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

Abstract

Aims/hypothesisWe 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.MethodsWe 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.ResultsWe 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.ConclusionsType 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3434-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

microManaging glucose and lipid metabolism in skeletal muscle: Role of microRNAs

“…1). However, while miR-15b is upregulated in skeletal muscle from subjects with T2D as compared to healthy (unrelated) control subjects [12], mIR-15b was one of the most significantly down-regulated miRNA when comparing monozygotic twins discordant for T2D [13]. Whether this represents a genetic predisposition in the former case, and perhaps an adaptive response to ameliorate insulin resistance in the latter, remains to be determined.…”

“…A C C E P T E D M A N U S C R I P T [13]. Changes in miRNA could be adaptive or pathologic, however, the specific roles of most of the identified dysregulated miRNAs remain to be assessed.…”

Mitochondrial dynamics, quality control and miRNA regulation in skeletal muscle: implications for obesity and related metabolic disease

“…More specifically, the muscle-specific miRNA miR-133a was down-regulated in type 2 diabetic subjects and miR-133a expression displayed a tight relationship with fasting glucose level [42]. Furthermore, a recent study, revealed differential expression of miRNAs between monozygotic twins with T2DM and their non-diabetic co-twins [43], although it should be noted that 80 % of the non-diabetic co-twins were already characterized by impaired glucose tolerance [43]. Nonetheless, 20 miRNAs, including miR-15b, miR-16 and miR-106b, of the 571 studied were down-regulated, whereas no miRNAs were up-regulated in this cohort [43].…”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…A large study on 1368 (531 MZ and 837 DZ) twins demonstrated that a wide range of unfavorable alterations in the serum metabolome are associated with abdominal obesity, insulin resistance and low-grade inflammation, while twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability [24]. Other authors suggest additional non-genomic mechanisms in T2DM development as several miRNAs are downregulated in affected MZ twins compared to their non-diabetic co-twins, with the most statistically significant differences for members of the miR-15 family, which are associated with levels of key insulin signaling proteins [25]. Moreover, a large study on nondiabetic twins investigated baseline metabolic and anthropometric traits predicting incident diabetes and the genetic/environmental relationship between these traits and HB1Ac at follow-up.…”