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Cardiovascular complications in diabetic individuals or population account for significant morbidity and mortality. Data based on clinical as well as epidemiological studies have also confirmed the increased incidence and prevalence of cardiovascular complications in diabetes. Heart failure in diabetes in the absence of known cardiac complications such as myocardial infarction, coronary artery disease etc supports the existence Diabetic cardiomyopathy (DCM). Both myocytes hypertrophy and myocardial fibrosis are the established pathological features of the diabetic cardiomyopathy and are associated with differential expression genes involved in various signaling pathways regulation both these pathological feature of DCM. In molecular biology, Central dogma states that expression of protein coding genes can be regulated at various levels from transcription to translation. In the past, most studies have focused on protein coding genes and their regulation at the transcriptional level, information in account of post-transcription or translational gene expression regulation, is at nescent stage. Recent studies have opens the potential of tiny noncoding regulatory RNAs, known as microRNAs (miRNAs or miRs), in the transcriptional and post transcriptional regulation of gene expression. Further, microRNAs have been reported to regulate diverse aspects of cardiac function and also play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodeling. Present review summarizes various in-vivo as well as in-vitro studies validating microRNAs and their target genes leading to heart failure in diabetes.
The epidemic of diabetes in both developing and industrialized world is alarming and it has been estimated that by the year 2025, 300 million people will become affected by the disease22. Among the vast array of vascular complications associated with diabetes, cardiovascular complications significantly contribute to morbidity and mortality22, 23. Nearly 80% of the deaths associated with diabetes are reported to be due to cardiac complications5. The Framingham study demonstrated several fold increased incidence of congestive heart failure in diabetic males (2.4:1) and females (5:1), independent of age, hypertension, obesity, coronary artery disease (CAD) and hyperlipidaemia24. Other prospective studies also show that diabetic patients have a significantly increased lifetime risk of developing heart failure (HF) 25, 26. Although previous studies have focused on coronary artery disease (CAD) and autonomic neuropathy as the primary cardiac complication, over the last 30 years, diabetic cardiomyopathy has been identified as a significant entity27.
Accumulating data from experimental, pathological, epidemiological, and clinical studies have shown that diabetes mellitus results in functional and structural changes in the myocardium which are independent of hypertension, coronary artery disease, or any other known cardiac disease and support the existence of diabetic cardiomyopathy. Diabetic cardiomyopathy is characterized functionally by myocyte loss, myocardial fibrosis and left ventricular hypertrophy, leading to decreased elasticity and impaired contractile function. It is associated with diastolic or systolic dysfunction or a combination of both.
The pathophysiology of diabetic cardiomyopathy is incompletely understood, but appears to be initiated both by hyperglycemia and changes in cardiac metabolism. The pathogenesis of diabetic cardiomyopathy is multifactorial and several hypotheses have been proposed including metabolic derangements, abnormalities in ion homeostasis, alteration in structural proteins, oxidative stress, inflammation, endothelial dysfunction. Recent studies have revealed that dysregulated expression of several pathway specific genes may significantly contribute to these processes.
Gene expression is the process by which the DNA sequence of a gene is converted into the final product (i.e., proteins or, sometimes, RNA). Each cell of a multicellular organism contains the same set of genes, yet, each with a distinctive pattern of gene expression. Control of gene expression in eukaryotic cells is known to occur at several levels, including chromatin structure, transcriptional initiation, transcript processing, transcript stability, translational initiation, post-translational modification, and protein stability. However, the recent discovery of the existence of microRNAs (miRNAs) has introduced an additional mechanism of control of gene expression. Growing evidence indicates that miRNAs are involved in modulating gene expression of more than 50% of protein coding genes. Information from recent studies also indicates that microRNAs are involved in the regulation of cardiac development and pathophysiology.
Mature microRNAs are novel class of non-coding single-stranded gene regulatory RNAs of approximatly ~22 nucleotides. In mammals, the majority of microRNAs are located within introns of either protein-coding or noncoding host genes, while others, depending on the occurrence of alternative splicing, are present either in an exon or an intron 74. A significant number of microRNAs are also assembled in clusters in which two or three microRNAs are generated from a common parent mRNA. Each microRNA may regulate the expression of more than one target gene, making them one of the most abundant classes of regulators with a pattern of expression that is often perturbed in disease states 76-78. Cell and tissue-specific expression is an important feature of microRNA expression. A specific expression pattern can be imposed by host genes when microRNAs are located in their respective introns 74. Indeed, one microRNA may be dominantly expressed in some tissue, but may have no or low expression in other tissues 79.
MicroRNAs and Cardiovascular Diseases
The overall importance of miRNAs was shown by Da Costa Martins et al., who reported that conditional deletion of dicer (an enzyme that is central to miRNA metabolism) in the mouse myocardium resulted in cardiomyocyte hypertrophy and remarkable ventricular fibrosis. Subsequent articles have helped to clarify the roles of individual miRNAs in cardiac hypertrophy and cardiac fibrosis. Several recent studies have reported altered expression of microRNAs in heart failure including dilated cardiomyopathy, myocardial ischemia and ischemic Cardiomyopathy and have been reviewed recently. Dysregulated expression of microRNAs has been also observed in diabetes and associated vascular complications.
MicroRNAs and Diabetic Cardiomyopathy:
Myocardial fibrosis and Myocardial hypertrophy are established pathological feature of Diabetic cardiomyopathy with varied etiologies and significantly contributes to heart failure. Cardiac fibrosis is characterized by excessive accumulation of extra cellular matrix (ECM) proteins resulting in impaired ventricular function and predisposing the heart to arrhythmias. Diffused myocardial fibrosis, extensive necrosis and replacement of contractile myofibres by fibrotic tissue is commonly seen in DCM. Myocardial hypertrophy is functionally manifest as defective cardiac contractility and is characterized by an increase in cardiomyocyte size, protein synthesis and changes in the organization of sarcomeric structures. But the molecular mechanisms that lead to myocardial fibrosis and hypertrophy in diabetes are not well elucidated.
Recent studies have shown a central role for miRNAs in etiology of cardiac fibrosis as well as in myocardial hypertrophy. The first evidence for role of microRNAs in cardiac fibrosis came from the study by -da Costa et al (2008) who showed that deletion of Dicer, an enzyme involved in the biogenesis of miRNAS, in the mouse myocardium resulted in cardiomyocyte hypertrophy and extensive myocardial fibrosis ( ). A distinct and differential expression of miRNAs has been observed in cardiac remodeling in human and murine hearts (20-23). Several microRNAs have been found to be differentially expressed in cardiac fibrosis and hypertrophy following different insults such as pressure overload, ischemia, transverse aortic constriction (TAC), etc. Global myocardial microRNA expression profile in mouse models that were made hypertrophic by transverse aortic binding (TAB) or by transgenic calcineurin has been carried out using microRNAs microarrays; Olson identified 28 differentially expressed miRNAs common to TAC and calcineurin-mediated hypertrophy and found that many of these were also over-expressed in failing human hearts 13. Sayed et al. identified miR-1 as among the earliest microRNAs down regulated during development of pressure-overload cardiac hypertrophy 73. Functional significance of microRNAs in cardiac biology has been validated by gain and loss of function studies. The aim of this review is to describe the role of microRNAs in diabetic cardiomypathy, with reference to differential expression of microRNAs involved in diabetes/hyperglycemia induced myocardial fibrosis and myocardial hypertrophy. Specifically, we have looked at their role in regulating the expression of various genes known to be involved in the pathophysiology of DCM. We performed literature search with key words diabetic cardiomyopathy, hyperglycemia, cardiac fibrosis, cardiac hypertrophy, microRNAs, using various online search tool and found research on role of microRNAs in diabetic cardiomyopathy is at very nascent stage. In present review, we discussed few of these microns whose expression as well as function has been validated in diabetic and heart failure.
microRNA-1 (miR-1) is a muscle specific microRNA and is most abundantly expressed in heart (Ref). It is specifically expressed in cardiac precursor cells, and its gene is a direct transcriptional target of muscle differentiation regulators, including SRFs (serum-response factors), MyoD (myogenic differentiation factor D) and Mef2 (myocyte-enhancing factor). miR-1 has been mapped on chromosome 20 and has two sub family members, miR-1-1 and miR1-2. miR-206 is an another microRNA, which is paralogs to miR-1.
miR-1 has been proposed to play an important in the pathophysiology of cardiac hypertrophy, myocardial infarction, and arrhythmias. miR-1 is overexpressed in individuals with coronary artery disease, and its overexpression in normal or infarcted rat hearts, was shown to exacerbate arrhythmogenesis, whereas its inhibition by an microRNA inhibitor in infarcted rat hearts shows arrhythmogenesis (Nature Medicine 13, 486 - 491 (2007) ). It has been also shown to be upregulated in the myocardial archival tissue (FFPE) from patients with myocardial infarction. Yang et al (2007) reported that miR-1 modulated the expression of potassium channel components, Connexin 43 and Kir2.1 and thus could to affect cardiac electrophysiology in pathological and normal conditions. miR-1 along with its paralogs miR-206 has been shown to regulate myocyte apoptosis by modulating the expression of IGF-1, HSP60, HSP70 and Connexin 43, which are involved in myocyte apoptosis during myocardial ischemia.
Xi-Yong Yu reported increased miR-1 expression in rat cardiomyocytes (H9C2) exposed to high glucose. They observed that H9C2 cells exposed to high glucose (25 mM) for 72 hrs had 4 fold increased miR-1 expression and decrease in mitochondrial membrane potential (Δψ) with increase in cytochrome-c release, and increased apoptosis. Glucose induced mitochondrial dysfunction, cytochrome-c release and apoptosis was blocked by IGF-1. Using prediction algorithms, they identified 3'-untranslated regions of IGF-1 gene as the target of miR-1. They observed that miR-1 mimics prevent glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis, via IGF-1. They concluded that hyperglycemia-induced increased apoptosis of cardiomyocytes was mediated insulin-like growth factor (IGF-1) signaling pathway regulated by miR-1. Increased miR-1 expression has been also reported in ventricular samples from diabetic patients . Recently Shan et al, 2010, also showed that increased levels of miR-1 and miR-206 in the hearts of STZ induced diabetic Sprague Dawley rats, in neonatal ventricular cardiomyocytes and in H9c2 cells exposed to high glucose. They reported a time-dependent increased cardiomyocytes apoptosis in the diabetic myocardium in STZ-induced SD rats. Serum response factor (SRF) is transcriptional factor shown to regulate miR-1 expression during cardiogenesis. SRF has been found to be upregulated in cardiomyocytes exposed to high glucose and shown to modulate miR-1 and miR-206 expression (ref). MiR-1 and miR-206 share an identical seed sequence and bind to the same site in the 3'-UTR of Hsp60 mRNA and thereby could regulate Hsp60 expression and glucose-mediated apoptosis in diabetic myocardium, however, this needs experimental validation.
miR-1 is an important mediator of gene regulation during heart failure induced by various stress including high glucose. miR-1 regulate various genes involved in pathological feature of heart failure such as myocytes hypertrophy and apoptosis, cardiac fibrosis etc. But its therapeutic potential not yet been elucidated.
MicroRNA-21 was one of the first mammalian microRNAs identified and its mature sequence is strongly conserved throughout evolution. The human microRNA-21 gene as been mapped on forward/plus strand of chromosome 17q23.2 (55273409-55273480) within a coding gene TMEM49 (also called vacuole membrane protein).
Despite being located in intronic regions of a coding gene in the direction of transcription, miR-21has its own promoter regions and which transcribe ~3433-nt long primary transcript of miR-21 known as pri-miR-21. miR-21 is universally expressed in mammal organ systems such as the heart, the spleen, the small intestine and the colon and is recognized as oncomir.
Mir-21 is one of the highly differentially expressed microRNAs and has been implicated in various human diseases including cardiovascular diseases. It is expressed in vascular smooth muscle cell (VSMC) , endothelial cell , cardiomyocytes , and cardiac fibroblasts . miR -21 has been proposed to mediate cardiac hypertrophy and cardiac fibrosis under different forms of cardiac stress. For example, it was shown to be upregulated in cardiac fibroblasts after ischemic reperfusion injury (Roy et al.2004) and downregulated in infarcted areas in a mouse model of acute myocardial infarction. Thum et al.2008,recently showed thar miR-21 was upregulated selectively in fibroblasts of the pressure-overloaded heart, but not in cardiomyocytes.
Data from the various studies based on differential expression of microRNA showed mir-21 is the commonest microRNA found to be differentially expressed in the different rodent models of heart failure such as transverse aortic constriction (TAC), β-1-adrenergic receptor transgenic mice, isoproterenol and also in human patients of heart failure such as myocardial ischemia, idiopathic cardiomyopathy, dilated cardiomyopathy etc.
Preliminary work of our laboratory showed increased expression of mir-21 in streptozotocin induced Wistar rat model of Diabetic cardiomyopathy and also in cardiac fibroblasts exposed to hyperglycemia. We also found increased expression of mir-21 in formalin fixed paraffin embedded archival tissue of human patients of Diabetic cardiomyopathy.
But functional characterization of mir-21 and its role on cardiac hypertrophy and fibrosis is not well elucidated. There are few reports suggesting that mir-21 may regulate the genes involved in cardiac fibrosis. For example, over expression of mir-21 was shown to increase fibroblast survival resulting in fibrosis by down regulating SPRY1, a potent inhibitor of the Ras/MEK/ERK pathway (Ref). Inhibition of miR-21 was also reported to attenuate cardiac remodeling in response to stress, confirming its role in cardiac fibrosis (ref). miR-21 has been also shown to increase expression of matrix metalloprotease-2 (MMP-2) by down regulating PTEN expression in cardiac fibroblasts in response to Ischemia/Reperfusion in the mouse hearts, suggesting that mir-21 may contribute to the modulation of cardiac fibrosis in ischemic injury( Roy et al).
MiR-21 has been also proposed to play a role in cardiac hypertrophy and remodeling, however, the results so far have been conflicting; Thum et al reported that miR 21 inhibition by a cholesterol-modified antagomir prevented overload induced cardiac hypertrophy and fibrosis in rodents ,whereas Patrick et al 2010 showed that miR-21-null mice displayed cardiac hypertrophy, fibrosis and concluded that miR -21 was not involved in the etiology of stress induced cardiac hypertrophy and remodeling.
The role of miR-21 in diabetes associated cardiac hypertrophy and fibrosis is not well known but diabetes is known to induce the increased expression of mir-21. Nirmalya De 2011, identified mir-21 as a connecting link between renal cell hypertrophy and PTEN, negative regulator of PI3-Akt pathway. They found significantly increased expression mir-21 in renal cortex of the OVE26 type 1 diabetic mouse with reduced PTEN expression. They also found that high glucose increased the expression of mir-21 in renal mesangial cells.. However, whether similar pathway is operational in diabetic heart remains to be explored.
