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

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

AIM: To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. METHOD: A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. RESULTS: HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. CONCLUSION The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.
Animals ; Blood Glucose ; metabolism ; Coumarins ; pharmacology ; Diabetes Mellitus ; blood ; drug therapy ; Diabetes Mellitus, Type 2 ; drug therapy ; Exenatide ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; therapeutic use ; Glucagon-Like Peptide-1 Receptor ; Glucose Tolerance Test ; Glycated Hemoglobin A ; metabolism ; HEK293 Cells ; Humans ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Peptides ; pharmacology ; Receptors, Glucagon ; metabolism ; Venoms ; pharmacology

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does.
Alzheimer Disease ; drug therapy ; Animals ; Diabetes Mellitus, Type 2 ; drug therapy ; Disease Models, Animal ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; Humans ; Liraglutide ; Mice ; Mice, Transgenic ; Neuroprotective Agents ; pharmacology ; Parkinson Disease ; drug therapy ; Peptides ; pharmacology ; Receptors, Glucagon ; agonists ; Venoms ; pharmacology

<b>BACKGROUNDb>A number of studies have shown that oxidative stress and mitochondrial involvement are major triggering factors in the development of neurodegenerative diseases. Cobalt chloride (CoCl(2))-induced cell death in PC12 cells may serve a simple and convenient in vitro model of hypoxia-induced neuronal cytotoxicity. To explore the effect of geniposide on CoCl(2) which induced cytotoxicity and mitochondrial function in rat pheochromocytoma PC12 cells, we analyzed the influence of geniposide on the expression of apoptosis-related proteins.

<b>METHODSb>PC12 cells and RNAi PC12 cells were treated with 0, 12.5, 25, 50, 100 micromol/L geniposide for 12 hours and then exposure to 400 micromol/L CoCl(2) for 12 hours. Cell viability, cell morphology, and expression of Bcl-2, Bax, P53 and caspase-9 were determined using Western blotting.

<b>RESULTSb>Pretreatment with geniposide markedly improved the cells viability and morphology, decreased the expression of Bax, P53 and caspase-9, and increased the expression of Bcl-2 in PC12 cells challenged by CoCl(2)2. However, in the RNAi PC12 cells, geniposide had no significant effect on the expression of these proteins.

<b>CONCLUSIONb>Geniposide protects PC12 cells from CoCl(2) involved in mitochondrial mediated apoptosis, and GLP-1R might play a critical role in the neuroprotection of geniposide in PC12 cells.

Animals ; Apoptosis ; drug effects ; Cobalt ; toxicity ; Glucagon-Like Peptide-1 Receptor ; Iridoids ; pharmacology ; Mitochondria ; physiology ; Neuroprotective Agents ; pharmacology ; PC12 Cells ; Proto-Oncogene Proteins c-bcl-2 ; physiology ; Rats ; Receptors, Glucagon ; drug effects ; physiology ; Signal Transduction ; bcl-2-Associated X Protein ; physiology

<b>OBJECTIVEb>To look for the evidences of motilin receptor expression on interstitial cells of Cajal (ICC) of the rabbit.

<b>METHODb>Smooth muscle segments with ICC were isolated from the small intestine of 10-day old rabbits. The tissue segments equilibrated in Ca(2+)-free Hanks' solution were dispersed with an enzyme solution containing collagenase type II and then Ficoll density centrifugation was used to dissociate ICC. The cells were suspended and cultured in the M199 medium. The c-kit antibody was applied to distinguish the cultured ICC. The motilin receptor was identified by immunocytochemical assay with GPR38 antibody, c-kit antibody and hoechst 33342 combined to label ICC. Cells cultured for a few days were sorted for ICC with c-kit stained green fluorescent through flow cytometry. The total RNA and proteins extracted from the sorted ICC were respectively used to verify motilin receptor on the ICC by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting.

<b>RESULTb>We had successfully dissociated and cultured ICC of rabbit small intestine in vitro. Fluorescent staining with c-kit antibody confirmed that the culture ICC was successful. Triple-labeled immunofluorescent staining had detected the motilin receptor on membrane of ICC. Flow cytometry analysis showed that the ratio of c-kit positive cell in the cultured cells was 64.3%. The number of sorted ICC was 6.7 × 10(5) and 5.6 × 10(6). The results of RT-PCR and Western blot confirmed that the ICC had motilin receptor expression.

<b>CONCLUSIONb>Our study demonstrated presence of motilin receptor on ICC of the rabbit. The present results may suggest that ICC play an important role in gastrointestinal movement induced by motilin.

Animals ; Cells, Cultured ; Interstitial Cells of Cajal ; metabolism ; Intestine, Small ; cytology ; Rabbits ; Receptors, Gastrointestinal Hormone ; metabolism ; Receptors, Neuropeptide ; metabolism

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

<b>OBJECTIVEb>To investigate the effect of interstitial cells of Cajal (ICC) on contraction of intestinal tract smooth muscle induced by motilin receptor agonist.

<b>METHODSb>Two kinds of smooth muscle segments were isolated from the duodenum and colon of rabbit. Both kinds of smooth muscle were divided into two groups: group a (normal ICC group of duodenum); group c (impaired ICC group of duodenum); group b (normal ICC group of colon); group d (impaired ICC group of colon), each group contained 20 segments. The impairment of ICC was induced by selectively destroying ICC in the smooth muscle via treatment with methylene blue plus light. Then the frequency and amplitude of contraction of group a and c, group b and d was compared. Then motilin receptor agonist (ABT-229) was added into the Krebs solution, the frequency and amplitude of smooth muscle contraction before and after adding ABT-229 were recorded and compared.

<b>RESULTSb>The electron microscopy demonstrated that ICC in methylene blue plus light group were destroyed; the smooth muscle cells and neuron scattered close to ICC were normal. In group a, the contraction frequency, (17.89 +/- 1.88) times/min, was significantly lower as compared with that measured after ABT-229 was added [(18.76 +/- 1.18) times/min (P > 0.05)]; the amplitude of group a was (343 +/- 28) mg, which was lower as compared with that after adding ABT-229 [(597 +/- 68) mg (P < 0.001)]; in group b, the frequency was (5.89 +/- 1.03) times/min, the amplitude was (724 +/- 85) mg, after ABT-229 was added, the construction frequency increased to (8.45 +/- 0.69) times/min (P < 0.001), and the amplitude was (897 +/- 89) mg (P < 0.05), which was not affected by pretreatment with TTX, however it could be weakened by nifedipine significantly. In group c and d, the rhythmic contraction almost disappeared: in group c the contraction frequency was (1.06 +/- 0.24) times/min, and the amplitude were (50 +/- 10) mg. In group d, the amplitude and frequency significantly decreased as compared with the normal group (P < 0.001), in group c, and d, no significant difference in amplitude and frequency was found between the values measured before and after adding ABT-229 (P > 0.05). After Ach (100 micromol/L) was added, both group c and d could generate contraction.

<b>CONCLUSIONb>ICC may play an important role in the rhythmic contraction of intestinal tract. The promoting effect of motilin receptor agonist on intestinal tract may be mediated by ICC. ICC deficiency may cause functional impairment of gastrointestinal tract motivation. The medication may become ineffective when the number of ICC is reduced to a certain extent or the network of ICC is incomplete.

Animals ; Erythromycin ; analogs & derivatives ; pharmacology ; Female ; Gastrointestinal Motility ; drug effects ; physiology ; Interstitial Cells of Cajal ; physiology ; Male ; Rabbits ; Receptors, Gastrointestinal Hormone ; agonists ; Receptors, Neuropeptide ; agonists

<b>AIMb>In order to explore the mechanism of central motilin-induced feeding behavior, the effects of erythromycin, a motilin receptor agonist, on glucose responsive neurons in hypothalamus were observed.

<b>METHODSb>Extracellular recordings were made from single neurons in region of lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) in anesthetized rats. On the basis of their responsiveness to intracarotid injection of 0.58 mol/L glucose solution 0.2 ml, glucose-sensitive neurons (GSNs) in LHA and glucoreceptor neurons (GRNs) in VMH were recognized. Effects of intracerebroventricularly (i. c. v.) administration of 4 microg erythromycin on neural activities of glucose responsive neurons and non-glucose responsive neurons were examined. The mixture of EM and GM-109 1 microl were used to GSNs and GRNs which were sensitive to i. c. v. administration of EM.

<b>RESULTSb>In LHA, EM increased activity of GSNs significantly (P < 0.05 vs non-glucose-sensitive neurons group). Whereas in VMH, EM significantly decreased the activities of GRNs (P < 0.01 vs non-glucoreceptor neurons group). The mixture of EM and GM-109 had no effect on GSNs and GRNs.

<b>CONCLUSIONb>EM, a motilin receptor agonist, can stimulate GSNs in LHA and suppress GRNs in VMH and this may contribute to central motilin's effect on feeding behavior.

Animals ; Erythromycin ; pharmacology ; Hypothalamus ; cytology ; Neurons ; cytology ; drug effects ; Rats ; Rats, Wistar ; Receptors, Cell Surface ; metabolism ; Receptors, Gastrointestinal Hormone ; antagonists & inhibitors ; Receptors, Neuropeptide ; antagonists & inhibitors

It is well known that both insulin resistance and decreased insulin secretory capacity are important factors in the pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, obesity and lipotoxicity can increase the risk of T2DM. Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antidiabetic drugs with multiple effects. They can stimulate glucose-dependent insulin secretion, inhibit postprandial glucagon release, delay gastric emptying, and induce pancreatic β-cell proliferation. They can also reduce the weight of patients with T2DM and relieve lipotoxicity at the cellular level. Many intracellular targets of GLP-1 have been found, but more remain to be identified. Elucidating these targets could be a basis for developing new potential drugs. My colleagues and I have investigated new targets of GLP-1, with a particular focus on pancreatic β-cell lines and hepatic cell lines. Herein, I summarize the recent work from my laboratory, with profound gratitude for receiving the prestigious 2016 Namgok Award.
Awards and Prizes ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Gastric Emptying ; Glucagon ; Glucagon-Like Peptide 1* ; Glucagon-Like Peptide-1 Receptor ; Hepatocytes* ; Humans ; Hypoglycemic Agents ; Insulin ; Insulin Resistance ; Obesity