AIMS/HYPOTHESIS: One of the major processes by which insulin exerts its multiple biological actions is through gene expression regulation. Thus, the identification of transcription factors affected by insulin in target tissues represents an important challenge. The aim of the present study was to gain a greater insight into this issue through the identification of transcription factor genes with insulin-regulated expression in human skeletal muscle. METHODS: Using microarray analysis, we defined the sets of genes modulated during a 3 h hyperinsulinaemic-euglycaemic clamp (2 mU min(-1) kg(-1)) in the skeletal muscle of insulin-sensitive control volunteers and in moderately obese insulin-resistant type 2 diabetic patients. RESULTS: Of the 1,529 and 1,499 genes regulated during the clamp in control and diabetic volunteers, respectively, we identified 30 transcription factors with impaired insulin-regulation in type 2 diabetic patients. Analysis of the promoters of the genes encoding these factors revealed a possible contribution of the transcriptional repressor basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2), insulin regulation of which is strongly altered in the muscle of diabetic patients. Gene ontology analysis of BHLHB2 target genes, identified after BHLHB2 overexpression in human primary myotubes, demonstrated that about 10% of the genes regulated in vivo during hyperinsulinaemia are potentially under the control of this repressor. The data also suggested that BHLHB2 is situated at the crossroads of a complex transcriptional network that is able to modulate major metabolic and biological pathways in skeletal muscle, including the regulation of a cluster of genes involved in muscle development and contraction. CONCLUSIONS/ INTERPRETATION: We have identified BHLHB2 as a potential novel mediator of insulin transcriptional action in human skeletal muscle.
AIMS/HYPOTHESIS: One of the major processes by which insulin exerts its multiple biological actions is through gene expression regulation. Thus, the identification of transcription factors affected by insulin in target tissues represents an important challenge. The aim of the present study was to gain a greater insight into this issue through the identification of transcription factor genes with insulin-regulated expression in human skeletal muscle. METHODS: Using microarray analysis, we defined the sets of genes modulated during a 3 h hyperinsulinaemic-euglycaemic clamp (2 mU min(-1) kg(-1)) in the skeletal muscle of insulin-sensitive control volunteers and in moderately obese insulin-resistant type 2 diabeticpatients. RESULTS: Of the 1,529 and 1,499 genes regulated during the clamp in control and diabetic volunteers, respectively, we identified 30 transcription factors with impaired insulin-regulation in type 2 diabeticpatients. Analysis of the promoters of the genes encoding these factors revealed a possible contribution of the transcriptional repressor basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2), insulin regulation of which is strongly altered in the muscle of diabeticpatients. Gene ontology analysis of BHLHB2 target genes, identified after BHLHB2 overexpression in human primary myotubes, demonstrated that about 10% of the genes regulated in vivo during hyperinsulinaemia are potentially under the control of this repressor. The data also suggested that BHLHB2 is situated at the crossroads of a complex transcriptional network that is able to modulate major metabolic and biological pathways in skeletal muscle, including the regulation of a cluster of genes involved in muscle development and contraction. CONCLUSIONS/ INTERPRETATION: We have identified BHLHB2 as a potential novel mediator of insulin transcriptional action in human skeletal muscle.