In summary, results from both basic and clinical studies suggest that miR-21 may play important role in diverse cardiovascular diseases. Although its role in diabetic cardiomyopathy is not yet fully elucidated but initial studies have confirms miR-21 was differentially expressed in diabetic myocardium and also regulates the pathological pathways in other human disease, common to diabetic cardiomyopathy.
miR-221 is known to be involved in endothelial cell migration and proliferation. It has been consistently found to be differentially expressed in heart failure caused by either genetic or metabolic causes. However its role in heart failure remains to be elucidated. Preliminary data suggest that miR-221 has some anti-hypertrophic and anti-angiogenic function. For example, miR-221 was shown to be up-regulated in patients with hypertrophic cardiomyopathy and as well as in transverse aortic constricted mice. Over-expression of miR-221 in isolated cardiomyocytes was found to increase their cell size and induced the re-expression of fetal genes, which could be inhibited by inhibition of endogenous miR-221. miR-221 was proposed to induce cardiomyocyte hypertrophy through down-regulation of p27.
miR-221 has been proposed to contribute to endothelial dysfunction in diabetes. Decreased expression of miR-221 has been observed in human umbilical vein endothelial cells (HUVECs) treated with high glucose concentrations. Down regulation of mir-221 was found to trigger the inhibition of c-kit and impaired HUVECs migration. (Yangxin Li 2009) Thus modulation of miR 221 may offer a novel strategy for treatment for diabetic patients in vascular dysfunction and a potential intervention target for cardiac hypertrophy in heart failure.
miR-320 family has several miRs such as miR-320a, miR-320b-1, miR-320b-2, miR-320c-1, miR-320c-2 and miR-320d-1, miR-320d-2, miR-320e. miR 320 is known to regulate Akt/PI3K pathway via Phosphatase and tensin homolog (PTEN) in tumor microenvironment, a pathway that is also known to be dysregualted in diabetic heart, indicating its potential role in diabetic cardiomyopathy.
Ren et al (2009) reported decreased miR-320 expression in murine hearts during ischemia/reperfusion (I/R). Transgenic mice with cardiac-specific overexpression of miR-320 showed increased apoptosis and infarction size in the hearts on I/R. In vitro gain of function of mir-320 enhanced cardiomyocyte apoptosis whereas knockdown was benificial, on simulated I/R. These studies suggested a role of miR 320 in cardiac patho-physiological processes.
A potential role of miR 320 in diabetes has been suggested by some recent findings; for example, Zampetaki et al (2010), have recently reported decreased miR-320 expression in plasma from type 2 diabetic individuals. A 50 fold increased expression of miR-320 has been observed in insulin resistant 3T3-L1 adipocytes (Ling HY, 2009); miR-320 was shown to regulate insulin resistance in these adipocytes by targeting Akt/PI3K pathways via phosphorylation of Akt and by increasing insulin-stimulated glucose uptake through increased protein expression of the glucose transporter GLUT4.
miR-320 has been also found to be upregulated in myocardial microvascular endothelial cells (MMVEC) of type 2 diabetic Goto-Kakizaki (GK) rats. Transfection of miR-320 inhibitor into MMVEC from GK rats showed that miR-320 was mediating impaired angiogenesis via regulating its target gene IGF-1.
In summary, it appears that miR-320 may have a role diabetic cardiomyopathy but further studies are needed to identify its target pathways/mechanisms in diabetic heart.
miR-223 is a hematopoietic specific, platelet enriched microRNA with crucial functions in myeloid lineage development. MicroRNA-223 selectively targets transcripts harboring AU-rich elements. More specifically, it targets RhoB, which is a member of the Rho GTP-binding protein family. Its role in heart disease was shown by van Rooij et al who reported. that miR-223 expression was increased in end-stage ischemic cardiomyopathy. Recent studies suggest that it may play an important role in type 2 diabetes. And associated complications. For example It was found that loss of RhoB, a target of miR-223, prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice. miR-223 levels were found to be increased in the myocardium of diabetic patients in the absence of concomitant myocardial infarction Lu et al. 2010. However, in another study, that mir-223 expression was reported to be decreased in the failing myocardium Simona G et al. It has been suggested that decreased miR-223 expression likely represents a compensatory adaptive mechanism in a failing myocardium since its decrease is less evident both in the remote regions of diabetic heart failure patients and in the border zone of non-diabetic heart failure patients. Recently, expression of mir-223 along with other microRNAs has been also found to be significantly decreased in plasma of diabetic patients.
