Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

• Published in: Diabetologia Vol. 49; no. 3; pp. 588 - 597
• Main Authors: Bryzgalova, G, Gao, H, Ahren, B, Zierath, J.R, Galuska, D, Steiler, T.L, Dahlman-Wright, K, Nilsson, S, Gustafsson, J.-Å, Efendic, S, Khan, A
• Format: Journal Article
• Language: English
• Published: Berlin Berlin/Heidelberg : Springer-Verlag 01-03-2006; Springer
• Subjects: Adiponectin - blood; Animals; Biological and medical sciences; Clinical Medicine; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Estrogen Receptor alpha - deficiency; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene Expression Profiling; Glucose - metabolism; Glucose homeostasis; Homeostasis; In Vitro Techniques; Insulin - metabolism; insulin resistance; Insulin Secretion; Islets of Langerhans - metabolism; Klinisk medicin; leptin; Leptin - blood; Leptin receptor; Liver - metabolism; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - metabolism; receptor; Resistin - blood; Sensitivity and Specificity; Stearoyl-CoA desaturase 1; Endocrinopathy; Pancreatic hormone; Digestive system; Glucose homeostasis; Diabetes mellitus; Liver; Rodentia; Estrogen; Homeostasis; Glucose; Insulin; Ovarian hormone; Oestrogen receptors; Vertebrata; Sensitivity; Mammalia; Mouse; Leptin receptor; Animal; Insulin resistance; Stearoyl-CoA desaturase 1; Sex steroid hormone; Biological receptor
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-005-0105-3

Aims/hypothesis We used oestrogen receptor-α (ERα) knockout (ERKO) and receptor-β (ERβ) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. Methods Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. Results ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemic-hyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. Conclusions/interpretation We conclude that oestrogens, acting via ERα, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.