Application of microRNAs in diabetes mellitus

in Journal of Endocrinology

MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic β-cells, while T2D is caused by islet β-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in β-cells, and β-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.

Abstract

MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic β-cells, while T2D is caused by islet β-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in β-cells, and β-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.

Introduction

Diabetes mellitus (DM) affects 347 million people worldwide. The World Health Organization predicts that diabetes-related deaths could double between 2005 and 2030. The research conducted by American Diabetes Association estimated that the national economic burden of diagnosed diabetes in the USA in 2012 was $245 billion, including $176 billion in direct medical costs and $69 billion in reduced productivity, a 41% increase from the estimates in 2009 (American Diabetes Association 2013). DM is a complex disease characterized by high blood glucose levels. There are two major forms of diabetes. Type 1 diabetes (T1D) results from a lack of insulin production in pancreatic β-cells. T2D is due to resistance to insulin, resulting in ineffective use of insulin in the body. Long-term hyperglycemia in both T1D and T2D may lead to macrovascular (coronary artery disease, peripheral arterial disease, and stroke) and microvascular complications (diabetic nephropathy, neuropathy, and retinopathy) (Fowler 2008). Though conventional treatments for diabetes are effective, recent advances in molecular biology have provided a better understanding of diabetes and the potential to develop molecular theranostics for the disease.

MicroRNAs (miRNAs) play a crucial role in the regulation of protein-encoding genes. They are single-stranded non-coding RNA molecules of approximately 22 nucleotides in length, which function as regulators of gene expression by binding to the 3′ UTR region of mRNAs and destabilizing them or inhibiting their translation (Bartel 2004). A number of studies show that miRNAs play an important role in the etiology and pathogenesis of DM and its complications. Though miRNAs and their roles in diabetes remain largely unknown, results from a number of studies indicate that miRNAs may serve as potential biomarkers for the diagnosis and prognosis of diabetes. In this review, we summarize recent findings about the roles of miRNAs in diabetes, as well as their target genes and proteins. Moreover, we also discuss the potential application of miRNAs in diabetes.

Roles of miRNAs in diabetes

miRNAs and insulin release

Insulin release is initiated by electrical excitation of the β-cell membrane. Following a meal, glucose in circulation leads to an increased glucose uptake into β-cells through glucose transporters (called GLUTs). Glucose is metabolized in β-cells, which causes the production of ATP and an increase in the ATP:ADP ratio, resulting in the closure of ATP-sensitive potassium channels (KATP channels) in the cell membrane and subsequent depolarization of the membrane. The depolarization of cell membranes opens the voltage-gated calcium channel, leading to calcium influx, and the accumulation of calcium triggers the fusion of secretory vesicles to the plasma membrane to release insulin (Layden et al. 2010, Rorsman & Braun 2013). Insulin acts on the cells of peripheral tissues, mainly in fat, skeletal muscle, and liver, by binding the insulin receptors in cell membrane and, in turn, activates glucose uptake and metabolization. Insulin plays a crucial role in glucose homeostasis. The reduced production and incomplete utilization of insulin are the major mechanisms resulting in T1D and T2D. miRNAs are involved in β-cell membrane electrical excitation (initiated by an increase in ATP:ADP ratio), insulin synthesis, exocytosis processes (docking, fusion, and exocytosis of insulin granules), and β-cell fate and pancreatic mass formation (Fig. 1).

Figure 1
Figure 1

miRNAs involved in insulin release in pancreatic β-cells and β-cell fate. Foxa2, forkhead box A2; KATP channel, ATP-sensitive potassium channel; MAP4K4, MAPKKKK4; MCT1, monocarboxylate transporter 1; Mtpn, myotrophin; Onecut2, one cut homeobox 2; Pdcd4, programmed cell death 4; PDK1, phosphoinositide-dependent protein kinase 1; Rab27a, member RAS oncogene family; Sirt1, sirtuin (silent mating type information regulation 2 homolog) 1; Vamp2, vesicle-associated membrane protein 2; UCP2, uncoupling protein 2.

Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0544

miRNAs alter ATP:ADP ratio in insulin secretion

Uncoupling protein 2 (UCP2) in pancreatic β-cells reduces ATP levels, causes a decrease in ATP:ADP ratio, and subsequently decreases glucose-stimulated insulin secretion (Bordone et al. 2006). UCP2 is a direct target of miR-15a in β-cells. Prolonged stimulation of MIN6 cells with glucose downregulates miR-15a, resulting in an increase in UCP2 and a reduction in insulin secretion (Sun et al. 2011). miR-9 diminishes SIRT1 in β-cells and reduces the glucose-stimulated insulin secretion (Ramachandran et al. 2011), probably through enhanced expression of UCP2 (Bordone et al. 2006, Ramachandran et al. 2011, Sun et al. 2011). miR-29a and miR-29b also negatively control insulin release by reducing monocarboxylate transporter 1 (MCT1 (SLC16A1)), which acts as a substrate for mitochondrial oxidation to increase the cytosolic ATP:ADP ratio and triggers insulin release in β-cells (Pullen et al. 2011). miR-124a targets FOXA2, regulating the KATP channel subunits, Kir6.2 and Sur-1, and pancreatic development (Baroukh et al. 2007).

miRNAs control insulin granule exocytosis

miR-9 miRNA exerts a negative regulatory effect on insulin release by cleaving the target transcription factor, ONECUT2 (a Granuphilin gene repressor), and increasing the level of Granuphilin (SLP4) (a Rab3/27 effector), which facilitates exocytosis processing by mobilizing insulin granules from the readily releasable pool to the cell membrane (Plaisance et al. 2006). Interestingly, studies of miRNA expression profiles shows that the increase in miR-29a/b/c in the islets of prediabetic NOD mice is also associated with impaired glucose-induced insulin secretion by diminishing the expression of Onecut2 (Roggli et al. 2012). miR-96 is also negatively associated with Granuphilin, independently from ONECUT2, and negatively regulates insulin exocytosis (Huang et al. 2009). miR-375 is abundantly expressed in the islet cells and the overexpression of miR-375 suppresses glucose-stimulated insulin release by reducing myotrophin (Mtpn), a regulator of the actin network in membrane docking and fusion for insulin exocytosis (Poy et al. 2004). miR-124a directly targets RAB27A, downregulates NOC2, and upregulates SNAP25, RAB3A, and Synapsin1a, facilitating insulin exocytosis (Lovis et al. 2008a, Merrins & Stuenkel 2008). miR-34a is upregulated in db/db mice, in which miR-34a is associated with the decreased expression of vesicle-associated membrane protein 2 (Vamp2), a key player in docking and fusion of insulin granules in β-cell membranes (Lovis et al. 2008b).

miRNAs control insulin synthesis

miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 (PDK1) and decreases glucose-induced insulin gene expression and protein synthesis (Hashimoto et al. 2006, El Ouaamari et al. 2008). miR-30d induces insulin expression in β-cells via targeting MAP4K4, the negative regulator of the insulin transcription factor, MAFA (Zhao et al. 2012).

miRNAs control pancreatic cell fate and pancreas formation

miR-375 is essential for the formation of insulin-secreting pancreatic islets (Kloosterman et al. 2007) and maintains the normal pancreatic α- and β-cell mass (Poy et al. 2009). It has been reported that increased expression of miR-21, miR-34a, and miR-146a has been induced by interleukin 1β (IL1β) and tumor necrosis factor α (TNFα) in db/db mice (Lovis et al. 2008b, Roggli et al. 2010). miR-21 targets PDCD4 and induces cell death through the Bax family of apoptotic proteins (Lu et al. 2008, Ruan et al. 2011). miR-146 contributes to the enhancement of free-acid-induced β-cell apoptosis (Lovis et al. 2008b).

miRNAs and insulin resistance

Insulin secreted from β-cells has numerous actions on the peripheral tissues that maintain glucose homeostasis during the uptake of food. In the skeletal muscle, insulin increases glucose transport, permitting glucose entry, and glycogen synthesis. In the liver, insulin promotes glycogen synthesis and inhibits gluconeogenesis. In the adipose tissue, insulin suppresses lipolysis and promotes lipogenesis (Rottiers & Naar 2012, Samuel & Shulman 2012). 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. (2009, 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.

miRNAs and hepatic insulin resistance

miRNAs regulate insulin resistance in liver and hepatocytes and this is well documented by many studies. Upregulation of miR-143 in the livers of diabetic rats (Jordan et al. 2011) and obese mice (Takanabe et al. 2008) has been observed. Further study has shown that miR-143 downregulates Orp8, and in turn impairs the ability of insulin to induce the activation of PKB (Akt) signaling, a central signaling node of insulin action to induce glucose metabolism (Jordan et al. 2011). miR-802 is upregulated in the livers of obese mice and obese human subjects, the increase in miR-802 silences HNF1B, resulting in a diminished ability of insulin to activate PKB signaling (Kornfeld et al. 2013).

