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).
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).
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 Association Economic costs of diabetes in the U.S. in 2012 Diabetes Care 36 2013 1033–1046. (doi:10.2337/dc12-2625)
- Aronovich et al. 2011↑
Aronovich EL, McIvor RS & Hackett PB 2011 The sleeping beauty transposon system: a non-viral vector for gene therapy. Human Molecular Genetics 20 R14–R20. (doi:10.1093/hmg/ddr140)
- Baroukh et al. 2007↑
Baroukh N, Ravier MA, Loder MK, Hill EV, Bounacer A, Scharfmann R, Rutter GA & Van Obberghen E 2007 MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic β-cell lines. Journal of Biological Chemistry 282 19575–19588. (doi:10.1074/jbc.M611841200)
- Bartel, 2004↑
Bartel DP 2004 MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116 281–297. (doi:10.1016/S0092-8674(04)00045-5)
- Bordone et al. 2006↑
Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M & Szilvasi A et al. 2006 Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biology 4 e31. (doi:10.1371/journal.pbio.0040031)
- Chen et al. 2011↑
Chen HY, Huang XR, Wang W, Li JH, Heuchel RL, Chung AC & Lan HY 2011 The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes 60 590–601. (doi:10.2337/db10-0403)
- Chen et al. 2013↑
Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, Chen BS, Chazenbalk G & Azziz R 2013 miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 62 2278–2286. (doi:10.2337/db12-0963)
- Chen et al. 2014↑
Chen HY, Zhong X, Huang XR, Meng XM, You Y, Chung AC & Lan HY 2014 MicroRNA-29b inhibits diabetic nephropathy in db/db mice. Molecular Therapy 22 842–853. (doi:10.1038/mt.2013.235)
- Czech et al. 2011↑
Czech MP, Aouadi M & Tesz GJ 2011 RNAi-based therapeutic strategies for metabolic disease. Nature Reviews. Endocrinology 7 473–484. (doi:10.1038/nrendo.2011.57)
- Dou et al. 2013↑
Dou L, Zhao T, Wang L, Huang X, Jiao J, Gao D, Zhang H, Shen T, Man Y & Wang S et al. 2013 miR-200s contribute to interleukin-6 (IL-6)-induced insulin resistance in hepatocytes. Journal of Biological Chemistry 288 22596–22606. (doi:10.1074/jbc.M112.423145)
- El Ouaamari et al. 2008↑
El Ouaamari A, Baroukh N, Martens GA, Lebrun P, Pipeleers D & van Obberghen E 2008 miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic β-cells. Diabetes 57 2708–2717. (doi:10.2337/db07-1614)
- Erener et al. 2013↑
Erener S, Mojibian M, Fox JK, Denroche HC & Kieffer TJ 2013 Circulating miR-375 as a biomarker of β-cell death and diabetes in mice. Endocrinology 154 603–608. (doi:10.1210/en.2012-1744)
- Fernandez-Valverde et al. 2011↑
Fernandez-Valverde SL, Taft RJ & Mattick JS 2011 MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Diabetes 60 1825–1831. (doi:10.2337/db11-0171)
- Fowler, 2008↑
Fowler MJ 2008 Microvascular and macrovascular complications of diabetes. Clinical Diabetes 26 77–82. (doi:10.2337/diaclin.26.2.77)
- Frost and Olson, 2011↑
Frost RJ & Olson EN 2011 Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. PNAS 108 21075–21080. (doi:10.1073/pnas.1118922109)
- Guay and Regazzi, 2013↑
Guay C & Regazzi R 2013 Circulating microRNAs as novel biomarkers for diabetes mellitus. Nature Reviews. Endocrinology 9 513–521. (doi:10.1038/nrendo.2013.86)
- Guay et al. 2011↑
Guay C, Roggli E, Nesca V, Jacovetti C & Regazzi R 2011 Diabetes mellitus, a microRNA-related disease? Translational Research 157 253–264. (doi:10.1016/j.trsl.2011.01.009)
- Hashimoto et al. 2006↑
