Endocrine Abstracts

The enzyme 5β-reductase (AKR1D1) catalyses an essential step in bile acid (BA) synthesis, but in addition, controls intra-cellular steroid hormone availability by inactivation. Steroid hormones and BA are regulators of global lipid and carbohydrate metabolism. As disturbances in steroid hormone and BA metabolism have potent effects on metabolic health, we hypothesize that AKR1D1 may play a role in metabolic homeostasis. The role of AKR1D1 in regulating glucose homeostasis and pancreatic function remains unexplored. We generated a global AKR1D1 knockout (KO) mouse and using immunohistochemical and stereological techniques, defined whole pancreas and islet morphology in mice at 12 weeks of age (12w) compared against wild-type (WT) controls. Additionally, pancreatic islets were isolated from male WT and KO mice at 30w. Insulin and glucagon secretion were assessed in static incubations. At 12w, relative pancreas mass was decreased in AKR1D1 KO mice compared to WT controls, in both males (g/kg: WT: 12.7±1.3, KO: 7.5±1.0) and females (g/kg: WT: 9.2±0.7, KO: 6.3±0.2, P<0.05). Pancreatic islet volume and relative beta-cell mass were decreased in male KO mice only. At 30w, insulin secretion was increased in isolated KO islets upon treatment with 1mM (basal) glucose (mean as % islet content: WT: 0.07±0.01, KO: 0.12±0.01, P<0.05), without any change in total islet insulin content. However, in response to 20 mM glucose, the increase in insulin secretion was lower in KO islets when expressed relative to basal (WT: 3.5-fold change, KO: 2.6-fold change, P=0.08). Compared to WT controls, the KO islets failed to suppress glucagon release in the presence of 20 mM glucose (mean as % change in glucagon secretion: WT: −29±20, KO: 61±14). Indeed, we observed a paradoxical increase in glucagon secretion with increasing glucose concentration (1 mM glucose; WT: 5.8±1.1, KO: 7.4±3.9 pg/islet per hour. 20 mM glucose; WT: 4.0±0.7, KO: 8.7±3.0 pg/islet per hour). Whilst endogenous expression of AKR1D1 in the murine pancreatic islet is very low, alterations in steroid hormone and BA exposure modifies pancreatic islet cell function. AKR1D1 KO male mice have a dysregulation of insulin and glucagon secretion, which may have profound effects on normal glucose homeostasis. The mechanisms underpinning the changes observed remain to be determined. Further characterization is warranted to define the role of AKR1D1 and to determine whether it has potential as a therapeutic target in metabolic disease.