Hepatic Sirt1 deficiency in mice has been demonstrated to impair mTORC2/AKT signaling and results in hyperglycemia and insulin resistance (Wang et al. 2011). The upregulation of miR-181a in diabetic liver and hepatocytes decreases Sirt1, inactivating insulin signaling and glucose metabolism (Zhou et al. 2012). miR-96 and miR-126 directly target the insulin receptor substrate 1 (IRS1) 3′ UTR. The reduction in IRS1 is involved in insulin resistance under conditions of mitochondrial dysfunction in hepatocytes (Ryu et al. 2011, Jeong et al. 2013).

Protein tyrosine phosphatase 1B (PTP1B), a target of miR-122, inhibits hepatic insulin signaling by dephosphorylating tyrosine residues in the insulin receptor (IR) and IRS. A high-fat diet induces the phosphorylation of JUNK1 in mice, and decreases the expression of miR-122, resulting in an increase in hepatic insulin resistance (Yang et al. 2012). Another study has shown that the reduction in miR-200a/b/c in the livers of db/db mice is associated with the inactivation of the AKT/GSK signaling pathway. A decrease in Fog2, a direct target of miR-200a/b/c, impairs the AKT/GSK-mediated glycogenesis in liver, resulting in hepatic insulin resistance (Dou et al. 2013).

miRNAs and insulin resistance of adipose tissue

miR-103 and miR-107 are well studied in adipocytes. Upregulation of miR-103/-107 was demonstrated in obese mice. Overexpression of miR-103/-107 in either liver or fat impaired the insulin sensitivity, and silencing of miR-103/107 in adipocytes enhanced insulin signaling, decreased adipocyte size, and enhanced insulin-stimulated glucose uptake via upregulating Caveolin-1, a critical regulator for stabilizing the insulin receptor (Trajkovski et al. 2011). miR-221 is positively associated with BMI, and is upregulated in human pre-adipocytes. A study showed that miR-221 could downregulate adiponectin receptor 1 (ADIPOR1)-mediated actions of insulin, possibly via peroxisome proliferator-activated receptor (PPAR) signaling (Meerson et al. 2013). An increase in miR-93 in the adipocytes of polycystic ovary syndrome patients diminished the GLUT4 expression by directly binding the 3′ UTR, indicating the mechanism of insulin resistance in diabetes patients (Chen et al. 2013).

In addition, studies have shown that many miRNAs were highly associated with insulin resistance in adipose tissue though the directly targeted gene was not identified. Upregulation of miR-29 in adipose tissue of GK rats and 3T3-L1 adipocytes led to repression of insulin-stimulated glucose uptake, through inhibition of AKT activation. However, AKT is not the direct target of miR-29 (He et al. 2007). Downregulation of miR-21 was found in insulin-resistant adipocytes but overexpressing miR-21 significantly increased insulin-induced phosphorylation of AKT and GSK3β and the translocation of GLUT4 in insulin-resistant adipocytes (Ling et al. 2012). The target gene of miR-21 was not identified, but was possibly a component of the PTEN–AKT pathway. miR-320 was upregulated in insulin-resistant adipocytes and anti-miR-320 oligonucleotides activated AKT signaling, possibly by targeting the p85 subunit of PI3K, and increased the protein expression of GLUT4, sequentially enhancing insulin-stimulated glucose uptake (Ling et al. 2009).

miRNAs and insulin resistance of skeletal muscle

Let-7 suppressed the multiple components of the insulin–PI3K–mTOR pathway, via targeting insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), and IRS2 to mediate insulin resistance in skeletal muscle (Zhu et al. 2011). Frost & Olson (2011) demonstrated that knockdown of let-7 improved insulin sensitivity in liver and muscle, resulting in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. The upregulation of miR-223 was found in insulin-resistant heart muscle of T2D patients, while overexpression of miR-223 was positively associated with GLUT4, but not PI3K signaling or MAPK activity in cardiomyocytes (Lu et al. 2010). The upregulation of miR-494 induced by TNFα desensitizes C2C12 muscle cells to the effects of insulin by inhibiting the pathway downstream of Akt, which was associated with the regulation of STXBP5 (an inhibitor of glucose transport) and SLC2A4 (the gene encoding GLUT4) expression (Lee et al. 2013). Katta et al. (2013) demonstrated that miR-1 and miR-133 were associated with insulin resistance in insulin-resistant obese Zucker rats. Recently, several studies involving miRNA microarray analysis have been conducted using the GK diabetic model. 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. However, the molecular mechanism of these miRNAs in insulin resistance requires further investigation.

Taken together, miRNAs regulate insulin sensitivity and resistance mainly by targeting the components of the insulin/PKB signaling pathway and GLUT4-mediated glucose uptake and metabolism (Fig. 2).

Figure 2
Figure 2

miRNAs involved in insulin sensitivity and insulin resistance. ADIPOR1, adiponectin receptor 1; Zfpm2, zinc finger protein friend of GATA family member 2; GLUT4, glucose transporter type 4; GSK, glycogen synthase kinase; Hnf1b, hepatocyte nuclear factor 1β; IGF1R, insulin-like growth factor 1 receptor; INSR, insulin receptor; IRS1, insulin receptor substrate 1; IRS2, insulin receptor substrate 2; mTOR, mammalian target of rapamycin; mTORC2, mTOR complex 2; ORP8, oxysterol-binding protein-related proteins; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PPAR, peroxisome proliferator-activated receptor; PTP1B, protein-tyrosine phosphatase 1B; Slc2A4, solute carrier family 2 member 4; Sirt1, sirtuin (silent mating type information regulation 2 homolog) 1; Stxbp5, syntaxin-binding protein 5.

Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0544

Potential application of miRNAs in diabetes

Therapeutic targets for improving insulin release and insulin sensitivity

Altered expression of miRNAs in diabetes causes malfunction of insulin release and insulin resistance. Restoration of expression of miRNAs to normal levels may have therapeutic potential for maintaining sufficient insulin secretion and insulin sensitivity. Several approaches have been developed to restore miRNAs to normal levels. Anti-miRNA oligonucleotides (AMOs) are one of the most common strategies in miRNA gene therapy, in which AMOs directly and specifically bind to miRNA sequences to prevent binding of miRNA to the target. The other oligonucleotide-based techniques include miRNA mimics, which comprise the same nucleotide sequences as the endogenous miRNA. The regulation of miRNA with viral-based and reagent-based transfection has been successfully used in animal experiments, showing the therapeutic potential for diabetes.

Anti-miRNA oligonucleotides

AMOs have been shown to possess therapeutic potential in targeting miRNAs-related human diseases (Weiler et al. 2006). AMOs are chemically modified oligonucleotide analogs, allowing small RNA to cross the physical barrier and improving the efficiency of therapeutics, e.g. 2′-fluoro and 2′-O-methyl conjugations and 2′-4′-methylene bridges, linking with a locked nucleic acid (LNA; Weiler et al. 2006, Czech et al. 2011). Though AMO is not clinically used for diabetes, some studies have demonstrated that the antisense oligonucleotides exert effects on miRNA-mediated diabetes as described below.

El Ouaamari et al. (2008) showed that application of 2′-O-methyl-miR-375 antisense oligonucleotides increased expression of its target gene PDK1 and reverted insulin release back to normalcy in INS-1E cells. Trajkovski et al. (2011) showed that the inhibition of miR-103 and miR-107 by 2′-O-methyl-miR-103 and -107 antisense oligonucleotides improves glucose homeostasis and insulin sensitivity in ob/ob mice. Roggli et al. (2010) found that blocking the miR-21, miR-34a, or miR-146a function with antisense molecules could prevent the reduction in glucose-induced insulin secretion in MIN6 β-cells under ILβ treatment, but Lovis et al. (2008b) showed that blocking the miR-34a or miR-146 activity using oligonucleotides partially protected palmitate-treated MIN6B1 β-cell lines from apoptosis but was insufficient to restore normal insulin secretion.

Inhibition of miR-320 using anti-miR-320 oligonucleotides restored the insulin sensitivity in insulin-resistant 3T3-L1 adipocytes, evidenced by activation of insulin – PI3K signaling pathways and insulin-stimulated glucose uptake (Ling et al. 2009). Treatment with antisense oligonucleotides (2′-O-methyl-miR-181a) increases SIRT1 protein levels and activity, and improves insulin sensitivity in HepG2 hepatocytes (Zhou et al. 2012).

The inhibition of miR-29 with LNA antisense-based anti-miR29 increased insulin-induced AKT signaling, but barely augmented insulin-dependent glucose uptake (He et al. 2007). The discrepancy with AMO treatment indicated the involvement of numerous other target molecules of the insulin-signaling pathway (He et al. 2007). LNA antisense-based anti-let-7 improved the impaired glucose tolerance, at least in liver and muscle, of mice (Frost & Olson 2011).

Virus-based miRNA regulation

miRNA expression can also be manipulated by introducing the expression plasmid into cells through virus-based transfection and reagent-based transfection (Trajkovski et al. 2011). Mice that received injections of adenovirus expressing miR-107 displayed an increase in both random and fasting blood-glucose levels, impaired glucose tolerance after an i.p. glucose injection, and decreased insulin sensitivity (Trajkovski et al. 2011). Overexpression of miR-181a using adenovirus-based transfection in C57/BL6 mice by tail vein injection impaired hepatic insulin signaling and attenuated glucose homeostasis, while downregulation of miR-181a with i.p. injection of LNA antisense oligonucleotides improved glucose homeostasis in mice with diet-induced obesity (Zhou et al. 2012). Recently, non-viral-based miRNA regulation has been successfully developed to treat diabetic complications and other diseases, such as diabetic nephropathy, lung fibrosis, and cardiac fibrosis (Xiao et al. 2012, Chen et al. 2014, Zhang et al. 2014). These studies showed that miRNA regulation by virus-based and reagent-based transfection may be applicable to T1D and T2D though the potential risks of the therapy need to be further investigated.

Therapeutic chemical compounds

miRNA inhibits the expression of the target gene and in turn affects the downstream signaling. A decrease in miR-122 led to hepatic insulin resistance, while licorice flavonoids had been shown to reduce obesity-induced insulin resistance (Yang et al. 2012). Joven et al. (2012) showed that plant-derived polyphenols could regulate the expression of miRNA paralogs, miR-103/-107 and miR-122, and prevent diet-induced fatty liver disease in hyperlipidemic mice. Moreover, Parra et al. (2010) showed that adipose miRNAs (miR-103/-107, miR-122, and miR-123) were sensitive to dietary conjugated linoleic acid treatment in mice. Although the mechanisms involved are unclear, the discovery and development of therapeutic drugs to disturb miRNAs implicated in pathogenesis of diabetes might be an alternative approach.

miRNAs as potential biomarkers of DM

miRNAs are potential biomarkers for many diseases, e.g. acute myocardial infarction (AMI) and hepatocellular carcinoma (HCC). Wang et al. (2010) showed that circulating miR-208a was found in individuals with AMI with 90.9% sensitivity and 100% specificity. Li et al. (2010) demonstrated that three serum miRNAs (miR-25, miR-375, and let-7) could be used as biomarkers that distinguished hepatitis B virus-positive HCC from the controls with 97.9% sensitivity and 99.1% specificity, while miR-375 alone predicted HCC with 96% specificity and 100% sensitivity. However, the diagnostic potential of miRNAs in diabetes is largely unexplored. Several studies have shown that circulating miRNAs can serve as potential biomarkers for diabetes (Guay & Regazzi 2013).

Potential miRNA biomarkers in T1D

Circulating miR-375 levels have been shown to be a biomarker of β-cell death, and were significantly increased at 2 weeks before onset of diabetes in NOD mice, a model of autoimmune diabetes (Erener et al. 2013). Elevated expression of miR-326 was found in peripheral blood lymphocytes of T1D patients with ongoing islet autoimmunity (Sebastiani et al. 2011). Clinically, Nielsen et al. (2012) showed the upregulation of twelve serum miRNAs (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, and miR-200a) in T1D patients; particularly they found that miR-25 was negatively associated with β-cell function. SalasPerez et al. (2013) detected downregulation of miR-21a and miR-93 in peripheral blood mononuclear cells from T1D patients.

Potential miRNA biomarkers in T2D

A serum miRNA analysis of T2D patients shows that seven miRNAs (miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a, and miR-375) were significantly elevated compared with individuals with normal glucose tolerance (NGT) and five miRNAs in the above list (miR-9, miR-29a, miR-34a, miR-146a, and miR-375) were significantly upregulated compared with levels in individuals with prediabetes, although miRNA expression was not significantly different between NGT and pre-diabetes (Kong et al. 2011). Zampetaki et al. (2010) found lower levels of plasma miRNAs (miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486) in T2D patients, but a modest increase in miR-28-3p. Importantly, a decrease in miR-15a, miR-29b, miR-126, and miR-223 and an increase in miR-28-3p levels in plasma indicated the manifestation of disease, indicating their value for predicting T2D. Karolina et al. (2011) identified miR-144, miR-146a, miR-150, and miR-182 in the blood of T2D patients as the signature miRNAs for predicting of T2D. In addition, Pescador et al. (2013) showed that three serum miRNAs (miR-138, miR-376a, and miR-15b) are potential biomarkers for distinguishing obese patients from obese-T2D and T2D patients; meanwhile, the combination of miR-503 and miR-138 can distinguish diabetic from obese-diabetic patients. Furthermore, Zhao et al. (2011) found that three serum miRNAs (miR-132, miR-29a, and miR-222) can predict gestational DM with 66.7% sensitivity and 63.3% specificity (area under the curve=0.642).

So far no commercial products are available for diabetes diagnosis. The potential clinical use of miRNAs as diabetic biomarkers still needs further investigation.

Discussion and prospects

miRNAs play multiple roles in the maintenance of glucose homeostasis in the human body by regulating β-cell development and differentiation, insulin secretion, and insulin actions on the insulin target tissues, liver, adipose tissue, muscle, etc. Upregulation and downregulation of miRNAs are strongly associated with T1D and T2D. miRNAs directly target genes involved in β-cell survival and insulin exocytosis, and insulin resistance is the central mechanism of miRNAs-mediated T1D and T2D (Fernandez-Valverde et al. 2011, Guay et al. 2011, Rottiers & Naar 2012, Samuel & Shulman 2012, Williams & Mitchell 2012). Manipulation of miRNAs and insulin signaling may have therapeutic potential. AMOs for miRNAs (anti-miR-181a, anti-miR-320, etc.) have demonstrated the sufficient ability to restore miRNA to normal levels and revert the abnormalities of insulin signaling. Nevertheless, resistance of tissues to the uptake of AMOs is a major obstacle for developing AMO strategy for the clinical use (Xiao et al. 2012). Virus-based gene delivery (adenovirus vectors, lentivirus vectors, etc.) is the most widely used gene delivery approach with high transfection rate; however, toxicity, host immune response, and potential mutagenesis limit the clinical benefits (Mah et al. 2002, Jia & Zhou 2005). Advances in science have led to the development of nonviral vectors-mediated gene therapies to overcome the shortcomings, e.g. the sleeping beauty transposon system (Aronovich et al. 2011) and the ultrasound microbubble-mediated gene delivery system (Lan et al. 2003, Chen et al. 2011, Zhong et al. 2013). Transposon-based miR-29b overexpression via mouse tail vein injection resulted in higher levels of transfection and long-term expression of miR-29b in the lungs of mice, without obvious pathological changes (Xiao et al. 2012). Ultrasound microbubble-mediated miR-21 small hairpin RNA transfer caused a twofold increase in miR-21 expression in diabetic kidney, which attenuated renal fibrosis and inflammation in db/db mice (Zhong et al. 2013). However, these gene delivery approaches remain at the preclinical stage and are far from the clinical use. The development of safe, highly efficient, tissue-specific miRNA gene therapy is still a big challenge. Interestingly, some chemical compounds, e.g. licorice flavonoids and linoleic acid, regulated miRNAs and attenuated the pathogenesis of diabetes (Parra et al. 2010, Yang et al. 2012). The development of chemical compounds to regulate miRNAs implicated in diabetes could be another potential strategy to manipulate diabetes.

Though miRNAs and their roles in diabetes remain under-explored, some studies have demonstrated that miRNAs may act as potential biomarkers for diagnosis and prognosis of diabetes. The sensitivity and specificity of miRNAs in the identification of pancreatic β-cell fate, insulin secretion, and insulin action have not satisfied the clinical need so far in pilot studies. As each miRNA may have numerous targets, and is involved in complex processes of physiology and pathology, we believe that a cluster of miRNAs, instead of a single miRNA, could be used as diabetes biomarker with better sensitivity and specificity that meet the clinical requirements.

Though the understanding of the involvement of miRNAs in diabetes is in its infancy, advances in investigating the role of miRNA in diabetes may potentially provide a powerful tool to predict, diagnose, treat, and prognose diabetes in the future.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

The work was supported by grants funding from the Chinese University of Hong Kong, CUHK5/CRF09 and CUHK3/CRF/12R.

