My group is greatly interested in understading how miRNAs contribute to maintain pancreatic ß-cell identity and function, which is altered in type 2 diabetes (T2D). At the moment, we are studying the role that miRNAs play in AMPK-dependant regulation of ß-cell function. AMPK is a critical energy sensor and a suggested target of widely used antidiabetic drugs such as metformin. Our most recent work (Martinez-Sanchez et al., 2018) demonstrated that AMPK regulates the expression of several miRNAs important for ß-cell proliferation, survival and differentiation. An example is miR-184, essential for ß-cell compensatory proliferation during pregnancy and diabetes. Currently, we are studying the role of other AMPK-regulated miRNAs and the molecular mechanisms by which these miRNAs exert their action. With our work, we hope to gain a better understanding of the importance of these small molecules in the maintenance of glucose homeostasis and aid the development of more efficient drugs for the treatment of diabetes
Martinez-Sanchez et al., FASEBJ, 2018. miRNAs regulated by AMPK are involved in pathways important for b-cell function. A, B) Cytoscape-generated layout of down-regulated (square, red nodes) (A) and up-regulated (square, green nodes) (B) miRNAs and their predicted targets that are up-regulated (circle, green nodes) (A) and down-regulated (circle, red nodes) (B), respectively, in bAMPKdKO vs. control islets. Node size represents the degree of the fold change (the larger, the stronger). The intensity of the gene node color (circles) indicates the target prediction score according to TargetScan (the darker, the stronger)
Rutter et al., Biochem J., 2015. In the ß-cell, glucose metabolism is coupled to insulin secretion. Regulatory molecules, including fatty acids and fatty acid derivatives influence this proccess by several uncompletely-understood mechanisms.
Martinez-Sanchez et al., Mol Endocrinol., 2015. Depletion of mature miRNAs specifically in the ß-cell (KO: Dicer KO) leads to impaired insulin secretion and, eventually, ß-cell death. The figure represents a control (C) and Dicer KO (KO) pancreatic islet.
1. Martinez-Sanchez, A. et al. Disallowance of Acot7 in ÃÂÃÂ²-cells is required for normal glucose tolerance and insulin secretion. Diabetes. In press. PMID: 26861785
2. Martinez-Sanchez, A. et al. DICER inactivation identifies pancreatic ÃÂÃÂ²-cell ÃÂ¢ÃÂÃÂdisallowedÃÂ¢ÃÂÃÂ genes targeted by microRNAs. Mol Endocrinol. 2015. PMID:26038943
3. Seidl, CI., Martinez-Sanchez, A. and Murphy CL. Derepresion of miRNA-138 contributes to loss of the human articular chondrocyte phenotype. Arthritis Rheumatol. 2015. PMID:26359943
4. Kone, M., Pullen, TJ., Sun G., Ibberson, M., Martinez-Sanchez, A. et al. LKB1 and AMPK differentially regulate pancreatic beta cell identity. FASEB J. 2014. PMID: 25070369
5. Martinez-Sanchez, A. and Murphy C.L. MiR-1247 functions by targeting cartilage transcription factor SOX9. J. Biol Chem. 2013 PMID: 24014021
6. Martinez-Sanchez, A. et al. Regulation of human chondrocyte function through direct inhibition of cartilage master-regulator SOX9 by miRNA-145., J Biol Chem. 2012 PMID: 22102413
7. Dudek, KA., Lafont, JE., Martinez-Sanchez, A. and Murphy, CL.Type II Collagen Expression Is Regulated by Tissue-specific miR-675 in Human Articular Chondrocytes. 2010 J Biol Chem. PMID: 20529846
8. Cuesta, R.*. Martinez-Sanchez, A.* and Gebauer, F. *equal contribution. MiR-181a regulates cap-dependent translation of p27kip1 mRNA in myeloid cells. Mol Cell Biol. 2009. PMID:19273599
1. Rutter, GA., Pullen, TJ., Hodson, DJ. and Martinez-Sanchez, A. Pancreatic ÃÂÃÂ²-cell identity and the control of insulin secretion. Biochem J. 2015. PMID:25697093. Review
2. Martinez-Sanchez, A. and and Murphy, CL. MicroRNA Target IdentificationÃÂ¢ÃÂÃÂExperimental Approaches. 2013. Biology. 2013. PMID: 24832658. Review
3. Martinez-Sanchez, A. and Gebauer F. Regulation of p27kip1 expression by miRNAs. Prog Mol Subcell Biol. 2010. PMID:19841881. Book chapter