G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress.
The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Kayla A
KA
Boortz
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Kristen E
KE
Syring
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Chunhua
C
Dai
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Lynley D
LD
Pound
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
James K
JK
Oeser
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
David A
DA
Jacobson
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Jen-Chywan
JC
Wang
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Owen P
OP
McGuinness
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Alvin C
AC
Powers
Departments of Molecular Physiology and Biophysics (K.A.B., K.E.S., L.D.P., J.K.O., D.A.J., O.P.M., R.M.O.) and Medicine (C.D., A.C.P.), Vanderbilt University School of Medicine, and VA Tennessee Valley Healthcare System (A.C.P.), Nashville, Tennessee 37232-0615; and Department of Nutritional Sciences and Toxicology (J.-C.W.), University of California, Berkeley, Berkeley, California 94720-3104.
Richard M
RM
O'Brien
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005215:Fasting / Q000097:blood*; D005786:Gene Expression Regulation / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics
D001786:Blood Glucose; D003907:Dexamethasone; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse