Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes

Abstract

Aims/hypothesisMicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility.MethodsUsing microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto–Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (n = 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions.ResultsWe found 29 significantly differentiated microRNAs (padjusted < 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (padjusted = 0.0005) and miR-27a (padjusted = 0.006) were upregulated in adipose tissue; miR-195 (padjusted = 0.006) and miR-103 (padjusted = 0.04) were upregulated in liver; and miR-10b (padjusted = 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (p = 0.008), miR-27a (p = 0.02) and the previously reported miR-29a (p = 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes.ConclusionThe expression patterns of miR-222, miR-27a, miR-195, miR-103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto–Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1667-2) contains supplementary material, which is available to authorised users.

Application of microRNAs in diabetes mellitus

“…Huang et al (2009) showed at least a twofold decrease in miR-23a/b, miR-24, miR-126, miR-130a, miR-424, and miR-450 and at least a twofold increase in miR-307 and let-7f in the skeletal muscle of GK rats vs Wistar rats. Herrera et al (2010) found a significant decrease in miR-10b in the skeletal muscle of GK rats compared with Wistar Kyoto rats and Brown Norway rats. He et al (2007) found an increase in miR-29a/b/c in the skeletal muscle of GK rats compared with normal Wistar rats.…”

“…Insulin resistance indicates that the peripheral tissues fail to respond to the normal level of insulin, and manifests as an elevated glucose level with decreased insulin-mediated glucose uptake in the skeletal muscle and adipose tissue, and as an impaired suppression of glucose output in the liver (Peppa et al 2010). Herrera et al (2009Herrera et al ( , 2010 profiled a cluster of miRNAs in insulin target tissues in Goto-Kakizaki (GK) rats, a spontaneous rat model of T2D, and found upregulation of miR-222 and miR-27a in adipose tissue; upregulation of miR-125a, miR-195, and miR-103 in liver; and downregulation of miR-10b in muscle.…”

Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs

“…Additionally, metabolic disorders such as diabetes are associated with changes in the expression levels of the miR-200 family at peripheral tissues. Indeed, miR-200a is decreased in the kidney of non-obese diabetic apoE KO mice (Wang et al 2011) and in the liver of spontaneous diabetic non-obese GK rats (Herrera et al 2010). Interestingly, miR-200a is increased in liver of obese diabetic ob/ob mice (Li et al 2009) as well as in liver and pancreatic islets of obese diabetes-resistant B6-ob mice (Zhao et al 2009).…”

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

“…miR-278 mediates energy balance by regulating insulin responsiveness in Drosophila, and miR-278 mutants are insulin resistant [18]. Aberrant expression of miRNAs has been observed in the insulin-target tissues of rat and mouse models of type 2 diabetes [19][20][21]. In adipocytes, miR-320 induces insulin resistance by inhibiting the insulin-phosphoinositide 3-kinase (PI3K) signalling pathway [22].…”