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Peptides ; 177: 171218, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38621590

ABSTRACT

G-protein coupled receptor-120 (GPR120; FFAR4) is a free fatty acid receptor, widely researched for its glucoregulatory and insulin release activities. This study aimed to investigate the metabolic advantage of FFAR4/GPR120 activation using combination therapy. C57BL/6 mice, fed a High Fat Diet (HFD) for 120 days to induce obesity-diabetes, were subsequently treated with a single daily oral dose of FFAR4/GPR120 agonist Compound A (CpdA) (0.1µmol/kg) alone or in combination with sitagliptin (50 mg/kg) for 21 days. After 21-days, glucose homeostasis, islet morphology, plasma hormones and lipids, tissue genes (qPCR) and protein expression (immunocytochemistry) were assessed. Oral administration of CpdA improved glucose tolerance (34% p<0.001) and increased circulating insulin (38% p<0.001). Addition of CpdA with the dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin, further improved insulin release (44%) compared to sitagliptin alone and reduced fat mass (p<0.05). CpdA alone (50%) and in combination with sitagliptin (89%) induced marked reductions in LDL-cholesterol, with greater effects in combination (p<0.05). All treatment regimens restored pancreatic islet and beta-cell area and mass, complemented with significantly elevated beta-cell proliferation rates. A marked increase in circulating GLP-1 (53%) was observed, with further increases in combination (38%). With treatment, mice presented with increased Gcg (proglucagon) gene expression in the jejunum (130% increase) and ileum (120% increase), indicative of GLP-1 synthesis and secretion. These data highlight the therapeutic promise of FFAR4/GPR120 activation and the potential for combined benefit with incretin enhancing DPP-IV inhibitors in the regulation of beta cell proliferation and diabetes.


Subject(s)
Cell Proliferation , Diet, High-Fat , Dipeptidyl-Peptidase IV Inhibitors , Glucagon-Like Peptide 1 , Insulin-Secreting Cells , Obesity , Receptors, G-Protein-Coupled , Sitagliptin Phosphate , Animals , Glucagon-Like Peptide 1/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Mice , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Diet, High-Fat/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Sitagliptin Phosphate/pharmacology , Cell Proliferation/drug effects , Obesity/drug therapy , Obesity/metabolism , Obesity/pathology , Male , Dipeptidyl Peptidase 4/metabolism , Mice, Inbred C57BL , Homeostasis/drug effects , Insulin/metabolism , Insulin/blood , Glucose/metabolism , Mice, Obese
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