Over expression of miR-223 in cardiomyocytes has been shown to increase cardiac glucose uptake by increasing glucose transporter 4 (Glut4) protein expressions (ref).
In summary, miR-223 expression in the failing human heart may be dependent on the severity as well as kind of stress leading to heart failure. It's over expression enhances PI3K-independent glucose uptake to cardiomyocytes by post-transcriptional upregulation of Glut4 and demonstrate the pleiotropy of microRNA function.
miR-133 is recognized as myomiR and was first experimentally characterized in mice (Lagos-Quintana et al 2002). In the human genome miR-133 encodes three genes: miR-133a-1, miR-133a-2 and miR-133b detected on chromosomes 18, 20 and 6 respectively (Michael V G Latronico et al 2011). miR-133 regulates cardiac and skeletal muscle differentiation and has been proposed to mediate cardiac hypertrophy under different forms of cardiac stress. miR-133 is a key regulator of cardiac hypertrophy and modulate the expression of GTPases like RhoA, a GDP-GTP exchange protein; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis (Carè A et al 2007). The decrease in the expression of miR-1 and miR-133 leads to the re-expression of HCN2 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2) /HCN4 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4) in a rat model and also in angiotensin II-induced ventricular hypertrophy (Luo X et al 2008). miR-133, along with miR-30c another heart specific miRNA plays an important role in the control of myocardial matrix remodeling by targeting the connective tissue growth factor (Ctgf ), a proï¬brotic protein (Duisters RF et al 2009). miR-133 was demonstrated to negatively regulate Nfatc4 (Nuclear factor of activated T-cells, cytoplasmic 4) mRNA and attenuate cardiomyocyte hypertrophy. Two conserved base- pairing sites between miR-133a and Nfatc4 3'UTR were confirmed with luciferase assay. Mutation of these sites in the NFATc4 3'UTR completely hinder the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation (Li Q et al 2010). Dong DL et al 2010 have suggested that apart from Nfatc4, calcineurin is a direct target of miR-133 and have shown that the expression and activity of calcineurin increases and miR-133 expression decreases in the hypertrophic heart, and inhibition of calcineurin or increase of miR-133 expression protects against cardiac hypertrophy (Dong DL et al 2010).
The role of miR-133 in diabetes associated cardiac hypertrophy is not well known but diabetes is known to down regulate the expression of miR-133. Xiao J et al have shown that the expression of ether-a-go-go related gene (ERG), a long QT syndrome gene encoding a key K(+) channel (I(Kr)) is down regulated in diabetic subjects and simultaneously they have found increased expression of miR-133 in hearts from a rabbit model of diabetes, along with the expression of serum response factor (SRF), which is known to be a transactivator of miR-133. When they delivered exogenous miR-133 into the rabbit myocytes and cell lines produced post-transcriptional repression of ERG, down-regulating ERG protein level without altering its transcript level and caused substantial depression of I(Kr) (Xiao J et al 2007). Over expression of miR-133 reduced the expression of its target gene KLF15 (Krüppel-like factor 15) and down stream target GLUT4 shows that miR-133 regulates the expression KLF15 and GLUT4 which is involved in metabolic control in cardiac myocytes (Horie T et al 2009). An impaired regulation of miR-1 and miR-133a by insulin in the skeletal muscle of type 2 diabetic patients, likely as consequences of altered SREBP-1c activation (Granjon A et al2009). In- vitro exposure to hyperglycemia decreased the expression of miR-133a and developed hypertrophic changes in cardiomyocyte and augmented the gene expression of MEF2A, MEF2C, SGK1 and IGF1R (Biao Feng et 2009).
In summary, miR-133 is the newest piece of the puzzle and may introduce new prospects for the management in the field of diabetic cardiomyopathy.
