At present, surgery has become one of the treatments for type 2 diabetes, but it is still unclear about the therapeutic mechanism. Many experiments has proved that the anatomical and physiological structure has been altered leading to significant changes related to the secretion of gastrointestinal hormones and neuropeptides. These molecular are related to the metabolism of glucose, functions of islet cells and sensitivity of insulin. Intensive studies of glucagon-like peptide-1 (GLP-1) play an important role in the surgical treatment of diabetes and now it has gained increasing recognition. However, GLP-1 must be combined with GLP-1 receptor (GLP-1R) to execute its function. In this paper we reviewed the role of GLP-1 and its receptor in the mechanism of metabolic surgery.
Diabetes Mellitus, Type 2 ; surgery ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Humans ; Receptors, Glucagon

Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from alpha-cell has languished whereas beta-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant alpha-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted alpha-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of alpha-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from alpha-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on alpha-cell dysfunction and therapeutic potentials of targeting alpha-cell in T2D.
Diabetes Mellitus, Type 2 ; Fasting ; Glucagon ; Glucagon-Like Peptide 1 ; Glucagon-Secreting Cells ; Glucose ; Hyperglycemia ; Hypoglycemia ; Insulin ; Insulin-Secreting Cells ; Receptors, Glucagon

New therapeutics for type 2 diabetes using incretin hormone were introduced recently. Incretin-based therapies consist of two types: GLP-1 agonists mainly acting on the GLP-1 receptor and dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors). The former is resistant to DPP-4 and injectable. The latter is oral medications raising endogenous GLP-1 by inhibiting the degrading enzyme DPP-4. The incretin based therapies are promising and more commonly used due to their action and safety profile. Stimulation of insulin secretion by these drugs occurs in a glucose-dependent manner. Incretin based therapies have low risk for hypoglycemia. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and vildagliptin.
Adamantane ; Dipeptidyl-Peptidase IV Inhibitors ; Glucagon-Like Peptide 1 ; Hypoglycemia ; Incretins ; Insulin ; Nitriles ; Peptides ; Pyrazines ; Pyrrolidines ; Receptors, Glucagon ; Triazoles ; Venoms ; Glucagon-Like Peptide-1 Receptor ; Liraglutide ; Sitagliptin Phosphate

Non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is caused by the disruption of hepatic lipid homeostasis. It is associated with insulin resistance as seen in type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1) is an incretin that increases insulin sensitivity and aids glucose metabolism. In recent in vivo and in vitro studies, GLP-1 presents a novel therapeutic approach against NAFLD by increasing fatty acid oxidation, decreasing lipogenesis, and improving hepatic glucose metabolism. In this report, we provide an overview of the role and mechanism of GLP-1 in relieving NAFLD.
Diabetes Mellitus, Type 2 ; Fatty Liver ; Glucagon-Like Peptide 1 ; Glucose ; Homeostasis ; Incretins ; Insulin Resistance ; Lipogenesis ; Liver Diseases ; Receptors, Glucagon

The incretin hormones glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have recently received much attention for their roles in type 2 diabetes therapy. GLP-1 stimulated insulin secretion in a glucose-dependent manner and is secreted by intestinal L cells. It also regulates blood glucose concentration, stomach motility, appetite, and body weight. These actions are mediated through G-protein-coupled receptors highly expressed on pancreatic beta cells and also exert indirect metabolic actions. Activation of GLP-1 receptors also produces nonglycemic effects in various tissues. The pleiotropic effects of GLP-1 have been recently reported. The mechanisms identified in preclinical studies have potential translational relevance for the treatment of disease. Here, the nonglycemic effects of GLP-1, especially those on the liver, central nervous system, and bone, were reviewed.
Appetite ; Blood Glucose ; Body Weight ; Central Nervous System ; Enteroendocrine Cells ; Glucagon ; Glucagon-Like Peptide 1 ; Incretins ; Insulin ; Insulin-Secreting Cells ; Liver ; Receptors, G-Protein-Coupled ; Stomach

OBJECTIVETo establish Caco2 cell line with stable expression of glucagon like peptide-2 receptor( GLP-2R) , in order to establish an in vitro model for the study of protective mechanism of GLP-2 of the intestinal tract.

METHODSThe GLP-2R/pcDNA3. 1 ( + ) plasmid was verified by restriction endonuclease and sequencing , and then it was transfected into Caco2 cells with lipofectamine. After G418 selection, the clones with stable expression of GLP-2R were obtained by limited dilution cloning and expanding. The mRNA and protein expression of GLP-2R in normal human intestine, Caco2 cells, HER293, VE cells, as well as in transfected Caco2 cells were determined with RT-PCR and Western blot.

RESULTSThe sequence of GLP-2R/pcDNA 3. 1 plasmid was correct. No expression of GLP-2R mRNA and protein was found in HER293 and VE cells, but weak expression were found in Caco2 cells, and strong expression was found in normal human intestines. The expression of GLP-2R mRNA and protein expression in Caco2/GLP-2R ( + ) cells were obviously increased after transfection.

CONCLUSIONGLP-2R has special distribution. The expression of GLP-2R is weak in normal Caco2 cells. The establishment of Caco2/GLP-2R ( + ) cellular model is beneficial for the further research of the mechanism of action of GLP-2.

Caco-2 Cells ; Cellular Structures ; metabolism ; Cloning, Molecular ; Gene Expression ; Genetic Vectors ; Glucagon-Like Peptide 2 ; genetics ; metabolism ; Glucagon-Like Peptide-2 Receptor ; Humans ; Receptors, Glucagon ; genetics ; metabolism ; Transfection

OBJECTIVETo investigate the effects of activation of the GLP-1 receptor on the p38MAPK signaling pathway in hepatic stellate cells (HSCs).