References

  • American Diabetes Association 2013

    American Diabetes AssociationEconomic costs of diabetes in the U.S. in 2012Diabetes Care36201310331046. (doi:10.2337/dc12-2625)

  • Aronovich et al. 2011

    AronovichELMcIvorRSHackettPB2011The sleeping beauty transposon system: a non-viral vector for gene therapy. Human Molecular Genetics20R14R20. (doi:10.1093/hmg/ddr140)

    • Search Google Scholar
    • Export Citation
  • Baroukh et al. 2007

    BaroukhNRavierMALoderMKHillEVBounacerAScharfmannRRutterGAVan ObberghenE2007MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic β-cell lines. Journal of Biological Chemistry2821957519588. (doi:10.1074/jbc.M611841200)

    • Search Google Scholar
    • Export Citation
  • Bartel, 2004

    BartelDP2004MicroRNAs: genomics, biogenesis, mechanism, and function. Cell116281297. (doi:10.1016/S0092-8674(04)00045-5)

  • Bordone et al. 2006

    BordoneLMottaMCPicardFRobinsonAJhalaUSApfeldJMcDonaghTLemieuxMMcBurneyMSzilvasiA2006Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biology4e31. (doi:10.1371/journal.pbio.0040031)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2011

    ChenHYHuangXRWangWLiJHHeuchelRLChungACLanHY2011The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes60590601. (doi:10.2337/db10-0403)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2013

    ChenYHHeneidiSLeeJMLaymanLCSteppDWGamboaGMChenBSChazenbalkGAzzizR2013miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes6222782286. (doi:10.2337/db12-0963)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2014

    ChenHYZhongXHuangXRMengXMYouYChungACLanHY2014MicroRNA-29b inhibits diabetic nephropathy in db/db mice. Molecular Therapy22842853. (doi:10.1038/mt.2013.235)

    • Search Google Scholar
    • Export Citation
  • Czech et al. 2011

    CzechMPAouadiMTeszGJ2011RNAi-based therapeutic strategies for metabolic disease. Nature Reviews. Endocrinology7473484. (doi:10.1038/nrendo.2011.57)

    • Search Google Scholar
    • Export Citation
  • Dou et al. 2013

    DouLZhaoTWangLHuangXJiaoJGaoDZhangHShenTManYWangS2013miR-200s contribute to interleukin-6 (IL-6)-induced insulin resistance in hepatocytes. Journal of Biological Chemistry2882259622606. (doi:10.1074/jbc.M112.423145)

    • Search Google Scholar
    • Export Citation
  • El Ouaamari et al. 2008

    El OuaamariABaroukhNMartensGALebrunPPipeleersDvan ObberghenE2008miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic β-cells. Diabetes5727082717. (doi:10.2337/db07-1614)

    • Search Google Scholar
    • Export Citation
  • Erener et al. 2013

    ErenerSMojibianMFoxJKDenrocheHCKiefferTJ2013Circulating miR-375 as a biomarker of β-cell death and diabetes in mice. Endocrinology154603608. (doi:10.1210/en.2012-1744)

    • Search Google Scholar
    • Export Citation
  • Fernandez-Valverde et al. 2011

    Fernandez-ValverdeSLTaftRJMattickJS2011MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Diabetes6018251831. (doi:10.2337/db11-0171)

    • Search Google Scholar
    • Export Citation
  • Fowler, 2008

    FowlerMJ2008Microvascular and macrovascular complications of diabetes. Clinical Diabetes267782. (doi:10.2337/diaclin.26.2.77)

  • Frost and Olson, 2011

    FrostRJOlsonEN2011Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. PNAS1082107521080. (doi:10.1073/pnas.1118922109)

    • Search Google Scholar
    • Export Citation
  • Guay and Regazzi, 2013

    GuayCRegazziR2013Circulating microRNAs as novel biomarkers for diabetes mellitus. Nature Reviews. Endocrinology9513521. (doi:10.1038/nrendo.2013.86)

    • Search Google Scholar
    • Export Citation
  • Guay et al. 2011

    GuayCRoggliENescaVJacovettiCRegazziR2011Diabetes mellitus, a microRNA-related disease?Translational Research157253264. (doi:10.1016/j.trsl.2011.01.009)

    • Search Google Scholar
    • Export Citation
  • Hashimoto et al. 2006

    HashimotoNKidoYUchidaTAsaharaSShigeyamaYMatsudaTTakedaATsuchihashiDNishizawaAOgawaW2006Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nature Genetics38589593. (doi:10.1038/ng1774)

    • Search Google Scholar
    • Export Citation
  • He et al. 2007

    HeAZhuLGuptaNChangYFangF2007Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Molecular Endocrinology2127852794. (doi:10.1210/me.2007-0167)

    • Search Google Scholar
    • Export Citation
  • Herrera et al. 2009

    HerreraBMLockstoneHETaylorJMWillsQFKaisakiPJBarrettACampsCFernandezCRagoussisJGauguierD2009MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of type 2 diabetes. BMC Medical Genomics254. (doi:10.1186/1755-8794-2-54)

    • Search Google Scholar
    • Export Citation
  • Herrera et al. 2010

    HerreraBMLockstoneHETaylorJMRiaMBarrettACollinsSKaisakiPArgoudKFernandezCTraversME2010Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia5310991109. (doi:10.1007/s00125-010-1667-2)

    • Search Google Scholar
    • Export Citation
  • Huang et al. 2009

    HuangBQinWZhaoBShiYYaoCLiJXiaoHJinY2009MicroRNA expression profiling in diabetic GK rat model. Acta Biochimica et Biophysica Sinica41472477. (doi:10.1093/abbs/gmp035)

    • Search Google Scholar
    • Export Citation
  • Jeong et al. 2013

    JeongHJParkSYYangWMLeeW2013The induction of miR-96 by mitochondrial dysfunction causes impaired glycogen synthesis through translational repression of IRS-1 in SK-Hep1 cells. Biochemical and Biophysical Research Communications434503508. (doi:10.1016/j.bbrc.2013.03.104)

    • Search Google Scholar
    • Export Citation
  • Jia and Zhou, 2005

    JiaWZhouQ2005Viral vectors for cancer gene therapy: viral dissemination and tumor targeting. Current Gene Therapy5133142. (doi:10.2174/1566523052997460)

    • Search Google Scholar
    • Export Citation
  • Jordan et al. 2011

    JordanSDKrugerMWillmesDMRedemannNWunderlichFTBronnekeHSMerkwirthCKashkarHOlkkonenVMBottgerT2011Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nature Cell Biology13434446. (doi:10.1038/ncb2211)

    • Search Google Scholar
    • Export Citation
  • Joven et al. 2012

    JovenJEspinelERullAAragonesGRodriguez-GallegoECampsJMicolVHerranz-LopezMMenendezJABorrasI2012Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice. Biochimica et Biophysica Acta1820894899. (doi:10.1016/j.bbagen.2012.03.020)

    • Search Google Scholar
    • Export Citation
  • Karolina et al. 2011

    KarolinaDSArmugamATavintharanSWongMTLimSCSumCFJeyaseelanK2011MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PLoS ONE6e22839. (doi:10.1371/journal.pone.0022839)

    • Search Google Scholar
    • Export Citation
  • Katta et al. 2013

    KattaAThulluriSManneNDAddagarlaHSArvapalliRNalabotuSKGaddeMRiceKMBloughER2013Overload induced heat shock proteins (HSPs), MAPK and miRNA (miR-1 and miR133a) response in insulin-resistant skeletal muscle. Cellular Physiology and Biochemistry 31219229. (doi:10.1159/000343363)

    • Search Google Scholar
    • Export Citation
  • Kloosterman et al. 2007

    KloostermanWPLagendijkAKKettingRFMoultonJDPlasterkRH2007Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biology5e203. (doi:10.1371/journal.pbio.0050203)

    • Search Google Scholar
    • Export Citation
  • Kong et al. 2011

    KongLZhuJHanWJiangXXuMZhaoYDongQPangZGuanQGaoL2011Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetologia486169. (doi:10.1007/s00592-010-0226-0)

    • Search Google Scholar
    • Export Citation
  • Kornfeld et al. 2013

    KornfeldJWBaitzelCKonnerACNichollsHTVogtMCHerrmannsKSchejaLHaumaitreCWolfAMKnippschildU2013Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature494111115. (doi:10.1038/nature11793)

    • Search Google Scholar
    • Export Citation
  • Lan et al. 2003

    LanHYMuWTomitaNHuangXRLiJHZhuHJMorishitaRJohnsonRJ2003Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. Journal of the American Society of Nephrology1415351548. (doi:10.1097/01.ASN.0000067632.04658.B8)

    • Search Google Scholar
    • Export Citation
  • Layden et al. 2010

    LaydenBTDuraiVLoweWLJr2010G-protein-coupled receptors, pancreatic islets, and diabetes. Nature Education 313.