MicroRNAs involved in Diabetic metabolism:
Esguerra et al.2011, studied the differential expression of miRNAs in the pancreatic islets of Wistar and Goto-Kakizaki (GK) rats- a non-obese model of T2DM that displays hyperglycaemia, impaired glucose tolerance (IGT), insulin resistance, and defects in insulin secretion. They found various microRNAs found to be differentially expressed in heart and regulates various metabolic pathways involved in diabetes but are not functionally characterize in diabetic cardiomyopathy.
They found, miR-375 is was most abundant miRNAs present in islet cells and its overexpression negatively regulates glucose-stimulated insulin secretion (GSIS) via downregulation of myotrophin (Mtpn) expression, a protein involved in insulin-granule fusion. Indeed, Myotrophin also functions as a transcription activator of NF-kB in cardiomyocytes, suggesting that the regulation of myotrophin by miR-375 may lead to changes in NF-kB activity.
Similarly, miR-375 also negatively regulates the expression of phosphoinositide-dependent protein kinase-1, a key component in the phosphatidylinositol 3-kinase (PI 3-kinase) signaling cascade, thus resulting in decreased insulin-induced phosphorylation of AKT and GSK3 (glycogen synthase kinase 3). Surprisingly, miR-375 knockout mice are hyperglycaemic and glucose intolerant and also show increased numbers of α-cells and an elevated plasma glucagons.
Role of mir-375 has not been yet studied in diabetic heart but in one of the report, mir-375 expression was found to be decreased by 50 fold in plasma during myocardial infarction.
Similarly, miR-30d overexpression increases insulin gene expression in MIN6 cells, whereas its inhibition attenuates glucose-stimulated insulin gene transcription. Whereas, miR-15a promotes insulin biosynthesis in mouse b-cells, by inhibiting endogenous UCP-2 (uncoupling protein-2) expression, an inhibitor of GSIS.
In the heart, mir-30d as well as mir-15a was also found to be differentially expressed in during DCM, ICM and AS.
miR-29 family was significantly upregulated in the context of diabetes. miR-29a/b/c overexpression targets insulin-induced gene -1 and thereby reduce insulin-induced glucose import by 3T3-L1 adipocytes, signifying a role in insulin resistance, and this was paralleled by a decrease in Akt activation, suggesting that the miR-29 family acts by silencing components of the insulin signalling pathway. Role of mir-29 family has already been validated in heart failure.
Ling et al.2009; found that miR-320 inhibition increases the insulin sensitivity by targeting p85 in insulin-resistant adipocytes and contributes to cell growth by increasing Akt phosphorylation and GLUT4 levels.
More recently, miR-27b and miR-130 overexpression impairs adipogenesis by targeting peroxisome proliferator-activated receptor (PPARg) expression, the receptor target for thiazolidinediones-insulin-sensitising agents used for treating T2DM.
miR-33a and miR-33b have been shown to regulate cholesterol homeostasis through interaction with sterol regulatory elementbinding proteins.48 Davalos et al.49 have recently reported the role of these two miRNAs in regulating fatty acid metabolism and insulin signalling. miR-33a/b inhibit the expression of insulin receptor substrate-2 (IRS-2) in hepatic cells, subsequently reducing the activation of downstream insulin signalling pathways, including AKT and ERK.
Another significant intermediate, Insulin Receptor Substrate-1 (IRS-1) is a major mediator of insulin signaling and its mutation or dysfunction has been associated with diabetes [42-44]. Although in a different context, miR-145 has been recently identified to target and downregulate the IRS-1 (Insulin Receptor Substrate 1) protein in human colon cancer cells  and this targeting has elaborate effects on the growth and proliferation of these cells. Considering the role that IRS proteins play in insulin signaling and thereby on glucose homeostasis, it may be worthwhile to undertake in depth studies to unravel the role of this miRNA in insulin action, if any.
Diabetic cardiomyopathy: miRNA and their Targets