AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet

Mulder, Niels L.; Havinga, Rick; Kluiver, Joost; Groen, Albert K.; Kruit, Janine K.

doi:10.1530/joe-18-0287

Cited by 17 publications

(22 citation statements)

References 30 publications

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“…No link between miR-132 expression and pancreatitis was reported so far. However, miR-132 expression is reported to be upregulated in beta cells of the pancreas in response to hyperglycemia and obesity 56,57 . In previous studies we could prove that hyperglycemia is not observed during a cerulein induced pancreatitis 58,59 .…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases

Kumstel

Janssen-Peters

Abdelrahman

et al. 2020

Sci Rep

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Severity assessment of animal experiments is mainly conducted by using subjective parameters. A widely applicable biomarker to assess animal distress could contribute to an objective severity assessment in different animal models. Here, the distress of three murine animal models for gastrointestinal diseases was assessed by multiple behavioral and physiological parameters. To identify possible new biomarkers for distress 750 highly conserved microRNAs were measured in the blood plasma of mice before and after the induction of pancreatitis. Deregulated miRNA candidates were identified and further quantified in additional animal models for pancreatic cancer and cholestasis. MiR-375 and miR-203 were upregulated during pancreatitis and down regulated during cholestasis, whereas miR-132 was upregulated in all models. Correlation between miR-132 and plasma corticosterone concentrations resulted in the highest correlation coefficient, when compared to the analysis of miR-375, miR-203 and miR-30b. These results indicate that miR-132 might function as a general biomarker for distress, whereas the other miRNAs were altered in a disease specific manner. In conclusion, plasma miRNA profiling may help to better characterize the level of distress in mouse models for gastrointestinal diseases.

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Section: Discussionmentioning

confidence: 99%

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases

Kumstel

Janssen-Peters

Abdelrahman

et al. 2020

Sci Rep

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“…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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“…Mulder et al used a different approach to treat high-fat diet fed mice. In this case, the authors generated an AAV8 construct that enables the overexpression of miR-132 [66], a miRNA with a beneficial impact on β-cell function and that is normally involved in the adaptation of β-cells to insulin resistance (see above). The expression of the construct was under the control of the rat insulin promoter and was therefore restricted to β-cells [66].…”

Section: Mirnas As Potential Therapeutic Targets For T2dmentioning

confidence: 99%

“…In this case, the authors generated an AAV8 construct that enables the overexpression of miR-132 [66], a miRNA with a beneficial impact on β-cell function and that is normally involved in the adaptation of β-cells to insulin resistance (see above). The expression of the construct was under the control of the rat insulin promoter and was therefore restricted to β-cells [66]. Interestingly, overexpression of miR-132 did not affect glucose homeostasis in mice kept on regular chow diet but enhanced insulin secretion and increased β-cell proliferation in mice on high-fat diet, resulting in improved blood glucose control [66].…”

Section: Mirnas As Potential Therapeutic Targets For T2dmentioning

confidence: 99%

“…The expression of the construct was under the control of the rat insulin promoter and was therefore restricted to β-cells [66]. Interestingly, overexpression of miR-132 did not affect glucose homeostasis in mice kept on regular chow diet but enhanced insulin secretion and increased β-cell proliferation in mice on high-fat diet, resulting in improved blood glucose control [66]. In a more recent study, Bijirk et al investigated the effect of in vivo injection of cholesterol-conjugated antagomirs targeting miR-132 on islet function in mice [67].…”

Section: Mirnas As Potential Therapeutic Targets For T2dmentioning

confidence: 99%

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Micro(RNA) Management and Mismanagement of the Islet

Eliasson

Regazzi

2020

Journal of Molecular Biology

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Pancreatic β-cells located within the islets of Langerhans play a central role in metabolic control. The main function of these cells is to produce and secrete insulin in response to a rise in circulating levels of glucose and other nutrients. The release of insufficient insulin to cover the organism needs results in chronic hyperglycemia and diabetes development. β-cells insure a highly specialized task and to efficiently accomplish their function they need to express a specific set of genes. MicroRNAs (miRNAs) are small non-coding RNAs and key regulators of gene expression. Indeed, by partially pairing to specific sequences in the 3' untranslated regions of target mRNAs, each of them can control the translation of hundreds of transcripts. In this review, we focus on few key miRNAs controlling islet function and discuss: their differential expression in Type 2 diabetes (T2D), their regulation by genetic and environmental factors, and their therapeutic potential. Genetic and epigenetic changes or prolonged exposure to hyperglycemia and/or hyperlipidemia can affect the β-cell miRNA expression profile, resulting in impaired β-cell function and survival leading to the development of T2D. Experimental approaches permitting to correct the level of mis-expressed miRNAs have been shown to prevent or treat T2D in animal models, suggesting that these small RNAs may become interesting therapeutic targets. However, translation of these experimental findings to the clinics will necessitate the development of innovative strategies allowing safe and specific delivery of compounds modulating the level of the relevant miRNAs to the β-cells.

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AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet

Cited by 17 publications

References 30 publications

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases

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

Micro(RNA) Management and Mismanagement of the Islet

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