METHODSHSCs were isolated and identified according to morphological features; the levels of GLP-1R protein were determined by western blotting.The HSCs were randomly divided into a control grouP (normal saline treatment) and experimental grouP(liraglutide treatment); after 120 hours, the expression of p38MAPK mRNA was examined by RT-PCR and of phosphorylated (p)-p38MAPK protein was detected by western blotting.

RESULTSGLP-1R proteins were detected in the HSCs. Compared with the control group, the experimental group showed significantly decreased p38MAPK mRNA and p-p38MAPK protein (both P < 0.01).

CONCLUSIONThe p38MAPK signaling pathway could be down-regulated when GLP-1R is activated in HSCs.

Cells, Cultured ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; Hepatic Stellate Cells ; metabolism ; Humans ; Liraglutide ; MAP Kinase Signaling System ; RNA, Messenger ; Receptors, Glucagon ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

There is a close correlation between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) in the course of pathophysiological processes. The neuroprotective action of glucagon-like peptide 1 (GLP-1), a latest drug for clinical treatment of T2DM, is being more deeply investigated at present, and a novel therapeutic strategy for AD with GLP-1 has been proposed boldly. This review mainly discussed the correlation of pathogenesis between T2DM and AD, the synthesis and secretion of GLP-1, the distribution and physiological effects of GLP-1 receptor in the brain, and the progresses on the study of GLP-1 in the treatment of AD.
Alzheimer Disease ; drug therapy ; physiopathology ; Amyloid beta-Peptides ; drug effects ; metabolism ; Animals ; Brain ; metabolism ; Diabetes Mellitus, Type 2 ; physiopathology ; Glucagon-Like Peptide 1 ; pharmacology ; therapeutic use ; Glucagon-Like Peptide-1 Receptor ; Humans ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Receptors, Glucagon ; metabolism

BACKGROUND: Insulin receptor substrate 2 (IRS-2) is a key regulator of beta cell proliferation and apoptosis. This study was aimed to investigate effect of the glucolipotoxicity on apoptosis in INS-1 cell, and the effect of Exendin-4, a GLP-1 receptor agonist, on IRS-2 expression in the glucolipotoxicity induced INS-1 cell. The goal was to discover the new action mechanism and function of Exendin-4 in beta cell apoptosis. METHOD: INS-1 cells were cultured in glucolipotoxic condition for 2, 4 or 6 days and were categorized as G groups. Another group in which 50 nM Exendin-4 was added to INS-1 cells, cultured in glucolipotoxic condition, were named as Ex-4 groups. We investigated the expression of IRS-2 by RT-PCR, phosphorylated IRS-2 and phosphorylated Akt protein levels by western blot. We measured the apoptosis ratio of INS-1 cell in glucolipotoxic condition by TUNEL staining in both groups. RESULT: IRS-2 expression of INS-1 cells decreased with correlation to the time of exposure to glucolipotoxic condition. pIRS-2 and pAkt protein levels decreased in the similar pattern in glucolipotoxicity group. However, this effect of glucolipotoxicity on INS-1 cell was inhibited by the Exendin-4 treatment. In the Ex-4 groups, IRS-2 expression, pIRS-2 and pAkt protein levels remained at the similar level to low glucose condition state. Also, apoptosis induced by glucolipotoxicity was suppressed by Exendin-4 treatment significantly. CONCLUSION: We showed that the long-term treatment of Exendin-4 inhibited the apoptosis of beta cells significantly in glucolipotoxic condition and that this effect of Exendin-4 was related with IRS-2 and Akt among the beta cell's intracellular signal transduction pathway.
Apoptosis ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Glucose ; In Situ Nick-End Labeling ; Insulin Receptor Substrate Proteins ; Peptides ; Phosphorylation ; Receptors, Glucagon ; Signal Transduction ; Venoms

BACKGROUND: The characteristic feature of pancreatic beta cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important function, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various stress conditions can interfere with ER function. Pancreatic beta cells may be particularly vulnerable to ER stress that causes to impair insulin biosynthesis and beta cell survival through apoptosis. Glucagon like peptide-1 (GLP-1) is a new drug for treatment of type 2 diabetes and has effects on stimulation of insulin secretion and beta cell preservation. Also, it may have an antiapoptotic effect on beta cells, but detailed mechanisms are not proven. Therefore, we investigated the protective mechanism of GLP-1 in beta cells through ER stress response induced by 2-deoxy-D-glucose (2DG). METHODS: For induction of the ER stress, HIT-T15 cells (hamster beta cell line) were treated with 2DG (10 mM). Apoptosis was evaluated with MTT assay, hoechst 33342 staining and Annexin/PI flow cytometry. Expression of ER stress-related molecules was determined by real-time PCR or western blot. For blocking ER stress, we pretreated HIT-T15 cells with exendin-4 (Ex-4; GLP-1 receptor agonist) for 1 hour before stress induction. RESULTS: After induction with ER stress (2DG), beta cells were lost by apoptosis. We found that Ex-4 had a protective effect through ER stress related molecules (GRP78, GRP94, XBP-1, eIF2alpha, CHOP) modulation. Also, Ex-4 recovered the expression of insulin2 mRNA in beta cells. CONCLUSION: These results suggest that GLP-1 may protect beta cells apoptosis through ER stress modulation.
Apoptosis ; Benzimidazoles ; Blotting, Western ; Cell Survival ; Deoxyglucose ; Endoplasmic Reticulum ; Flow Cytometry ; Glucagon ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; HSP70 Heat-Shock Proteins ; Insulin ; Insulin-Secreting Cells ; Membrane Proteins ; Peptides ; Protein Processing, Post-Translational ; Proteins ; Real-Time Polymerase Chain Reaction ; Receptors, Glucagon ; RNA, Messenger ; Venoms