeostasis by Glucocorticoids

Abstract

Glucocorticoids are steroid hormones that regulate multiple aspects of glucose homeostasis. Glucocorticoids promote gluconeogenesis in liver, whereas in skeletal muscle and white adipose tissue they decrease glucose uptake and utilization by antagonizing insulin response. Therefore, excess glucocorticoid exposure causes hyperglycemia and insulin resistance. Glucocorticoids also regulate glycogen metabolism. In liver, glucocorticoids increase glycogen storage, whereas in skeletal muscle they play a permissive role for catecholamine-induced glycogenolysis and/or inhibit insulin-stimulated glycogen synthesis. Moreover, glucocorticoids modulate the function of pancreatic α and β cells to regulate the secretion of glucagon and insulin, two hormones that play a pivotal role in the regulation of blood glucose levels. Overall, the major glucocorticoid effect on glucose homeostasis is to preserve plasma glucose for brain during stress, as transiently raising blood glucose is important to promote maximal brain function. In this chapter we will discuss the current understanding of the mechanisms underlying different aspects of glucocorticoid-regulated mammalian glucose homeostasis.

Fig. 5.1

Glucocorticoid effects on glucose homeostasis. The effects of cortisol on glucose homeo-stasis in peripheral tissues

Fig. 5.2

Gluconeogenic pathway in hepatocytes. Lactate and alanine are converted to pyruvate, which enters the mitochondria and is then converted to OAA by enzyme PC. Through malate-aspartate shuttle, OAA exits the mitochondria to form PEP. OAA can also be converted to PEP directly within the mitochondria. PEP then feeds into the gluconeogenic pathway. In addition, glycerol is metabolized to DHAP, which is then converted directly or indirectly through G3P to F1,6BP. The final product, glucose, is produced in the ER by enzyme G6PC. The key enzymes are boxed, with GR primary targets shown in yellow. Abbreviation: OAA oxaloacetate, PEP phospho-enolpyruvate, DHAP dihydroxyacetone phosphate, G3P glyceraldehyde-3-phosphate, F1,6BP fructose-1,6-bisphosphate, 2-PG 2-phosphoglycerate, 3-PG 3-phosphoglycerate, 1,3-BPG 1,3-bisphosphoglycerate, G3P glyceraldehyde-3-phosphate, F1,6BP fructose-1,6-bisphosphate, F2,6BP fructose-2,6-bisphosphate, F6P fructose-6-phosphate, and G6P glucose-6-phosphate. Enzyme abbreviation: PC pyruvate carboxylase, m-PCK1 mitochondrial phosphoenolpyruvate carboxykinase, PCK1 cytosolic phosphoenolpyruvate carboxykinase, FBP1 fructose-1,6-bisphosphatase 1, PFK1 phosphofructokinase 1, PFKFB1 phosphofructokinase 2/fructose bispho-sphatase 2, G6PC glucose-6-phosphatase catalytic subunit

Fig. 5.3

Hormone response units in the PEPCK gene. Binding sites for various regulatory and transcription factors are shown in the top row, with the number indicating the center nucleotide position of each element with respect to the transcription start site. Four hormone-specific response units are drawn: proximal glucocorticoid response unit (GRU), cyclic AMP response unit (CRU), retinoic acid response unite (RARU), and insulin response unit (IRU). In the absence of the other hormones, the components of each response unit are depicted. These units interact functionally, cooperating or competing, to comprise the PEPCK promoter. Except for gAF2, DNA elements involved in IRU are not yet identified

Fig. 5.4

Models of glucocorticoid-regulated insulin action. Mechanisms of glucocorticoid-induced insulin resistance are depicted. In myotubes, glucocorticoids (GC) decrease the tyrosine phosphorylation of insulin receptor (IR) and the expression of IRS1. They increase the serine 307 phosphorylation while decrease the tyrosine 608 phosphorylation of IRS1. GC also increase the expression of Pik3r1, which results in decreased activity of Akt and p70 S6 kinase (S6K). In the liver, GC increase the gene expression of enzymes involved in ceramide synthesis, including Sptlc2, Cers1 and Cers6, which results in increased levels of ceramides. These ceramides then interfere with insulin signaling. The GC-regulated genes are shown in yellow