  • Lee et al. 2013

    LeeHJeeYHongKHwangGSChunKH2013MicroRNA-494, upregulated by tumor necrosis factor-α, desensitizes insulin effect in C2C12 muscle cells. PLoS ONE8e83471. (doi:10.1371/journal.pone.0083471)

    • Search Google Scholar
    • Export Citation
  • Li et al. 2010

    LiLMHuZBZhouZXChenXLiuFYZhangJFShenHBZhangCYZenK2010Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Research7097989807. (doi:10.1158/0008-5472.CAN-10-1001)

    • Search Google Scholar
    • Export Citation
  • Ling et al. 2009

    LingHYOuHSFengSDZhangXYTuoQHChenLXZhuBYGaoZPTangCKYinWD2009Changes in microRNA (miR) profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clinical and Experimental Pharmacology & Physiology36e32e39. (doi:10.1111/j.1440-1681.2009.05207.x)

    • Search Google Scholar
    • Export Citation
  • Ling et al. 2012

    LingHYHuBHuXBZhongJFengSDQinLLiuGWenGBLiaoDF2012miRNA-21 reverses high glucose and high insulin induced insulin resistance in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue. Experimental and Clinical Endocrinology & Diabetes120553559. (doi:10.1055/s-0032-1311644)

    • Search Google Scholar
    • Export Citation
  • Lovis et al. 2008a

    LovisPGattescoSRegazziR2008aRegulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs. Biological Chemistry389305312. (doi:10.1515/BC.2008.026)

    • Search Google Scholar
    • Export Citation
  • Lovis et al. 2008b

    LovisPRoggliELaybuttDRGattescoSYangJYWidmannCAbderrahmaniARegazziR2008bAlterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes5727282736. (doi:10.2337/db07-1252)

    • Search Google Scholar
    • Export Citation
  • Lu et al. 2008

    LuZLiuMStribinskisVKlingeCMRamosKSColburnNHLiY2008MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene2743734379. (doi:10.1038/onc.2008.72)

    • Search Google Scholar
    • Export Citation
  • Lu et al. 2010

    LuHBuchanRJCookSA2010MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovascular Research86410420. (doi:10.1093/cvr/cvq010)

    • Search Google Scholar
    • Export Citation
  • Mah et al. 2002

    MahCByrneBJFlotteTR2002Virus-based gene delivery systems. Clinical Pharmacokinetics41901911. (doi:10.2165/00003088-200241120-00001)

  • Meerson et al. 2013

    MeersonATraurigMOssowskiVFlemingJMMullinsMBaierLJ2013Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia5619711979. (doi:10.1007/s00125-013-2950-9)

    • Search Google Scholar
    • Export Citation
  • Merrins and Stuenkel, 2008

    MerrinsMJStuenkelEL2008Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic β-cells. Journal of Physiology58653675381. (doi:10.1113/jphysiol.2008.158477)

    • Search Google Scholar
    • Export Citation
  • Nielsen et al. 2012

    NielsenLBWangCSorensenKBang-BerthelsenCHHansenLAndersenMLHougaardPJuulAZhangCYPociotF2012Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual β-cell function and glycaemic control during disease progression. Experimental Diabetes Research2012896362. (doi:10.1155/2012/896362)

    • Search Google Scholar
    • Export Citation
  • Parra et al. 2010

    ParraPSerraFPalouA2010Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS ONE5e13005. (doi:10.1371/journal.pone.0013005)

    • Search Google Scholar
    • Export Citation
  • Peppa et al. 2010

    PeppaMKoliakiCNikolopoulosPRaptisSA2010Skeletal muscle insulin resistance in endocrine disease. Journal of Biomedicine & Biotechnology2010527850. (doi:10.1155/2010/527850)

    • Search Google Scholar
    • Export Citation
  • Pescador et al. 2013

    PescadorNPerez-BarbaMIbarraJMCorbatonAMartinez-LarradMTSerrano-RiosM2013Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS ONE8e77251. (doi:10.1371/journal.pone.0077251)

    • Search Google Scholar
    • Export Citation
  • Plaisance et al. 2006

    PlaisanceVAbderrahmaniAPerret-MenoudVJacqueminPLemaigreFRegazziR2006MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. Journal of Biological Chemistry2812693226942. (doi:10.1074/jbc.M601225200)

    • Search Google Scholar
    • Export Citation
  • Poy et al. 2004

    PoyMNEliassonLKrutzfeldtJKuwajimaSMaXMacdonaldPEPfefferSTuschlTRajewskyNRorsmanP2004A pancreatic islet-specific microRNA regulates insulin secretion. Nature432226230. (doi:10.1038/nature03076)

    • Search Google Scholar
    • Export Citation
  • Poy et al. 2009

    PoyMNHausserJTrajkovskiMBraunMCollinsSRorsmanPZavolanMStoffelM2009miR-375 maintains normal pancreatic α- and β-cell mass. PNAS10658135818. (doi:10.1073/pnas.0810550106)

    • Search Google Scholar
    • Export Citation
  • Pullen et al. 2011

    PullenTJda Silva XavierGKelseyGRutterGA2011miR-29a and miR-29b contribute to pancreatic β-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Molecular and Cellular Biology3131823194. (doi:10.1128/MCB.01433-10)

    • Search Google Scholar
    • Export Citation
  • Ramachandran et al. 2011

    RamachandranDRoyUGargSGhoshSPathakSKolthur-SeetharamU2011Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin secretion in pancreatic β-islets. FEBS Journal27811671174. (doi:10.1111/j.1742-4658.2011.08042.x)

    • Search Google Scholar
    • Export Citation
  • Roggli et al. 2010

    RoggliEBritanAGattescoSLin-MarqNAbderrahmaniAMedaPRegazziR2010Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes59978986. (doi:10.2337/db09-0881)

    • Search Google Scholar
    • Export Citation
  • Roggli et al. 2012

    RoggliEGattescoSCailleDBrietCBoitardCMedaPRegazziR2012Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes6117421751. (doi:10.2337/db11-1086)

    • Search Google Scholar
    • Export Citation
  • Rorsman and Braun, 2013

    RorsmanPBraunM2013Regulation of insulin secretion in human pancreatic islets. Annual Review of Physiology75155179. (doi:10.1146/annurev-physiol-030212-183754)

    • Search Google Scholar
    • Export Citation
  • Rottiers and Naar, 2012

    RottiersVNaarAM2012MicroRNAs in metabolism and metabolic disorders. Nature Reviews. Molecular Cell Biology13239250. (doi:10.1038/nrm3313)

    • Search Google Scholar
    • Export Citation
  • Ruan et al. 2011

    RuanQWangTKameswaranVWeiQJohnsonDSMatschinskyFShiWChenYH2011The microRNA-21–PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death. PNAS1081203012035. (doi:10.1073/pnas.1101450108)

    • Search Google Scholar
    • Export Citation
  • Ryu et al. 2011

    RyuHSParkSYMaDAZhangJLeeW2011The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes. PLoS ONE6 e17343. (doi:10.1371/journal.pone.0017343)

    • Search Google Scholar
    • Export Citation
  • Salas-Perez et al. 2013

    Salas-PerezFCodnerEValenciaEPizarroCCarrascoEPerez-BravoF2013MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology218733737. (doi:10.1016/j.imbio.2012.08.276)

    • Search Google Scholar
    • Export Citation
  • Samuel and Shulman, 2012

    SamuelVTShulmanGI2012Mechanisms for insulin resistance: common threads and missing links. Cell148852871. (doi:10.1016/j.cell.2012.02.017)

    • Search Google Scholar
    • Export Citation
  • Sebastiani et al. 2011

    SebastianiGGriecoFASpagnuoloIGalleriLCataldoDDottaF2011Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes/Metabolism Research and Reviews27862866. (doi:10.1002/dmrr.1262)

    • Search Google Scholar
    • Export Citation
  • Sun et al. 2011

    SunLLJiangBGLiWTZouJJShiYQLiuZM2011MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Research and Clinical Practice9194100. (doi:10.1016/j.diabres.2010.11.006)

    • Search Google Scholar
    • Export Citation
  • Takanabe et al. 2008

    TakanabeROnoKAbeYTakayaTHorieTWadaHKitaTSatohNShimatsuAHasegawaK2008Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. Biochemical and Biophysical Research Communications376728732. (doi:10.1016/j.bbrc.2008.09.050)

    • Search Google Scholar
    • Export Citation
  • Trajkovski et al. 2011

    TrajkovskiMHausserJSoutschekJBhatBAkinAZavolanMHeimMHStoffelM2011MicroRNAs 103 and 107 regulate insulin sensitivity. Nature474649653. (doi:10.1038/nature10112)

