title: G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance.
abstract: The glucose-6-phosphatase catalytic subunit 2 (G6PC2) gene encodes an islet-specific glucose-6-phosphatase catalytic subunit. G6PC2 forms a substrate cycle with glucokinase that determines the glucose sensitivity of insulin secretion. Consequently, deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin. Although chronic elevation of FBG is detrimental to health, glucocorticoids induce G6PC2 expression, suggesting that G6PC2 evolved to transiently modulate FBG under conditions of glucocorticoid-related stress. We show, using competition and mutagenesis experiments, that the synthetic glucocorticoid dexamethasone (Dex) induces G6PC2 promoter activity through a mechanism involving displacement of the islet-enriched transcription factor MafA by the glucocorticoid receptor. The induction of G6PC2 promoter activity by Dex is modulated by a single nucleotide polymorphism, previously linked to altered FBG in humans, that affects FOXA2 binding. A 5-day repeated injection paradigm was used to examine the chronic effect of Dex on FBG and glucose tolerance in wild-type (WT) and G6pc2 knockout mice. Acute Dex treatment only induces G6pc2 expression in 129SvEv but not C57BL/6J mice, but this chronic treatment induced G6pc2 expression in both. In 6-hour fasted C57BL/6J WT mice, Dex treatment lowered FBG and improved glucose tolerance, with G6pc2 deletion exacerbating the decrease in FBG and enhancing the improvement in glucose tolerance. In contrast, in 24-hour fasted C57BL/6J WT mice, Dex treatment raised FBG but still improved glucose tolerance, with G6pc2 deletion limiting the increase in FBG and enhancing the improvement in glucose tolerance. These observations demonstrate that G6pc2 modulates the complex effects of Dex on both FBG and glucose tolerance.
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Boortz
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Syring
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lee
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: James K
authors.initials: JK
authors.lastname: Oeser
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Jen-Chywan
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., J.K.O., O.P.M., R.M.O.) and Medicine (C.D.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Nutritional Sciences and Toxicology (R.A.L., J.-C.W.), University of California at Berkeley, Berkeley, California 94720.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology*; D005215:Fasting / Q000097:blood; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D051473:Maf Transcription Factors, Large; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse