The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes

• Published in: Diabetologia 2011-05, Vol.54 (5), p.1098-1108
• Main Authors: Shimoda, M., Kanda, Y., Hamamoto, S., Tawaramoto, K., Hashiramoto, M., Matsuki, M., Kaku, K.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Diabetes; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; Diabetes. Impaired glucose tolerance; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - therapeutic use; Glucose; Human Physiology; Humans; Immunohistochemistry; Insulin; Insulin-Secreting Cells - drug effects; Internal Medicine; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kinases; Liraglutide; Male; Medical research; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Microdissection; Oxidative stress; Oxidative Stress - drug effects; Peptides; Polymerase Chain Reaction; Weight Gain - drug effects
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2069-9

Aims/hypothesis We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice. Methods Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. Results Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis. Conclusions/interpretation Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.