    • Search Google Scholar
    • Export Citation
  • Wang et al. 2010

    WangGKZhuJQZhangJTLiQLiYHeJQinYWJingQ2010Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. European Heart Journal31659666. (doi:10.1093/eurheartj/ehq013)

    • Search Google Scholar
    • Export Citation
  • Wang et al. 2011

    WangRHKimHSXiaoCYXuXLGavrilovaODengCX2011Hepatic Sirt1 deficiency in mice impairs mTORC2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. Journal of Clinical Investigation12144774490. (doi:10.1172/JCI46243)

    • Search Google Scholar
    • Export Citation
  • Weiler et al. 2006

    WeilerJHunzikerJHallJ2006Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?Gene Therapy13496502. (doi:10.1038/sj.gt.3302654)

    • Search Google Scholar
    • Export Citation
  • Williams and Mitchell, 2012

    WilliamsMDMitchellGM2012MicroRNAs in insulin resistance and obesity. Experimental Diabetes Research2012484696. (doi:10.1155/2012/484696)

    • Search Google Scholar
    • Export Citation
  • Xiao et al. 2012

    XiaoJMengXMHuangXRChungACFengYLHuiDSYuCMSungJJLanHY2012miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Molecular Therapy2012511260. (doi:10.1038/mt.2012.36)

    • Search Google Scholar
    • Export Citation
  • Yang et al. 2012

    YangYMSeoSYKimTHKimSG2012Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid. Hepatology5622092220. (doi:10.1002/hep.25912)

    • Search Google Scholar
    • Export Citation
  • Zampetaki et al. 2010

    ZampetakiAKiechlSDrozdovIWilleitPMayrUProkopiMMayrAWegerSOberhollenzerFBonoraE2010Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circulation Research107810817. (doi:10.1161/CIRCRESAHA.110.226357)

    • Search Google Scholar
    • Export Citation
  • Zhang et al. 2014

    ZhangYRu HuangXWeiLHChungACYuCMLanHY2014miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Molecular Therapy22974985. (doi:10.1038/mt.2014.25)

    • Search Google Scholar
    • Export Citation
  • Zhao et al. 2011

    ZhaoCDongJJiangTShiZYuBZhuYChenDXuJHuoRDaiJ2011Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS ONE6e23925. (doi:10.1371/journal.pone.0023925)

    • Search Google Scholar
    • Export Citation
  • Zhao et al. 2012

    ZhaoXMohanROzcanSTangX2012MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase 4 (MAP4K4) in pancreatic β-cells. Journal of Biological Chemistry2873115531164. (doi:10.1074/jbc.M112.362632)

    • Search Google Scholar
    • Export Citation
  • Zhong et al. 2013

    ZhongXChungACChenHYDongYMengXMLiRYangWHouFFLanHY2013miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia56663674. (doi:10.1007/s00125-012-2804-x)

    • Search Google Scholar
    • Export Citation
  • Zhou et al. 2012

    ZhouBLiCQiWZhangYZhangFWuJXHuYNWuDMLiuYYanTT2012Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia5520322043. (doi:10.1007/s00125-012-2539-8)

    • Search Google Scholar
    • Export Citation
  • Zhu et al. 2011

    ZhuHShyh-ChangNSegreAVShinodaGShahSPEinhornWSTakeuchiAEngreitzJMHaganJPKharasMG2011The Lin28/let-7 axis regulates glucose metabolism. Cell1478194. (doi:10.1016/j.cell.2011.08.033)

    • Search Google Scholar
    • Export Citation

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    miRNAs involved in insulin release in pancreatic β-cells and β-cell fate. Foxa2, forkhead box A2; KATP channel, ATP-sensitive potassium channel; MAP4K4, MAPKKKK4; MCT1, monocarboxylate transporter 1; Mtpn, myotrophin; Onecut2, one cut homeobox 2; Pdcd4, programmed cell death 4; PDK1, phosphoinositide-dependent protein kinase 1; Rab27a, member RAS oncogene family; Sirt1, sirtuin (silent mating type information regulation 2 homolog) 1; Vamp2, vesicle-associated membrane protein 2; UCP2, uncoupling protein 2.

  • View in gallery

    miRNAs involved in insulin sensitivity and insulin resistance. ADIPOR1, adiponectin receptor 1; Zfpm2, zinc finger protein friend of GATA family member 2; GLUT4, glucose transporter type 4; GSK, glycogen synthase kinase; Hnf1b, hepatocyte nuclear factor 1β; IGF1R, insulin-like growth factor 1 receptor; INSR, insulin receptor; IRS1, insulin receptor substrate 1; IRS2, insulin receptor substrate 2; mTOR, mammalian target of rapamycin; mTORC2, mTOR complex 2; ORP8, oxysterol-binding protein-related proteins; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PPAR, peroxisome proliferator-activated receptor; PTP1B, protein-tyrosine phosphatase 1B; Slc2A4, solute carrier family 2 member 4; Sirt1, sirtuin (silent mating type information regulation 2 homolog) 1; Stxbp5, syntaxin-binding protein 5.

  • American Diabetes Association 2013

    American Diabetes AssociationEconomic costs of diabetes in the U.S. in 2012Diabetes Care36201310331046. (doi:10.2337/dc12-2625)

  • Aronovich et al. 2011

    AronovichELMcIvorRSHackettPB2011The sleeping beauty transposon system: a non-viral vector for gene therapy. Human Molecular Genetics20R14R20. (doi:10.1093/hmg/ddr140)

    • Search Google Scholar
    • Export Citation
  • Baroukh et al. 2007

    BaroukhNRavierMALoderMKHillEVBounacerAScharfmannRRutterGAVan ObberghenE2007MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic β-cell lines. Journal of Biological Chemistry2821957519588. (doi:10.1074/jbc.M611841200)

    • Search Google Scholar
    • Export Citation
  • Bartel, 2004

    BartelDP2004MicroRNAs: genomics, biogenesis, mechanism, and function. Cell116281297. (doi:10.1016/S0092-8674(04)00045-5)

  • Bordone et al. 2006

    BordoneLMottaMCPicardFRobinsonAJhalaUSApfeldJMcDonaghTLemieuxMMcBurneyMSzilvasiA2006Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biology4e31. (doi:10.1371/journal.pbio.0040031)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2011

    ChenHYHuangXRWangWLiJHHeuchelRLChungACLanHY2011The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes60590601. (doi:10.2337/db10-0403)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2013

    ChenYHHeneidiSLeeJMLaymanLCSteppDWGamboaGMChenBSChazenbalkGAzzizR2013miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes6222782286. (doi:10.2337/db12-0963)

    • Search Google Scholar
    • Export Citation
  • Chen et al. 2014

    ChenHYZhongXHuangXRMengXMYouYChungACLanHY2014MicroRNA-29b inhibits diabetic nephropathy in db/db mice. Molecular Therapy22842853. (doi:10.1038/mt.2013.235)

    • Search Google Scholar
    • Export Citation
  • Czech et al. 2011

    CzechMPAouadiMTeszGJ2011RNAi-based therapeutic strategies for metabolic disease. Nature Reviews. Endocrinology7473484. (doi:10.1038/nrendo.2011.57)

    • Search Google Scholar
    • Export Citation
  • Dou et al. 2013

    DouLZhaoTWangLHuangXJiaoJGaoDZhangHShenTManYWangS2013miR-200s contribute to interleukin-6 (IL-6)-induced insulin resistance in hepatocytes. Journal of Biological Chemistry2882259622606. (doi:10.1074/jbc.M112.423145)

    • Search Google Scholar
    • Export Citation
  • El Ouaamari et al. 2008

    El OuaamariABaroukhNMartensGALebrunPPipeleersDvan ObberghenE2008miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic β-cells. Diabetes5727082717. (doi:10.2337/db07-1614)

    • Search Google Scholar
    • Export Citation
  • Erener et al. 2013

    ErenerSMojibianMFoxJKDenrocheHCKiefferTJ2013Circulating miR-375 as a biomarker of β-cell death and diabetes in mice. Endocrinology154603608. (doi:10.1210/en.2012-1744)

    • Search Google Scholar
    • Export Citation
  • Fernandez-Valverde et al. 2011

    Fernandez-ValverdeSLTaftRJMattickJS2011MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Diabetes6018251831. (doi:10.2337/db11-0171)

    • Search Google Scholar
    • Export Citation
  • Fowler, 2008

    FowlerMJ2008Microvascular and macrovascular complications of diabetes. Clinical Diabetes267782. (doi:10.2337/diaclin.26.2.77)

  • Frost and Olson, 2011

    FrostRJOlsonEN2011Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. PNAS1082107521080. (doi:10.1073/pnas.1118922109)

