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Deletion of the G Protein-Coupled Receptor 30 Impairs Glucose Tolerance, Reduces Bone Growth, Increases Blood Pressure, and Eliminates Estradiol-Stimulated Insulin Release in Female Mice

Units of Drug Target Discovery (U.E.A.M., J.D.-N., C.Ow., B.O., L.M.F.L.-L.), Vascular Physiology (M.F.G., K.S., P.H., B.-O.N.), and Circulation Physiology (P.-O.G.), Department of Experimental Medical Science, Lund University, SE-22184 Lund, Sweden; Division of Endocrinology and Diabetes (S.A.S., M.F.G., A.W., I.L.), Department of Clinical Sciences, Malmö, Lund University, SE-20502 Malmö, Sweden; Center for Bone Research at the Sahlgrenska Academy (S.W., N.A., C.Oh.), Department of Internal Medicine, Göteborg University, SE-41345 Göteborg, Sweden; The Jackson Laboratory (C.J.R.), Bar Harbor, Maine 04401; Department of Biochemistry (M.L.A.), The University of Texas Health Science Center, San Antonio, Texas 78229; and Oxford Centre for Diabetes Endocrinology and Metabolism (P.R.), University of Oxford, Churchill Hospital, Oxford OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: L. M. Fredrik Leeb-Lundberg, Department of Experimental Medical Science, Lund University, BMC, A12, SE-22184 Lund, Sweden. E-mail: fredrik.leeb-lundberg{at}med.lu.se.

In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30^(–/–) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.

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