The molecular mechanism of human glucagon-like pepetide-1 analog liraglutide on pancreatic beta-cell preservation in obese diabetic model db/db mice *
We investigated the molecular mechanism by which the human GLP-1 analogue liraglutide (LIRA) preserves the pancreatic β-cells. Ten-week-old male diabetic db/db mice received LIRA or vehicle for either a period of 2 days or 2 weeks. In addition to morphological and biochemical analysis of the pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. LIRA treatment for 2 weeks improved metabolic parameters and insulin sensitivity in db/db mice. Two-week LIRA treatment increased glucose-stimulated insulin secretion and islet insulin content, and reduced islet triglyceride content. LIRA treatment for 2 weeks up-regulated the expression of genes involved in cellular differentiation, proliferation, anti-apoptosis and anti-oxidative stress, and down-regulated genes related to anti-differentiation, pro-apoptosis, endoplasmic reticulum stress and lipid synthesis. In the 2-day experiment, LIRA slightly improved metabolic parameters, but glucose-stimulated insulin secretion, islet insulin and triglyceride contents were not affected. LIRA increased gene expressions associated with cellular differentiation, proliferation and anti-apoptosis, and suppressed gene expressions involved in pro-apoptosis. However, it had no effect on genes related to oxidative stress or endoplasmic reticulum stress. Morphometric results for cellular proliferation, apoptosis and oxidative stress in the pancreatic islets were consistent with the results of the gene expression analysis. LIRA increases the pancreatic β -cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative/ER stress, secondary to amelioration of glucolipotoxicity. (Accepted on October 22, 2010)