Hashimoto N, Kido Y, Uchida T, Asahara S, Shigeyama Y, Matsuda T, Takeda A, Tsuchihashi D, Nishizawa A & Ogawa W et al. 2006 Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nature Genetics 38 589–593. (doi:10.1038/ng1774)
- He et al. 2007↑
He A, Zhu L, Gupta N, Chang Y & Fang F 2007 Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Molecular Endocrinology 21 2785–2794. (doi:10.1210/me.2007-0167)
- Herrera et al. 2009↑
Herrera BM, Lockstone HE, Taylor JM, Wills QF, Kaisaki PJ, Barrett A, Camps C, Fernandez C, Ragoussis J & Gauguier D et al. 2009 MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of type 2 diabetes. BMC Medical Genomics 2 54. (doi:10.1186/1755-8794-2-54)
- Herrera et al. 2010↑
Herrera BM, Lockstone HE, Taylor JM, Ria M, Barrett A, Collins S, Kaisaki P, Argoud K, Fernandez C & Travers ME et al. 2010 Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53 1099–1109. (doi:10.1007/s00125-010-1667-2)
- Huang et al. 2009↑
Huang B, Qin W, Zhao B, Shi Y, Yao C, Li J, Xiao H & Jin Y 2009 MicroRNA expression profiling in diabetic GK rat model. Acta Biochimica et Biophysica Sinica 41 472–477. (doi:10.1093/abbs/gmp035)
- Jeong et al. 2013↑
Jeong HJ, Park SY, Yang WM & Lee W 2013 The 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 Communications 434 503–508. (doi:10.1016/j.bbrc.2013.03.104)
- Jia and Zhou, 2005↑
Jia W & Zhou Q 2005 Viral vectors for cancer gene therapy: viral dissemination and tumor targeting. Current Gene Therapy 5 133–142. (doi:10.2174/1566523052997460)
- Jordan et al. 2011↑
Jordan SD, Kruger M, Willmes DM, Redemann N, Wunderlich FT, Bronneke HS, Merkwirth C, Kashkar H, Olkkonen VM & Bottger T et al. 2011 Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nature Cell Biology 13 434–446. (doi:10.1038/ncb2211)
- Joven et al. 2012↑
Joven J, Espinel E, Rull A, Aragones G, Rodriguez-Gallego E, Camps J, Micol V, Herranz-Lopez M, Menendez JA & Borras I et al. 2012 Plant-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 Acta 1820 894–899. (doi:10.1016/j.bbagen.2012.03.020)
- Karolina et al. 2011↑
Karolina DS, Armugam A, Tavintharan S, Wong MT, Lim SC, Sum CF & Jeyaseelan K 2011 MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PLoS ONE 6 e22839. (doi:10.1371/journal.pone.0022839)
- Katta et al. 2013↑
Katta A, Thulluri S, Manne ND, Addagarla HS, Arvapalli R, Nalabotu SK, Gadde M, Rice KM & Blough ER 2013 Overload induced heat shock proteins (HSPs), MAPK and miRNA (miR-1 and miR133a) response in insulin-resistant skeletal muscle. Cellular Physiology and Biochemistry 31 219–229. (doi:10.1159/000343363)
- Kloosterman et al. 2007↑
Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD & Plasterk RH 2007 Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biology 5 e203. (doi:10.1371/journal.pbio.0050203)
- Kong et al. 2011↑
Kong L, Zhu J, Han W, Jiang X, Xu M, Zhao Y, Dong Q, Pang Z, Guan Q & Gao L et al. 2011 Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetologia 48 61–69. (doi:10.1007/s00592-010-0226-0)
- Kornfeld et al. 2013↑
Kornfeld JW, Baitzel C, Konner AC, Nicholls HT, Vogt MC, Herrmanns K, Scheja L, Haumaitre C, Wolf AM & Knippschild U et al. 2013 Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494 111–115. (doi:10.1038/nature11793)
- Lan et al. 2003↑
Lan HY, Mu W, Tomita N, Huang XR, Li JH, Zhu HJ, Morishita R & Johnson RJ 2003 Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. Journal of the American Society of Nephrology 14 1535–1548. (doi:10.1097/01.ASN.0000067632.04658.B8)
- Layden et al. 2010↑
Layden BT, Durai V & Lowe WL Jr 2010 G-protein-coupled receptors, pancreatic islets, and diabetes. Nature Education 3 13.
