Glucocorticoids and Diabetes

Abstract

Glucocorticoids (GCs), stress hormones produced by the adrenal gland, are involved in many pathways in physiology and metabolism including glucose homeostasis and inflammation. Excess GC signaling results in Cushing's syndrome and possibly metabolic syndrome. Diabetes, central adiposity, and hyperlipidemia are components of both syndromes. Here, we discuss the mechanisms of GC action, clinical syndromes of GC excess, modulation of glucose homeostasis by GCs, and future treatments for diabetes based on GC signaling.

Figure 1

Functions of Glucocorticoids in Peripheral Tissues to Regulate Glucose Homeostasis. Figure provided by Jen-Chywan Wang and adapted.

Figure 2

Gluconeogenic Pathway in Hepatocytes. Gluconeogenic precursors (lactate and alanine) are converted to pyruvate, which enters the mitochondria and is converted to oxaloacetate (OAA) by pyruvate carboxylase. Through the malate-aspartate shuttle, OAA exits the mitochondria to form phosphoenolpyruvate (PEP). OAA may also be converted to PEP directly within the mitochondria. PEP then feeds into the gluconeogenic pathway. In addition, glycerol is metabolized to dihydroxyacetone phosphate (DHAP), which is then converted to fructose-1,6-bisphosphate (F1,6BP). The final product, glucose, is produced in the ER by the glucose-6-phosphatase catalytic subunit (G6PC). The key enzymes are boxed, with GR primary targets shown in yellow. Abbreviations: OAA oxaloacetate, PEP phosphoenolpyruvate, 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, F6P fructose-6-phosphate, and G6P glucose- 6-phosphate. Enzyme abbreviations: PC pyruvate carboxylase, m-PCK1 mitochondrial phosphoenolpyruvate carboxykinase, PCK1 cytosolic phosphoenolpyruvate carboxykinase, FBP1 fructose-1,6- bisphosphatase 1, PFK1 phosphofructokinase 1, G6PC glucose-6-phosphatase catalytic subunit. Figure provided by Jen-Chywan Wang and adapted.