Cortisol promotes endoplasmic glucose production via pyridine nucleotide redox

Abstract

Both increased adrenal and peripheral cortisol production, the latter governed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to the maintenance of fasting blood glucose. In the endoplasmic reticulum (ER), the pyridine nucleotide redox state (NADP/NADPH) is dictated by the concentration of glucose-6-phosphate (G6P) and the coordinated activities of two enzymes, hexose-6-phosphate dehydrogenase (H6PDH) and 11β-HSD1. However, luminal G6P may similarly serve as a substrate for hepatic glucose-6-phophatase (G6Pase). A tacit belief is that the G6P pool in the ER is equally accessible to both H6PDH and G6Pase. Based on our inhibition studies and kinetic analysis in isolated rat liver microsomes, these two aforesaid luminal enzymes do share the G6P pool in the ER, but not equally. Based on the kinetic modeling of G6P flux, the ER transporter for G6P (T 1 ) preferentially delivers this substrate to G6Pase; hence, the luminal enzymes do not share G6P equally. Moreover, cortisol, acting through 11β-HSD1, begets a more reduced pyridine redox ratio. By altering this luminal redox ratio, G6P flux through H6PDH is restrained, allowing more G6P for the competing enzyme G6Pase. And, at low G6P concentrations in the ER lumen, which occur during fasting, this acute cortisol-induced redox adjustment promotes glucose production. This reproducible cortisol-driven mechanism has been heretofore unrecognized. Microsomal cortisol and glucosez wang and others

Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells

“…Stress-induced hormones control a number of important biological processes, such as metabolic events, immune activity, and apoptosis. Cortisol, a key stress hormone, improves the hypoglycemic profile by promoting gluconeogenesis (31) and endoplasmic glucose production via pyridine nucleotide redox reactions (32). Similarly, another vital stress hormone, epinephrine, stimulates glycogenolysis by activating glycogen synthase and increasing insulin-stimulated glucose uptake (33).…”

Biological effects of cortisol

“…Cortisol mostly has a catabolic effect favoring liberation of energy stores, critical for adaptation to acute stress or illness. The maintenance of blood glucose homeostasis is among the central physiological functions regulated by glucocorticoids, and more specifically cortisol [23]. Cortisol and the other glucocorticoids influence all aspects of glucose metabolism by exerting their collective effects on the liver, endocrine pancreas, skeletal muscle, and adipose tissue [24].…”

“…Additionally, the activity of glucose-6-phosphatase (G6P) is increased, further impairing the entry of G6P into the glycolytic cycle [34]. Cortisol also increases glucagon secretion in α cells [23,24]. Once insulin resistance occurs, due to elevated levels of cortisol, glycogenesis is no longer stimulated and glucose storage by the liver as glycogen is thus inhibited; thereby contributing to the hyperglycaemic effects of cortisol [24].…”