<i>In Vivo</i> Silencing of MicroRNA-132 Reduces Blood Glucose and Improves Insulin Secretion

Bijkerk, Roel; Esguerra, Jonathan L.S.; Ellenbroek, Johanne H.; Au, Yu Wah; Hanegraaf, Maaike; Koning, Eelco J.P. de; Eliasson, Lena; Zonneveld, Anton Jan van

doi:10.1089/nat.2018.0763

Cited by 30 publications

(18 citation statements)

References 19 publications

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“…Although T2D pathogenesis is multifactorial, growing evidence supports a role of miRNAs in regulation of glucose homeostasis and metabolism (5,26,27,34,40,41). miRNAs are important candidates, as a single miRNA can regulate multiple target genes that ultimately result in widespread changes in the protein levels of hundreds to thousands of genes.…”

Section: Discussionmentioning

confidence: 99%

Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

et al. 2019

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MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of diabetic patients. Here we investigated how miR-199 expression is regulated in β-cells by assessing expression of miR-199 precursors (primiR-199a1, primiR-199a2, and primiR-199b) and mature miR-199 (miR-199-3p and miR-199-5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma cells (MIN6) under different stimuli. We found that mouse islets equally express miR-199-3p and miR-199-5p. However, the primiRNA expression levels differed; although primiR-199a1 expression was about 30% greater than that of primiR-199a2, primiR-199b is barely detected in islets. We observed a 2-fold increase in primiR-199a1 and primiR-199a2 mRNA levels in mouse islets cultured in 10 mm glucose compared with 5.5 mm glucose. Similar responses to glucose were observed in MIN6 cells. Exposure to 30 mm KCl to induce membrane depolarization and calcium influx increased expression of primiR-199a2 but not of primiR-199a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 cells also revealed that primiR-199a2 promoter activity was enhanced by glucose and reduced by 2-deoxy-D-glucose–induced starvation. KCl and the potassium channel blocker tolbutamide also stimulated primiR-199a2 promoter activity. Calcium channel blockade by nifedipine reduced primiR-199a2 promoter activity in MIN6 cells, and diazoxide-mediated calcium influx inhibition blunted glucose up-regulation of miR-199-3p in islets. In conclusion, we uncover that glucose acutely up-regulates miR-199 family expression in β-cells. Glucose metabolism and calcium influx are involved in primiR-199a2 expression but not primiR-199a1 expression.

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Section: Discussionmentioning

confidence: 99%

Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

et al. 2019

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“…However, like any drug-development strategies, a huge challenge is tissue-specific delivery of these RNAbased therapeutics. In our work, systemic injection of antagomir-132 resulted in its delivery in the pancreatic islets resulting in reduced miR-132 levels and subsequent glycemic improvement in the mice (72). Although a promising "proof-of-concept" work in the field, specific delivery into the relevant cells/tissue of RNA-based drugs is highly desired.…”

Section: Mirnas As Therapeutic Tools In Diabetes Treatmentmentioning

confidence: 92%

“…Currently several candidates are in phase 1 and phase 2 clinical trials, e.g., a locked nucleic acid (LNA)-based drug to inhibit miR-92 has potential in wound healing (70). In attempts to treat T2D, studies in animal models have used strategies that could be potentially translated to humans (71)(72)(73). Different approaches to silence the miRNAs using chemically modified antagomirs have been employed in these studies.…”

Section: Mirnas As Therapeutic Tools In Diabetes Treatmentmentioning

confidence: 99%

MicroRNA Networks in Pancreatic Islet Cells: Normal Function and Type 2 Diabetes

Eliasson

Esguerra

2020

Diabetes

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Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA–mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto-Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.

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“…Many studies have explored the role of miRNA in RAGE–AGE signalling pathways involved in the progression of diabetic nephropathy and atherosclerosis, revealing elevated oxidative stress that mediates apoptosis (Feng et al, 2016; Hagiwara et al, 2013; Ma et al, 2017; Piperi et al, 2015). Intriguingly, Bijkerk et al (2019) demonstrated that DIAPH1 expression was a target of miRNA‐132. Decreased expression of miRNA‐132 is linked to decreased blood glucose and increased insulin secretion in mice with diabetes (Bijkerk et al, 2019).…”

Section: The Rage Diaph1 and Another Rage Ligands In Neurological Complications Of Dmmentioning

confidence: 99%

The cross‐talk between RAGE and DIAPH1 in neurological complications of diabetes: A review

Zglejc-Waszak

Mukherjee

Juranek

2021

Eur J of Neuroscience

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Neuropathy, or dysfunction of peripheral nerve, is one of the most common neurological manifestation in patients with diabetes mellitus (DM). DM is typically associated with a hyperglycaemic milieu, which promotes non‐enzymatic glycation of proteins. Proteins with advanced glycation are known to engage a cell‐surface receptor called the receptor for advanced glycation end products (RAGE). Thus, it is reasonable to assume that RAGE and its associated molecule‐mediated cellular signalling may contribute to DM‐induced symmetrical axonal (length‐dependent) neuropathy. Of particular interest is diaphanous related formin 1 (DIAPH1), a cytoskeletal organizing molecule, which interacts with the cytosolic domain of RAGE and whose dysfunction may precipitate axonopathy/neuropathy. Indeed, it has been demonstrated that both RAGE and DIAPH1 are expressed in the motor and sensory fibres of nerve harvested from DM animal models. Although the detailed molecular role of RAGE and DIAPH1 in diabetic neurological complications remains unclear, here we will discuss available evidence of their involvement in peripheral diabetic neuropathy. Specifically, we will discuss how a hyperglycaemic environment is not only likely to elevate advanced glycation end products (ligands of RAGE) and induce a pro‐inflammatory environment but also alter signalling via RAGE and DIAPH1. Further, hyperglycaemia may regulate epigenetic mechanisms that interacts with RAGE signalling. We suggest the cumulative effect of hyperglycaemia on RAGE–DIAPH1‐mediated signalling may be disruptive to axonal cytoskeletal organization and transport and is therefore likely to play a key role in pathogenesis of diabetic symmetrical axonal neuropathy.

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In Vivo Silencing of MicroRNA-132 Reduces Blood Glucose and Improves Insulin Secretion

Cited by 30 publications

References 19 publications

Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

MicroRNA Networks in Pancreatic Islet Cells: Normal Function and Type 2 Diabetes

The cross‐talk between RAGE and DIAPH1 in neurological complications of diabetes: A review

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