Objective: To investigate the protective mechanism of GLP-1 on β cell function by examining the GLP-1 effect on pancreatic insulin signaling pathway of high fat diet mice . Methods: High fat diet (HFD, 20 weeks) fed mice were administrated with vehicle or GLP-1 via osmotic pumps implanted subcutaneously (4 weeks). Blood samples were collected from survival mice from either retro-orbital sinus or tail vein for insulin or glucose measurement respectively. In the end of the experiments, the mice were euthanasia by carbon dioxide for sample collection. The islet structure was demonstrated by HE staining. Immunofluorescence antibodies targeting insulin and glucagon were used to examine α and ß cell distribution and insulin and glucagon abundance was measured by ELISA using pancreatic homogenates. The molecules involved in insulin signaling pathway (IRc, IRS-1, IRS-2, PI-3 kinase) were examined with immunohistochemistry or immunoblotting and their arbitrary densities as indices of the protein expressions were calculated and analyzed. Results: The normal structure of islet was deformed in chronic HFD mice shown by HE staining and the Islet area was significantly diminished by HFD (HFD vs. Control, p＜0.05). The normal pattern of α and ß cell distribution were disturbed by HFD. The expressions of IRc and IRS-1 from signaling pathway in the pancreas were significantly reduced or inhibited, insulin and glucagon contents were however increased (HFD vs. Control, p＜0.05). But all of the defected induced by HFD were reversed by GLP-1. Conclusion: Insulin signaling pathway in pancreas is suppressed as part of systematic insulin resistance induced by HFD but was reversed by GLP-1 which may play a beneficiary effect on ß cell function.