MicroRNAs in Diabetes Mellitus

Pancreas

The critical role of miRs in the development and function of pancreatic p-cells became evident when it was demonstrated that deletion of the nuclear ribonuclease III enzyme Dicer in the pancreas of mice led to abnormal p-cell development (Lynn et al. 2007). One of the most abundant miRNAs present in islet cells is miR-375. MiR-375 negatively regulates glucose-stimulated insulin secretion (GSIS). High glucose concentrations reduce the expression of miR-375, and the subsequent derepression of its two main targets myotrophin (Mtpn, involved in insulin granule fusion) and phosphoinositide-dependent protein kinase (PDK1, a component of the phosphatidylinositol 3-kinase signalling cascade) induces insulin secretion (Poy et al. 2004; El Ouaamari et al. 2008). MiR-375 levels are upregulated in the pancreatic islets of ob/ob mice (a model of obesity, insulin resistance and T2DM) (Poy et al. 2009), and deletion of miR-375 in these mice reduces the proliferative capacity of the endocrine pancreas and dramatically worsens the diabetic state (Poy et al.

2009). MiR-124a and miR-9 inhibit GSIS by targeting FOXa2 and Onecut-2, respectively, both transcription factors associated with insulin secretion (Plaisance et al. 2006; Puigserver and Rodgers 2006). Recently, in human pancreatic islets from type 2 diabetic patients, miR-187 was found to be upregulated, where it is involved in reducing GSIS through inhibition of homeodomain-interacting protein kinase-3 (HIPK3) (Locke et al. 2014). High levels of miR-34a are found in the islets of T2DM db/db mice, and this is associated with a reduced expression of the anti- apoptotic protein BCL2 and an increased p-cell death (Lovis et al. 2008). MiR-335 is upregulated in the islets of Goto-Kakizaki rats (a nonobese model of T2DM) where it targets the exocytotic protein Stxbp1 (Esguerra et al. 2011). A summary of the role of miRNAs in pancreatic p-cell dysfunction is found in Table 3.1.

Table 3.1 MicroRNAs involved in pancreatic p-cell dysfunction

microRNA

Change in diabetes

Target

Functional result

Reference

miR-9

Up

Onecut2

Decreases insulin secretion

Plaisance et al. (2006)

miR-34a

Up

Bcl2

Increases apoptosis

Lovis et al. (2008)

VAMP2

Decreases insulin secretion

Lovis et al. (2008)

miR-96

Up

Noc2

Decreases insulin secretion

Lovis et al. (2008)

miR-124a

Up

FOXa2

Decreases p-cell maturation

Puigserver and Rodgers (2006)

miR-187

Up

HIPK3

Decreases insulin secretion

Locke et al. (2014)

miR-335

Up

Stxbp1

Decreases insulin secretion

Esguerra et al. (2011)

miR-375

Up

Myotrophin

Decreases insulin secretion

Poy et al. (2004)

PDK1

Decreases insulin transcription

El Ouaamari et al. (2008)

 
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