Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes

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• 作者：Jette Bork-Jensen (1) (2)
  Camilla Scheele (3)
  Daniel V. Christophersen (1) (4)
  Emma Nilsson (1)
  Martin Friedrichsen (1) (2) (5)
  Denise S. Fernandez-Twinn (6)
  Louise G. Grunnet (2)
  Thomas Litman (7)
  Kim Holmstr酶m (8)
  Birgitte Vind (9)
  Kurt H酶jlund (9)
  Henning Beck-Nielsen (9)
  J酶rgen Wojtaszewski (5)
  Susan E. Ozanne (6)
  Bente K. Pedersen (3)
  Pernille Poulsen (1) (4)
  Allan Vaag (1) (2)
  
  1. Steno Diabetes Center ; Gentofte ; Denmark
  2. Department of Endocrinology (Diabetes and Metabolism) ; Rigshospitalet ; sec. 7652 ; Tagensvej 20 ; DK-2200 ; Copenhagen N ; Denmark
  3. Centre of Inflammation and Metabolism ; Faculty of Health Sciences ; University of Copenhagen ; Copenhagen ; Denmark
  4. Novo Nordisk ; Bagsv忙rd ; Denmark
  5. Department of Exercise and Sport Sciences ; University of Copenhagen ; Copenhagen ; Denmark
  6. University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit ; Wellcome Trust-Institute of Metabolic Science ; Addenbrooke鈥檚 Treatment Centre ; Addenbrooke鈥檚 Hospital ; Cambridge ; UK
  7. Molecular Biomedicine ; LEO Pharma ; Ballerup ; Denmark
  8. Bioneer ; H酶rsholm ; Denmark
  9. Odense University Hospital ; Odense ; Denmark
  
• 关键词：Insulin signalling ; Low birthweight ; MicroRNA ; miR ; 15b ; miR ; 16 ; Muscle ; Twins ; Type 2 diabetes
• 刊名：Diabetologia
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：58
• 期：2
• 页码：363-373
• 全文大小：348 KB
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• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Internal Medicine
  Metabolic Diseases
  Human Physiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0428

文摘

Aims/hypothesis We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. Methods We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes using arrays. Further investigations of selected miRNAs included target prediction, pathway analysis, silencing in cells and association analyses in a separate cohort of 164 non-diabetic MZ and dizygotic twins. The effects of elevated glucose and insulin levels on miRNA expression were examined, and the effect of low birthweight (LBW) was studied in rats. Results We identified 20 miRNAs that were downregulated in MZ twins with diabetes compared with their non-diabetic co-twins. Differences for members of the miR-15 family (miR-15b and miR-16) were the most statistically significant, and these miRNAs were predicted to influence insulin signalling. Indeed, miR-15b and miR-16 levels were associated with levels of key insulin signalling proteins, miR-15b was associated with the insulin receptor in non-diabetic twins and knockdown of miR-15b/miR-16 in myocytes changed the levels of insulin signalling proteins. LBW in twins and undernutrition during pregnancy in rats were, in contrast to overt type 2 diabetes, associated with increased expression of miR-15b and/or miR-16. Elevated glucose and insulin suppressed miR-16 expression in vitro. Conclusions Type 2 diabetes is associated with non-genetic downregulation of several miRNAs in skeletal muscle including miR-15b and miR-16, potentially targeting insulin signalling. The paradoxical findings in twins with overt diabetes and twins at increased risk of the disease underscore the complexity of the regulation of muscle insulin signalling in glucose homeostasis.