Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

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   Figure 1

   Effects of GCs on peripheral tissues involved in the control of glucose homeostasis. Excess or prolonged GC treatment may disrupt glucose homeostasis by interfering with several metabolic-related tissues. In visceral adipose tissue, GCs elevate LPL activity, leading to fat accumulation at this fat site. Fat in the limbs appears to respond to GCs with increased HSL activity, resulting in increased lipid (FFA and glycerol) release, supplying substrates for hepatic TG synthesis and gluconeogenesis, and also in intramuscular fat accumulation. These steroids may also affect insulin signalling in adipose tissue. GCs impair insulin-stimulated glucose uptake in skeletal muscles and induce muscle wasting, which, in turn, provides gluconeogenesis substrates. In the liver, GCs have a negative effect on rate-limiting enzymes controlled by insulin. Finally, GC in excess may also alter osteocalcin synthesis in osteoblast cells, leading to reduced osteocalcinaemia. FFA, free fatty acids; GCs, glucocorticoids; G6Pase, glucose-6-phospatase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; PEPCK, phophoenolpyruvate carboxykinase; TG, triacylglycerol.
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   Figure 2

   Sites of the insulin secretory process affected by in vitro or in vivo (ex vivo) exposure to glucocorticoids (GCs). In (A), the known components involved in the acute or chronic in vitro effects of GCs on the β-cell insulin secretory process are highlighted with a positive signal (indicates GCs stimulate/increase that action/function) or a negative signal (indicates GCs inhibit/diminish that action/function). Most notably, GCs impair β-cell glucose metabolism, favour repolarising K_v ⁺ currents, decrease PKA and PKC activation, induce ER dyshomeostasis, increase 11β-HSD1 activity and ROS generation and impair calcium handling. Together, these effects inhibit insulin secretion. In (B), the known components involved in β-cell function, which are affected by acute or long-term in vivo GC treatment, are highlighted with a positive signal, which indicates increased content or activity. Most notably, augmented glucose metabolism and cholinergic pathway activity cause increased calcium influx and insulin secretion. In this context, a positive GC effect on K⁺ and VDCC could not be excluded. AC, adenylyl cyclase; Ach, acetylcholine; αAR, α adrenergic receptor; DAG, diacylglycerol; ER, endoplasmic reticulum; Gi, G-coupled inhibitory protein; GLUT2, glucose transporter 2; IP₃, inositol triphosphate; K⁺, ATP- dependent K⁺ channel; K_v ⁺, voltage-dependent K⁺ channel; M3R, muscarinic receptor type 3; PIP₂, phosphatidylinositol bisphosphate; PKA, protein kinase A; PLC, phospholipase C; ROS, reactive oxygen species; VDCC, voltage-dependent Ca^{2 +} channel; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1.
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   Figure 3

   Diabetogenic effects of GC treatment: implication of islet hormones. GC treatment can induce IR in peripheral tissues. As a compensatory adaptive process, the endocrine pancreas increases insulin release, leading to hyperinsulinaemia. An adequate compensatory response to the insulin requirements imposed by IR allows for normoglycaemia. However, an insufficient β-cell response could lead to impaired glucose tolerance, which can progress to overt hyperglycaemia and type 2 diabetes. GC treatment also induces high plasma levels of glucagon and amylin, and may affect somatostatin concentrations. Although somatostatin inhibits α- and β-cells, the potential changes in this hormone induced by GCs do not appear to produce a significant negative effect in these conditions. Hyperglucagonaemia increases hepatic glucose output, which exacerbates hyperglycaemia and glucose intolerance and further opposes insulin action, decreasing the insulin effect. High amylin levels have been related with increased predisposition to amyloid formation in decreased insulin sensitivity conditions, such as those generated by GCs. Amyloid aggregation is related with increased β-cell death and malfunction. The molecular mechanisms underlying the high plasma levels of glucagon and amylin induced by GC treatment are still unknown.

• © 2014 Society for Endocrinology