title: Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells.
abstract: Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic β-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on glucose-stimulated insulin secretion. miRNA levels in INS-1 cells and isolated rodent and human islets treated with GLP-1 in vitro and in vivo (with osmotic pumps) were measured by real-time quantitative PCR. The role of miRNAs on insulin secretion was studied by transfecting INS-1 cells with either precursors or antisense inhibitors of miRNAs. Among the 250 miRNAs surveyed, miR-132 and miR-212 were significantly up-regulated by GLP-1 by greater than 2-fold in INS-1 832/3 cells, which were subsequently reproduced in freshly isolated rat, mouse, and human islets, as well as the islets from GLP-1 infusion in vivo in mice. The inductions of miR-132 and miR-212 by GLP-1 were correlated with cAMP production and were blocked by the protein kinase A inhibitor H-89 but not affected by the exchange protein activated by cAMP activator 8-pCPT-2'-O-Me-cAMP-AM. GLP-1 failed to increase miR-132 or miR-212 expression levels in the 832/13 line of INS-1 cells, which lacks robust cAMP and insulin responses to GLP-1 treatment. Overexpression of miR-132 or miR-212 significantly enhanced glucose-stimulated insulin secretion in both 832/3 and 832/13 cells, and restored insulin responses to GLP-1 in INS-1 832/13 cells. GLP-1 increases the expression of miRNAs 132 and 212 via a cAMP/protein kinase A-dependent pathway in pancreatic β-cells. Overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion.
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Hohmeier
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Mary
authors.initials: M
authors.lastname: Rabaglia
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Mufaddal
authors.initials: M
authors.lastname: Soni
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Departments of Metabolic Disorders-Diabetes (J.S., Y.F., N.A.T., A.D.H., Y.-P.Z.) and Target Validation (J.L., H.H.Z.) and Laboratory of Animal Research (X.S.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Biochemistry (M.P.K., M.R., M.S., A.D.A.), University of Wisconsin, Madison, Wisconsin 53076; Sarah W. Stedman Nutrition and Metabolism Center (H.E.H., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Department of Surgery/Transplant (Y.W.), University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C555650:8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate acetoxymethyl ester; D007328:Insulin; D007546:Isoquinolines; C547077:MIRN132 microRNA, human; C546976:MIRN132 microRNA, mouse; C548821:MIRN132 microRNA, rat; C551411:MIRN212 microRNA, human; C554518:MIRN212 microRNA, mouse; C552427:MIRN212 microRNA, rat; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide