Abstract
Glucagon like peptide 1 (GLP1) is an incretin hormone released from the enteroendocrine L-type cells of the lower gastrointestinal tract. The active isoforms of GLP1 are rapidly degraded (<2 min) by protease dipeptidyl peptidase-4 (DPP-4) after their release. Among its functions, GLP1 exerts a pivotal role in regulating glucose and lipid metabolism. In particular, GLP1 increases glucose stimulated insulin secretion, functional pancreatic β-cell mass and decreases glucagon secretion from pancreatic α-cells. GLP1 can also be a regulator of lipid and lipoprotein metabolism ameliorating diabetic dyslipidemia, liver steatosis, and promoting satiety. Interestingly, it has been found that GLP1 and GLP1 agonists can modulate the expression of different microRNAs (miRNAs), a ~22 nucleotides small non-coding RNAs, key modulators of protein expression. In particular, in pancreas, GLP1 increases the expression levels of miRNA-212 and miRNA-132, stimulating insulin secretion. Similarly, GLP1 decreases miRNA-338 levels, leading to an increase of pancreatic β-cell function, followed by an improvement of diabetic conditions. Moreover, GLP1 modulation of miRNAs expression in the liver regulates hepatic lipid storage. Indeed, GLP1 down-regulates miRNA-34a and miRNA-21 and up-regulates miRNA-200b and miRNA-200c expression in liver, reducing intra hepatic lipid accumulation and liver steatosis. Clinical and pre-clinical studies, discussed in this review, suggest that modulation of GLP1/miRNAs pathway may be a useful and innovative therapeutic strategy for prevention and treatment of metabolic disorders, such as diabetes mellitus and liver steatosis.
Highlights
Reviewed by: Gabriela Da Silva Xavier, University of Birmingham, United Kingdom Katja Hummitzsch, University of Adelaide, Australia
Gliptins and Glucagon like peptide 1 (GLP1)-RAs are recommended as hypoglycemic agents for the treatment of Type 2 Diabetes Mellitus (T2DM)
Ex-4 administration dramatically reduced miR-338 expression, increasing pancreatic duodenal homeobox-1 (Pdx1) gene expression levels and insulin secretion, this action might be due to its well-established anti-apoptotic effect. Taken together these findings suggest that effects of Bisphenol A (BPA) are finely controlled by the action of GLP1 on the GLP1-RmiR338-Pdx1 axis [47]
Summary
In patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), glucoseinduced GLP1 secretion was significantly decreased, suggesting that down-regulation of GLP1 levels may contribute to NAFLD and NASH [18] According to these results, several pre-clinical and clinical studies reported that GLP1-RAs and/or gliptins treatment reduced hepatic steatosis and ameliorated hepatic dyslipidemia [19,20,21]. Inhibition of miR-34a in both models significantly improved steatosis and triglycerides plasma levels, suggesting that miR-34a may be a novel pharmaceutical target for NAFLD [45] All these evidences suggest that liver and circulating miRNA profiles correlate with liver histological changes and may be used as diagnostic biomarkers for hepatic lipid dysfunction.
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