Evidence That Oestrogen Receptor-alpha Plays an Important Role in the Regulation of Glucose Homeostasis in Mice: Insulin Sensitivity in the Liver

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2006 Feb 8

PMID 16463047

Citations 177

Authors

G Bryzgalova

H Gao

B Ahren

J R Zierath

D Galuska

T L Steiler

K Dahlman-Wright

S Nilsson

J-A Gustafsson

S Efendic

A Khan

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: We used oestrogen receptor-alpha (ERalpha) knockout (ERKO) and receptor-beta (ERbeta) 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 ERalpha, 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.

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References

Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S . Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002; 8(11):1288-95. DOI: 10.1038/nm788. View

Efendic S, Luft R, Wajngot A . Aspects of the pathogenesis of type 2 diabetes. Endocr Rev. 1984; 5(3):395-410. DOI: 10.1210/edrv-5-3-395. View

Mauvais-Jarvis F, Virkamaki A, Michael M, Winnay J, Zisman A, Kulkarni R . A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes. Diabetes. 2000; 49(12):2126-34. DOI: 10.2337/diabetes.49.12.2126. View

Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T . Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol. 2003; 176(2):237-46. DOI: 10.1677/joe.0.1760237. View

Ahren B, Mansson S, Gingerich R, Havel P . Regulation of plasma leptin in mice: influence of age, high-fat diet, and fasting. Am J Physiol. 1997; 273(1 Pt 2):R113-20. DOI: 10.1152/ajpregu.1997.273.1.R113. View

Khan A, Landau B . Glucose-6-phosphatase activity in islets from ob/ob and lean mice and the effect of dexamethasone. Endocrinology. 1995; 136(5):1934-8. DOI: 10.1210/endo.136.5.7720640. View

Ntambi J, Miyazaki M, Stoehr J, Lan H, Kendziorski C, Yandell B . Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A. 2002; 99(17):11482-6. PMC: 123282. DOI: 10.1073/pnas.132384699. View

Jump D . Fatty acid regulation of gene transcription. Crit Rev Clin Lab Sci. 2004; 41(1):41-78. DOI: 10.1080/10408360490278341. View

Herbert V, Lau K, Gottlieb C, Bleicher S . Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965; 25(10):1375-84. DOI: 10.1210/jcem-25-10-1375. View

10.

Pierroz D, Ziotopoulou M, Ungsunan L, Moschos S, Flier J, Mantzoros C . Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity. Diabetes. 2002; 51(5):1337-45. DOI: 10.2337/diabetes.51.5.1337. View

11.

Winzell M, Nogueiras R, Dieguez C, Ahren B . Dual action of adiponectin on insulin secretion in insulin-resistant mice. Biochem Biophys Res Commun. 2004; 321(1):154-60. DOI: 10.1016/j.bbrc.2004.06.130. View

12.

Yamada H, Gohyama N, Honda S, Hara T, Harada N, Oguri K . Estrogen-dependent regulation of the expression of hepatic Cyp2b and 3a isoforms: assessment using aromatase-deficient mice. Toxicol Appl Pharmacol. 2002; 180(1):1-10. DOI: 10.1006/taap.2002.9366. View

13.

Falls J, Blake B, Cao Y, Levi P, Hodgson E . Gender differences in hepatic expression of flavin-containing monooxygenase isoforms (FMO1, FMO3, and FMO5) in mice. J Biochem Toxicol. 1995; 10(3):171-7. DOI: 10.1002/jbt.2570100308. View

14.

Firth R, Bell P, Rizza R . Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism. 1987; 36(11):1091-5. DOI: 10.1016/0026-0495(87)90031-x. View

15.

Hansen P, Gulve E, Gao J, Schluter J, Mueckler M, HOLLOSZY J . Kinetics of 2-deoxyglucose transport in skeletal muscle: effects of insulin and contractions. Am J Physiol. 1995; 268(1 Pt 1):C30-5. DOI: 10.1152/ajpcell.1995.268.1.C30. View

16.

Couse J, Curtis S, Washburn T, Lindzey J, Golding T, Lubahn D . Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol. 1995; 9(11):1441-54. DOI: 10.1210/mend.9.11.8584021. View

17.

Ahlborg G, Wahren J, FELIG P . Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise. J Clin Invest. 1986; 77(3):690-9. PMC: 423452. DOI: 10.1172/JCI112363. View

18.

Bailey C . Role of ovarian hormones in the long-term control of glucose homeostasis. Effects of insulin secretion. Diabetologia. 1980; 19(5):475-81. DOI: 10.1007/BF00281829. View

19.

Cohen P, Miyazaki M, Socci N, Hagge-Greenberg A, Liedtke W, Soukas A . Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002; 297(5579):240-3. DOI: 10.1126/science.1071527. View

20.

Ntambi J . The regulation of stearoyl-CoA desaturase (SCD). Prog Lipid Res. 1995; 34(2):139-50. DOI: 10.1016/0163-7827(94)00010-j. View