- Lee et al. 2013↑
Lee H, Jee Y, Hong K, Hwang GS & Chun KH 2013 MicroRNA-494, upregulated by tumor necrosis factor-α, desensitizes insulin effect in C2C12 muscle cells. PLoS ONE 8 e83471. (doi:10.1371/journal.pone.0083471)
- Li et al. 2010
Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY & Zen K 2010 Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Research 70 9798–9807. (doi:10.1158/0008-5472.CAN-10-1001)
- Ling et al. 2009↑
Ling HY, Ou HS, Feng SD, Zhang XY, Tuo QH, Chen LX, Zhu BY, Gao ZP, Tang CK & Yin WD et al. 2009 Changes in microRNA (miR) profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clinical and Experimental Pharmacology & Physiology 36 e32–e39. (doi:10.1111/j.1440-1681.2009.05207.x)
- Ling et al. 2012↑
Ling HY, Hu B, Hu XB, Zhong J, Feng SD, Qin L, Liu G, Wen GB & Liao DF 2012 miRNA-21 reverses high glucose and high insulin induced insulin resistance in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue. Experimental and Clinical Endocrinology & Diabetes 120 553–559. (doi:10.1055/s-0032-1311644)
- Lovis et al. 2008a↑
Lovis P, Gattesco S & Regazzi R 2008a Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs. Biological Chemistry 389 305–312. (doi:10.1515/BC.2008.026)
- Lovis et al. 2008b↑
Lovis P, Roggli E, Laybutt DR, Gattesco S, Yang JY, Widmann C, Abderrahmani A & Regazzi R 2008b Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes 57 2728–2736. (doi:10.2337/db07-1252)
- Lu et al. 2008↑
Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH & Li Y 2008 MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27 4373–4379. (doi:10.1038/onc.2008.72)
- Lu et al. 2010↑
Lu H, Buchan RJ & Cook SA 2010 MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovascular Research 86 410–420. (doi:10.1093/cvr/cvq010)
- Mah et al. 2002↑
Mah C, Byrne BJ & Flotte TR 2002 Virus-based gene delivery systems. Clinical Pharmacokinetics 41 901–911. (doi:10.2165/00003088-200241120-00001)
- Meerson et al. 2013↑
Meerson A, Traurig M, Ossowski V, Fleming JM, Mullins M & Baier LJ 2013 Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia 56 1971–1979. (doi:10.1007/s00125-013-2950-9)
- Merrins and Stuenkel, 2008↑
Merrins MJ & Stuenkel EL 2008 Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic β-cells. Journal of Physiology 586 5367–5381. (doi:10.1113/jphysiol.2008.158477)
- Nielsen et al. 2012↑
Nielsen LB, Wang C, Sorensen K, Bang-Berthelsen CH, Hansen L, Andersen ML, Hougaard P, Juul A, Zhang CY & Pociot F et al. 2012 Circulating 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 Research 2012 896362. (doi:10.1155/2012/896362)
- Parra et al. 2010↑
Parra P, Serra F & Palou A 2010 Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS ONE 5 e13005. (doi:10.1371/journal.pone.0013005)
- Peppa et al. 2010↑
Peppa M, Koliaki C, Nikolopoulos P & Raptis SA 2010 Skeletal muscle insulin resistance in endocrine disease. Journal of Biomedicine & Biotechnology 2010 527850. (doi:10.1155/2010/527850)
- Pescador et al. 2013↑
Pescador N, Perez-Barba M, Ibarra JM, Corbaton A, Martinez-Larrad MT & Serrano-Rios M 2013 Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS ONE 8 e77251. (doi:10.1371/journal.pone.0077251)
- Plaisance et al. 2006↑
Plaisance V, Abderrahmani A, Perret-Menoud V, Jacquemin P, Lemaigre F & Regazzi R 2006 MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. Journal of Biological Chemistry 281 26932–26942. (doi:10.1074/jbc.M601225200)
- Poy et al. 2004↑
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N & Rorsman P et al. 2004 A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432 226–230. (doi:10.1038/nature03076)
- Poy et al. 2009↑
Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M & Stoffel M 2009 miR-375 maintains normal pancreatic α- and β-cell mass. PNAS 106 5813–5818. (doi:10.1073/pnas.0810550106)
- Pullen et al. 2011↑
Pullen TJ, da Silva Xavier G, Kelsey G & Rutter GA 2011 miR-29a and miR-29b contribute to pancreatic β-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Molecular and Cellular Biology 31 3182–3194. (doi:10.1128/MCB.01433-10)
- Ramachandran et al. 2011↑
Ramachandran D, Roy U, Garg S, Ghosh S, Pathak S & Kolthur-Seetharam U 2011 Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin secretion in pancreatic β-islets. FEBS Journal 278 1167–1174. (doi:10.1111/j.1742-4658.2011.08042.x)
- Roggli et al. 2010↑
Roggli E, Britan A, Gattesco S, Lin-Marq N, Abderrahmani A, Meda P & Regazzi R 2010 Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes 59 978–986. (doi:10.2337/db09-0881)
- Roggli et al. 2012↑
Roggli E, Gattesco S, Caille D, Briet C, Boitard C, Meda P & Regazzi R 2012 Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes 61 1742–1751. (doi:10.2337/db11-1086)