    • Search Google Scholar
    • Export Citation
  • Guay and Regazzi, 2013

    GuayCRegazziR2013Circulating microRNAs as novel biomarkers for diabetes mellitus. Nature Reviews. Endocrinology9513521. (doi:10.1038/nrendo.2013.86)

    • Search Google Scholar
    • Export Citation
  • Guay et al. 2011

    GuayCRoggliENescaVJacovettiCRegazziR2011Diabetes mellitus, a microRNA-related disease?Translational Research157253264. (doi:10.1016/j.trsl.2011.01.009)

    • Search Google Scholar
    • Export Citation
  • Hashimoto et al. 2006

    HashimotoNKidoYUchidaTAsaharaSShigeyamaYMatsudaTTakedaATsuchihashiDNishizawaAOgawaW2006Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nature Genetics38589593. (doi:10.1038/ng1774)

    • Search Google Scholar
    • Export Citation
  • He et al. 2007

    HeAZhuLGuptaNChangYFangF2007Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Molecular Endocrinology2127852794. (doi:10.1210/me.2007-0167)

    • Search Google Scholar
    • Export Citation
  • Herrera et al. 2009

    HerreraBMLockstoneHETaylorJMWillsQFKaisakiPJBarrettACampsCFernandezCRagoussisJGauguierD2009MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of type 2 diabetes. BMC Medical Genomics254. (doi:10.1186/1755-8794-2-54)

    • Search Google Scholar
    • Export Citation
  • Herrera et al. 2010

    HerreraBMLockstoneHETaylorJMRiaMBarrettACollinsSKaisakiPArgoudKFernandezCTraversME2010Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia5310991109. (doi:10.1007/s00125-010-1667-2)

    • Search Google Scholar
    • Export Citation
  • Huang et al. 2009

    HuangBQinWZhaoBShiYYaoCLiJXiaoHJinY2009MicroRNA expression profiling in diabetic GK rat model. Acta Biochimica et Biophysica Sinica41472477. (doi:10.1093/abbs/gmp035)

    • Search Google Scholar
    • Export Citation
  • Jeong et al. 2013

    JeongHJParkSYYangWMLeeW2013The induction of miR-96 by mitochondrial dysfunction causes impaired glycogen synthesis through translational repression of IRS-1 in SK-Hep1 cells. Biochemical and Biophysical Research Communications434503508. (doi:10.1016/j.bbrc.2013.03.104)

    • Search Google Scholar
    • Export Citation
  • Jia and Zhou, 2005

    JiaWZhouQ2005Viral vectors for cancer gene therapy: viral dissemination and tumor targeting. Current Gene Therapy5133142. (doi:10.2174/1566523052997460)

    • Search Google Scholar
    • Export Citation
  • Jordan et al. 2011

    JordanSDKrugerMWillmesDMRedemannNWunderlichFTBronnekeHSMerkwirthCKashkarHOlkkonenVMBottgerT2011Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nature Cell Biology13434446. (doi:10.1038/ncb2211)

    • Search Google Scholar
    • Export Citation
  • Joven et al. 2012

    JovenJEspinelERullAAragonesGRodriguez-GallegoECampsJMicolVHerranz-LopezMMenendezJABorrasI2012Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice. Biochimica et Biophysica Acta1820894899. (doi:10.1016/j.bbagen.2012.03.020)

    • Search Google Scholar
    • Export Citation
  • Karolina et al. 2011

    KarolinaDSArmugamATavintharanSWongMTLimSCSumCFJeyaseelanK2011MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PLoS ONE6e22839. (doi:10.1371/journal.pone.0022839)

    • Search Google Scholar
    • Export Citation
  • Katta et al. 2013

    KattaAThulluriSManneNDAddagarlaHSArvapalliRNalabotuSKGaddeMRiceKMBloughER2013Overload induced heat shock proteins (HSPs), MAPK and miRNA (miR-1 and miR133a) response in insulin-resistant skeletal muscle. Cellular Physiology and Biochemistry 31219229. (doi:10.1159/000343363)

    • Search Google Scholar
    • Export Citation
  • Kloosterman et al. 2007

    KloostermanWPLagendijkAKKettingRFMoultonJDPlasterkRH2007Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biology5e203. (doi:10.1371/journal.pbio.0050203)

    • Search Google Scholar
    • Export Citation
  • Kong et al. 2011

    KongLZhuJHanWJiangXXuMZhaoYDongQPangZGuanQGaoL2011Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetologia486169. (doi:10.1007/s00592-010-0226-0)

    • Search Google Scholar
    • Export Citation
  • Kornfeld et al. 2013

    KornfeldJWBaitzelCKonnerACNichollsHTVogtMCHerrmannsKSchejaLHaumaitreCWolfAMKnippschildU2013Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature494111115. (doi:10.1038/nature11793)

    • Search Google Scholar
    • Export Citation
  • Lan et al. 2003

    LanHYMuWTomitaNHuangXRLiJHZhuHJMorishitaRJohnsonRJ2003Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. Journal of the American Society of Nephrology1415351548. (doi:10.1097/01.ASN.0000067632.04658.B8)

    • Search Google Scholar
    • Export Citation
  • Layden et al. 2010

    LaydenBTDuraiVLoweWLJr2010G-protein-coupled receptors, pancreatic islets, and diabetes. Nature Education 313.

  • Lee et al. 2013

    LeeHJeeYHongKHwangGSChunKH2013MicroRNA-494, upregulated by tumor necrosis factor-α, desensitizes insulin effect in C2C12 muscle cells. PLoS ONE8e83471. (doi:10.1371/journal.pone.0083471)

    • Search Google Scholar
    • Export Citation
  • Li et al. 2010

    LiLMHuZBZhouZXChenXLiuFYZhangJFShenHBZhangCYZenK2010Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Research7097989807. (doi:10.1158/0008-5472.CAN-10-1001)

    • Search Google Scholar
    • Export Citation
  • Ling et al. 2009

    LingHYOuHSFengSDZhangXYTuoQHChenLXZhuBYGaoZPTangCKYinWD2009Changes in microRNA (miR) profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clinical and Experimental Pharmacology & Physiology36e32e39. (doi:10.1111/j.1440-1681.2009.05207.x)

    • Search Google Scholar
    • Export Citation
  • Ling et al. 2012

    LingHYHuBHuXBZhongJFengSDQinLLiuGWenGBLiaoDF2012miRNA-21 reverses high glucose and high insulin induced insulin resistance in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue. Experimental and Clinical Endocrinology & Diabetes120553559. (doi:10.1055/s-0032-1311644)

    • Search Google Scholar
    • Export Citation
  • Lovis et al. 2008a

    LovisPGattescoSRegazziR2008aRegulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs. Biological Chemistry389305312. (doi:10.1515/BC.2008.026)

    • Search Google Scholar
    • Export Citation
  • Lovis et al. 2008b

    LovisPRoggliELaybuttDRGattescoSYangJYWidmannCAbderrahmaniARegazziR2008bAlterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes5727282736. (doi:10.2337/db07-1252)

    • Search Google Scholar
    • Export Citation
  • Lu et al. 2008

    LuZLiuMStribinskisVKlingeCMRamosKSColburnNHLiY2008MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene2743734379. (doi:10.1038/onc.2008.72)

    • Search Google Scholar
    • Export Citation
  • Lu et al. 2010

    LuHBuchanRJCookSA2010MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovascular Research86410420. (doi:10.1093/cvr/cvq010)

    • Search Google Scholar
    • Export Citation
  • Mah et al. 2002

    MahCByrneBJFlotteTR2002Virus-based gene delivery systems. Clinical Pharmacokinetics41901911. (doi:10.2165/00003088-200241120-00001)

  • Meerson et al. 2013

    MeersonATraurigMOssowskiVFlemingJMMullinsMBaierLJ2013Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia5619711979. (doi:10.1007/s00125-013-2950-9)

    • Search Google Scholar
    • Export Citation
  • Merrins and Stuenkel, 2008

    MerrinsMJStuenkelEL2008Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic β-cells. Journal of Physiology58653675381. (doi:10.1113/jphysiol.2008.158477)

    • Search Google Scholar
    • Export Citation
  • Nielsen et al. 2012

    NielsenLBWangCSorensenKBang-BerthelsenCHHansenLAndersenMLHougaardPJuulAZhangCYPociotF2012Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual β-cell function and glycaemic control during disease progression. Experimental Diabetes Research2012896362. (doi:10.1155/2012/896362)

    • Search Google Scholar
    • Export Citation
  • Parra et al. 2010

    ParraPSerraFPalouA2010Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS ONE5e13005. (doi:10.1371/journal.pone.0013005)

