Endocrine Abstracts

Type 2 diabetes manifests when pancreatic β-cells secrete inadequate insulin in response to elevated glucose. A known culprit in metabolic diseases is excessive exposure to glucocorticoids (GCs). GCs increase hepatic gluconeogenesis, decrease insulin sensitivity in skeletal muscle and adipose tissue and suppress the development of β-cells. In rodents, inactive GC 11-dehydrocorticosterone (A) is converted to active corticosterone (B) by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), requiring NADPH as a cofactor. Hexose-6-phosphate dehydrogenase (H6PDH) is co-localised with 11βHSD1 in the lumen of the endoplasmic reticulum and controls local NADPH availability.

We have previously shown by immunohistochemistry that 11βHSD1 is localised to the glucagon-producing α-cell, and not the β-cell. However, whilst expression of protein is evident in these cells, our aim is to demonstrate functional activity. Furthermore, we hypothesise that 11βHSD1 activity may impact upon glucose-stimulated insulin secretion (GSIS) acting in a paracrine manner.

Isolated islets were incubated in dexamethasone, A or B over a range of concentrations for 16 h (n=8). GSIS was established by treating islets with GCs in media containing 3 or 20 mM glucose and measuring insulin release by ELISA. Dexamethasone induced a dose dependent decrease on GSIS compared to control islets (5 pM: 49.5% of control – 500 nM: 15.5%, P<0.02). Both inactive A and active B inhibited GSIS (A: 38.1% of control, P<0.04; B: 34.5%, P<0.04). Specific 11βHSD1 inhibition reversed the effect of A (87.1% of control GSIS) but had no effect on B treatment (38.7%, P<0.04). To further verify the role of 11βHSD1 in inhibition of GSIS, treatments were repeated with islets from H6PDH-null mice, which lack oxo-reductase activity of 11βHSD1. While B inhibited GSIS (46.3% of control), A had no effect (100%).

These findings confirm the presence of active 11βHSD1 in pancreatic islets. We propose that local regeneration of GC within α-cells may have a paracrine effect on insulin secretion from β-cells. In addition, prevention of this activation with a selective inhibitor could lead to therapeutic advances in the control of type 2 diabetes.