Authors: F Andreelli; M Laville; P H Ducluzeau; N Vega; P Vallier; Y Khalfallah; J P Riou; H Vidal Journal: Diabetologia Date: 1999-03 Impact factor: 10.122
Authors: Dawn K Coletta; Bogdan Balas; Alberto O Chavez; Muhammad Baig; Muhammad Abdul-Ghani; Sangeeta R Kashyap; Franco Folli; Devjit Tripathy; Lawrence J Mandarino; John E Cornell; Ralph A Defronzo; Christopher P Jenkinson Journal: Am J Physiol Endocrinol Metab Date: 2008-03-11 Impact factor: 4.310
Authors: Aldi T Kraja; Heather A Lawson; Donna K Arnett; Ingrid B Borecki; Ulrich Broeckel; Lisa de las Fuentes; Steven C Hunt; Michael A Province; James Cheverud; D C Rao Journal: Metabolism Date: 2012-03-03 Impact factor: 8.694
Authors: Enda M Byrne; Tõnu Esko; Michael A Nalls; Marilyn C Cornelis; Andrea Ganna; Nina Paynter; Keri L Monda; Najaf Amin; Krista Fischer; Frida Renstrom; Julius S Ngwa; Ville Huikari; Alana Cavadino; Ilja M Nolte; Alexander Teumer; Kai Yu; Pedro Marques-Vidal; Rajesh Rawal; Ani Manichaikul; Mary K Wojczynski; Jacqueline M Vink; Jing Hua Zhao; George Burlutsky; Jari Lahti; Vera Mikkilä; Rozenn N Lemaitre; Joel Eriksson; Solomon K Musani; Toshiko Tanaka; Frank Geller; Jian'an Luan; Jennie Hui; Reedik Mägi; Maria Dimitriou; Melissa E Garcia; Weang-Kee Ho; Margaret J Wright; Lynda M Rose; Patrik Ke Magnusson; Nancy L Pedersen; David Couper; Ben A Oostra; Albert Hofman; Mohammad Arfan Ikram; Henning W Tiemeier; Andre G Uitterlinden; Frank Ja van Rooij; Inês Barroso; Ingegerd Johansson; Luting Xue; Marika Kaakinen; Lili Milani; Chris Power; Harold Snieder; Ronald P Stolk; Sebastian E Baumeister; Reiner Biffar; Fangyi Gu; François Bastardot; Zoltán Kutalik; David R Jacobs; Nita G Forouhi; Evelin Mihailov; Lars Lind; Cecilia Lindgren; Karl Michaëlsson; Andrew Morris; Majken Jensen; Kay-Tee Khaw; Robert N Luben; Jie Jin Wang; Satu Männistö; Mia-Maria Perälä; Mika Kähönen; Terho Lehtimäki; Jorma Viikari; Dariush Mozaffarian; Kenneth Mukamal; Bruce M Psaty; Angela Döring; Andrew C Heath; Grant W Montgomery; Norbert Dahmen; Teresa Carithers; Katherine L Tucker; Luigi Ferrucci; Heather A Boyd; Mads Melbye; Jorien L Treur; Dan Mellström; Jouke Jan Hottenga; Inga Prokopenko; Anke Tönjes; Panos Deloukas; Stavroula Kanoni; Mattias Lorentzon; Denise K Houston; Yongmei Liu; John Danesh; Asif Rasheed; Marc A Mason; Alan B Zonderman; Lude Franke; Bruce S Kristal; Juha Karjalainen; Danielle R Reed; Harm-Jan Westra; Michele K Evans; Danish Saleheen; Tamara B Harris; George Dedoussis; Gary Curhan; Michael Stumvoll; John Beilby; Louis R Pasquale; Bjarke Feenstra; Stefania Bandinelli; Jose M Ordovas; Andrew T Chan; Ulrike Peters; Claes Ohlsson; Christian Gieger; Nicholas G Martin; Melanie Waldenberger; David S Siscovick; Olli Raitakari; Johan G Eriksson; Paul Mitchell; David J Hunter; Peter Kraft; Eric B Rimm; Dorret I Boomsma; Ingrid B Borecki; Ruth Jf Loos; Nicholas J Wareham; Peter Vollenweider; Neil Caporaso; Hans Jörgen Grabe; Marian L Neuhouser; Bruce Hr Wolffenbuttel; Frank B Hu; Elina Hyppönen; Marjo-Riitta Järvelin; L Adrienne Cupples; Paul W Franks; Paul M Ridker; Cornelia M van Duijn; Gerardo Heiss; Andres Metspalu; Kari E North; Erik Ingelsson; Jennifer A Nettleton; Rob M van Dam; Daniel I Chasman Journal: Mol Psychiatry Date: 2014-10-07 Impact factor: 15.992