Endocrine Abstracts

The enzyme 5β-reductase (AKR1D1) controls intra-cellular steroid hormone availability through hormone clearance. Additionally, it catalyses an essential step in bile acid (BA) synthesis. Disturbances in steroid hormones and BA metabolism have potent effects on metabolic health, therefore 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 stereological techniques, defined islet morphology in mice at 12 weeks of age (12 w) compared against wild-type (WT) controls. Pancreatic islets were isolated from male WT and KO mice at 30 w. Insulin and glucagon secretion were assessed in static incubations. At 12 w, relative pancreas mass, islet volume and beta-cell mass were decreased in male KO mice compared to WT. Conversely, the alpha-cell fraction within male KO islets was increased. At 30 w, insulin secretion was increased in KO islets upon treatment with 1 mM glucose (% islet content: WT: 0.07±0.01, KO: 0.12±0.01), 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 levels (WT: 3.5-fold change, KO: 2.6-fold change, P=0.08). Additionally, KO islets failed to suppress glucagon release in the presence of 20 mM glucose. Indeed, we observed a paradoxical increase in glucagon secretion with increasing glucose concentration (1 mM glucose; pg/islet.hr: WT: 5.8±1.1, KO: 7.4±3.9. 20 mM glucose; WT: 4.0±0.7, KO: 8.7±3.0). Alterations in steroid hormone and BA exposure have been shown to modify 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. Further characterization is warranted to define the role of AKR1D1 and to determine whether it has potential as a therapeutic target in metabolic disease.