- Rorsman and Braun, 2013↑
Rorsman P & Braun M 2013 Regulation of insulin secretion in human pancreatic islets. Annual Review of Physiology 75 155–179. (doi:10.1146/annurev-physiol-030212-183754)
- Rottiers and Naar, 2012↑
Rottiers V & Naar AM 2012 MicroRNAs in metabolism and metabolic disorders. Nature Reviews. Molecular Cell Biology 13 239–250. (doi:10.1038/nrm3313)
- Ruan et al. 2011↑
Ruan Q, Wang T, Kameswaran V, Wei Q, Johnson DS, Matschinsky F, Shi W & Chen YH 2011 The microRNA-21–PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death. PNAS 108 12030–12035. (doi:10.1073/pnas.1101450108)
- Ryu et al. 2011↑
Ryu HS, Park SY, Ma DA, Zhang J & Lee W 2011 The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes. PLoS ONE 6 e17343. (doi:10.1371/journal.pone.0017343)
- Salas-Perez et al. 2013↑
Salas-Perez F, Codner E, Valencia E, Pizarro C, Carrasco E & Perez-Bravo F 2013 MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 218 733–737. (doi:10.1016/j.imbio.2012.08.276)
- Samuel and Shulman, 2012↑
Samuel VT & Shulman GI 2012 Mechanisms for insulin resistance: common threads and missing links. Cell 148 852–871. (doi:10.1016/j.cell.2012.02.017)
- Sebastiani et al. 2011↑
Sebastiani G, Grieco FA, Spagnuolo I, Galleri L, Cataldo D & Dotta F 2011 Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes/Metabolism Research and Reviews 27 862–866. (doi:10.1002/dmrr.1262)
- Sun et al. 2011↑
Sun LL, Jiang BG, Li WT, Zou JJ, Shi YQ & Liu ZM 2011 MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Research and Clinical Practice 91 94–100. (doi:10.1016/j.diabres.2010.11.006)
- Takanabe et al. 2008↑
Takanabe R, Ono K, Abe Y, Takaya T, Horie T, Wada H, Kita T, Satoh N, Shimatsu A & Hasegawa K 2008 Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. Biochemical and Biophysical Research Communications 376 728–732. (doi:10.1016/j.bbrc.2008.09.050)
- Trajkovski et al. 2011↑
Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, Heim MH & Stoffel M 2011 MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474 649–653. (doi:10.1038/nature10112)
- Wang et al. 2010↑
Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, Qin YW & Jing Q 2010 Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. European Heart Journal 31 659–666. (doi:10.1093/eurheartj/ehq013)
- Wang et al. 2011↑
Wang RH, Kim HS, Xiao CY, Xu XL, Gavrilova O & Deng CX 2011 Hepatic Sirt1 deficiency in mice impairs mTORC2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. Journal of Clinical Investigation 121 4477–4490. (doi:10.1172/JCI46243)
- Weiler et al. 2006↑
Weiler J, Hunziker J & Hall J 2006 Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? Gene Therapy 13 496–502. (doi:10.1038/sj.gt.3302654)
- Williams and Mitchell, 2012↑
Williams MD & Mitchell GM 2012 MicroRNAs in insulin resistance and obesity. Experimental Diabetes Research 2012 484696. (doi:10.1155/2012/484696)
- Xiao et al. 2012↑
Xiao J, Meng XM, Huang XR, Chung AC, Feng YL, Hui DS, Yu CM, Sung JJ & Lan HY 2012 miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Molecular Therapy 20 1251–1260. (doi:10.1038/mt.2012.36)
- Yang et al. 2012↑
Yang YM, Seo SY, Kim TH & Kim SG 2012 Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid. Hepatology 56 2209–2220. (doi:10.1002/hep.25912)
- Zampetaki et al. 2010↑
Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F & Bonora E et al. 2010 Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circulation Research 107 810–817. (doi:10.1161/CIRCRESAHA.110.226357)
- Zhang et al. 2014↑
Zhang Y, Ru Huang X, Wei LH, Chung AC, Yu CM & Lan HY 2014 miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Molecular Therapy 22 974–985. (doi:10.1038/mt.2014.25)
- Zhao et al. 2011↑
Zhao C, Dong J, Jiang T, Shi Z, Yu B, Zhu Y, Chen D, Xu J, Huo R & Dai J et al. 2011 Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS ONE 6 e23925. (doi:10.1371/journal.pone.0023925)
- Zhao et al. 2012↑
Zhao X, Mohan R, Ozcan S & Tang X 2012 MicroRNA-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 Chemistry 287 31155–31164. (doi:10.1074/jbc.M112.362632)
- Zhong et al. 2013↑
Zhong X, Chung AC, Chen HY, Dong Y, Meng XM, Li R, Yang W, Hou FF & Lan HY 2013 miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia 56 663–674. (doi:10.1007/s00125-012-2804-x)
- Zhou et al. 2012↑
Zhou B, Li C, Qi W, Zhang Y, Zhang F, Wu JX, Hu YN, Wu DM, Liu Y & Yan TT et al. 2012 Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 55 2032–2043. (doi:10.1007/s00125-012-2539-8)
- Zhu et al. 2011↑
Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP & Kharas MG et al. 2011 The Lin28/let-7 axis regulates glucose metabolism. Cell 147 81–94. (doi:10.1016/j.cell.2011.08.033)