    • Search Google Scholar
    • Export Citation
  • Peppa et al. 2010

    PeppaMKoliakiCNikolopoulosPRaptisSA2010Skeletal muscle insulin resistance in endocrine disease. Journal of Biomedicine & Biotechnology2010527850. (doi:10.1155/2010/527850)

    • Search Google Scholar
    • Export Citation
  • Pescador et al. 2013

    PescadorNPerez-BarbaMIbarraJMCorbatonAMartinez-LarradMTSerrano-RiosM2013Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS ONE8e77251. (doi:10.1371/journal.pone.0077251)

    • Search Google Scholar
    • Export Citation
  • Plaisance et al. 2006

    PlaisanceVAbderrahmaniAPerret-MenoudVJacqueminPLemaigreFRegazziR2006MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. Journal of Biological Chemistry2812693226942. (doi:10.1074/jbc.M601225200)

    • Search Google Scholar
    • Export Citation
  • Poy et al. 2004

    PoyMNEliassonLKrutzfeldtJKuwajimaSMaXMacdonaldPEPfefferSTuschlTRajewskyNRorsmanP2004A pancreatic islet-specific microRNA regulates insulin secretion. Nature432226230. (doi:10.1038/nature03076)

    • Search Google Scholar
    • Export Citation
  • Poy et al. 2009

    PoyMNHausserJTrajkovskiMBraunMCollinsSRorsmanPZavolanMStoffelM2009miR-375 maintains normal pancreatic α- and β-cell mass. PNAS10658135818. (doi:10.1073/pnas.0810550106)

    • Search Google Scholar
    • Export Citation
  • Pullen et al. 2011

    PullenTJda Silva XavierGKelseyGRutterGA2011miR-29a and miR-29b contribute to pancreatic β-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Molecular and Cellular Biology3131823194. (doi:10.1128/MCB.01433-10)

    • Search Google Scholar
    • Export Citation
  • Ramachandran et al. 2011

    RamachandranDRoyUGargSGhoshSPathakSKolthur-SeetharamU2011Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin secretion in pancreatic β-islets. FEBS Journal27811671174. (doi:10.1111/j.1742-4658.2011.08042.x)

    • Search Google Scholar
    • Export Citation
  • Roggli et al. 2010

    RoggliEBritanAGattescoSLin-MarqNAbderrahmaniAMedaPRegazziR2010Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes59978986. (doi:10.2337/db09-0881)

    • Search Google Scholar
    • Export Citation
  • Roggli et al. 2012

    RoggliEGattescoSCailleDBrietCBoitardCMedaPRegazziR2012Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes6117421751. (doi:10.2337/db11-1086)

    • Search Google Scholar
    • Export Citation
  • Rorsman and Braun, 2013

    RorsmanPBraunM2013Regulation of insulin secretion in human pancreatic islets. Annual Review of Physiology75155179. (doi:10.1146/annurev-physiol-030212-183754)

    • Search Google Scholar
    • Export Citation
  • Rottiers and Naar, 2012

    RottiersVNaarAM2012MicroRNAs in metabolism and metabolic disorders. Nature Reviews. Molecular Cell Biology13239250. (doi:10.1038/nrm3313)

    • Search Google Scholar
    • Export Citation
  • Ruan et al. 2011

    RuanQWangTKameswaranVWeiQJohnsonDSMatschinskyFShiWChenYH2011The microRNA-21–PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death. PNAS1081203012035. (doi:10.1073/pnas.1101450108)

    • Search Google Scholar
    • Export Citation
  • Ryu et al. 2011

    RyuHSParkSYMaDAZhangJLeeW2011The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes. PLoS ONE6 e17343. (doi:10.1371/journal.pone.0017343)

    • Search Google Scholar
    • Export Citation
  • Salas-Perez et al. 2013

    Salas-PerezFCodnerEValenciaEPizarroCCarrascoEPerez-BravoF2013MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology218733737. (doi:10.1016/j.imbio.2012.08.276)

    • Search Google Scholar
    • Export Citation
  • Samuel and Shulman, 2012

    SamuelVTShulmanGI2012Mechanisms for insulin resistance: common threads and missing links. Cell148852871. (doi:10.1016/j.cell.2012.02.017)

    • Search Google Scholar
    • Export Citation
  • Sebastiani et al. 2011

    SebastianiGGriecoFASpagnuoloIGalleriLCataldoDDottaF2011Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes/Metabolism Research and Reviews27862866. (doi:10.1002/dmrr.1262)

    • Search Google Scholar
    • Export Citation
  • Sun et al. 2011

    SunLLJiangBGLiWTZouJJShiYQLiuZM2011MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Research and Clinical Practice9194100. (doi:10.1016/j.diabres.2010.11.006)

    • Search Google Scholar
    • Export Citation
  • Takanabe et al. 2008

    TakanabeROnoKAbeYTakayaTHorieTWadaHKitaTSatohNShimatsuAHasegawaK2008Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. Biochemical and Biophysical Research Communications376728732. (doi:10.1016/j.bbrc.2008.09.050)

    • Search Google Scholar
    • Export Citation
  • Trajkovski et al. 2011

    TrajkovskiMHausserJSoutschekJBhatBAkinAZavolanMHeimMHStoffelM2011MicroRNAs 103 and 107 regulate insulin sensitivity. Nature474649653. (doi:10.1038/nature10112)

    • Search Google Scholar
    • Export Citation
  • Wang et al. 2010

    WangGKZhuJQZhangJTLiQLiYHeJQinYWJingQ2010Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. European Heart Journal31659666. (doi:10.1093/eurheartj/ehq013)

    • Search Google Scholar
    • Export Citation
  • Wang et al. 2011

    WangRHKimHSXiaoCYXuXLGavrilovaODengCX2011Hepatic Sirt1 deficiency in mice impairs mTORC2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. Journal of Clinical Investigation12144774490. (doi:10.1172/JCI46243)

    • Search Google Scholar
    • Export Citation
  • Weiler et al. 2006

    WeilerJHunzikerJHallJ2006Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?Gene Therapy13496502. (doi:10.1038/sj.gt.3302654)

    • Search Google Scholar
    • Export Citation
  • Williams and Mitchell, 2012

    WilliamsMDMitchellGM2012MicroRNAs in insulin resistance and obesity. Experimental Diabetes Research2012484696. (doi:10.1155/2012/484696)

    • Search Google Scholar
    • Export Citation
  • Xiao et al. 2012

    XiaoJMengXMHuangXRChungACFengYLHuiDSYuCMSungJJLanHY2012miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Molecular Therapy2012511260. (doi:10.1038/mt.2012.36)

    • Search Google Scholar
    • Export Citation
  • Yang et al. 2012

    YangYMSeoSYKimTHKimSG2012Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid. Hepatology5622092220. (doi:10.1002/hep.25912)

    • Search Google Scholar
    • Export Citation
  • Zampetaki et al. 2010

    ZampetakiAKiechlSDrozdovIWilleitPMayrUProkopiMMayrAWegerSOberhollenzerFBonoraE2010Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circulation Research107810817. (doi:10.1161/CIRCRESAHA.110.226357)

    • Search Google Scholar
    • Export Citation
  • Zhang et al. 2014

    ZhangYRu HuangXWeiLHChungACYuCMLanHY2014miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Molecular Therapy22974985. (doi:10.1038/mt.2014.25)

    • Search Google Scholar
    • Export Citation
  • Zhao et al. 2011

    ZhaoCDongJJiangTShiZYuBZhuYChenDXuJHuoRDaiJ2011Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS ONE6e23925. (doi:10.1371/journal.pone.0023925)

    • Search Google Scholar
    • Export Citation
  • Zhao et al. 2012

    ZhaoXMohanROzcanSTangX2012MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase 4 (MAP4K4) in pancreatic β-cells. Journal of Biological Chemistry2873115531164. (doi:10.1074/jbc.M112.362632)

    • Search Google Scholar
    • Export Citation
  • Zhong et al. 2013

    ZhongXChungACChenHYDongYMengXMLiRYangWHouFFLanHY2013miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia56663674. (doi:10.1007/s00125-012-2804-x)

    • Search Google Scholar
    • Export Citation
  • Zhou et al. 2012

    ZhouBLiCQiWZhangYZhangFWuJXHuYNWuDMLiuYYanTT2012Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia5520322043. (doi:10.1007/s00125-012-2539-8)

    • Search Google Scholar
    • Export Citation
  • Zhu et al. 2011

    ZhuHShyh-ChangNSegreAVShinodaGShahSPEinhornWSTakeuchiAEngreitzJMHaganJPKharasMG2011The Lin28/let-7 axis regulates glucose metabolism. Cell1478194. (doi:10.1016/j.cell.2011.08.033)

    • Search Google Scholar
    • Export Citation