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

<b>OBJECTIVESb>To understand the role cellular immunology plays in the pathogenesis of chronic hepatitis B (CHB) through analysis of T cell receptor (TCR) beta chain variable region gene (BV) family dominant usage and beta chain complementarity determining region3 (CDR3) sequences of peripheral blood mononuclear cells of the patients.

<b>METHODSb>TCR BV families were amplified by inverse polymerase chain reaction (RT-PCR), and the dominant usage of BV families and CDR3 repertoire were analyzed by immunoscope technology for 8 CHB patients during their acute exacerbations and for 4 healthy blood donors who served as controls. The clonality of the T cells suspected by immunoscope was further confirmed by CDR3 sequencing.

<b>RESULTSb>The TCR BV CDR3 repertoire of the 4 healthy blood donors showed a Gaussian distribution. In the 8 CHB patients, however, the clonal expansion of T cells showed different TCR BV families with each patient. The T cells of the clonal expansion shared different CDR3 sequences.

<b>CONCLUSIONb>The peripheral blood T cells of CHB patients during their acute exacerbation showed significantly a clonal expansion and their T cell clonal expansion may be stimulated by several HBV epitopes. These results indicate that cellular immunology is involved in the pathogenesis of the liver inflammation process of CHB.

Adult ; Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; Complementarity Determining Regions ; genetics ; Female ; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ; genetics ; Hepatitis B, Chronic ; genetics ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Receptors, Antigen, T-Cell ; genetics

<b>OBJECTIVEb>To analyze the characteristics of CDR3 of TCRbeta on CD8+ T cells in chronic hepatitis B patients.

<b>METHODSb>Eight patients with chronic hepatitis B (ALT more than 2 ULN) were enrolled in this study. CD8+ T cells were isolated from peripheral blood. RT-PCR was proformed to amplify the CDR3 of TCRbeta, and the PCR products were sequenced and analyzed.

<b>RESULTSb>The chronic hepatitis B patients showed obvious clonal expansion of T cell, and three perturbation patterns of T cell expansion were showed in the CDR3 of TCRbeta, including monoclonicity, oligoclonicity and skewed peak patterns. The number of perturbation families of CD8+ subpopulation was significantly higher than that of CD8- subpopulation (10.6+/-4.7 vs. 4.1+/-3.1, t = 6.619, P less than 0.01). In 3 out of 8 patients, the number of perturbation families of CD8+ subpopulation was also higher than that of PBMCs without depleting CD8+ subpopulation.

<b>CONCLUSIONSb>The characteristics of CDR3 of TCRbeta may help to understand the inflammatory response in CHB patients.

Adult ; CD8-Positive T-Lymphocytes ; immunology ; Complementarity Determining Regions ; genetics ; Genes, T-Cell Receptor beta ; Hepatitis B, Chronic ; blood ; immunology ; Humans ; Male ; Receptors, Antigen, T-Cell ; immunology ; Young Adult

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

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

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that is able to bind several different ligands, including advanced glycation endproducts, high-mobility group protein (B)1 (HMGB1), S-100 calcium-binding protein, amyloid-beta-protein, Mac-1, and phosphatidylserine. Its interaction is engaged in critical cellular processes, such as inflammation, proliferation, apoptosis, autophagy, and migration, and dysregulation of RAGE and its ligands leads to the development of numerous human diseases. In this review, we summarize the signaling pathways regulated by RAGE and its ligands identified up to date and demonstrate the effects of hyper-activation of RAGE signals on human diseases, focused mainly on renal disorders. Finally, we propose that RAGE and its ligands are the potential targets for the diagnosis, monitoring, and treatment of numerous renal diseases.
Apoptosis ; Autophagy ; Biomarkers* ; Diagnosis* ; Humans* ; Inflammation ; Kidney Diseases ; Ligands* ; Rage* ; Signal Transduction ; Advanced Glycosylation End Product-Specific Receptor

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 examine the changes of expressions of orexin A, orexin receptor-1 (OX1R), prepro-orexin (Prepro-OX) mRNA, OX1R mRNA and ob-R of hypothalamus in rats with chronic renal failure (CRF).

<b>METHODSb>Sixty-two male Wister rats weighing 200-250 g were divided into three groups, including group 1 (normal, n = 5), group 2 (sham-operated, n = 25) and group 3 (CRF, n = 32). Hypothalamus orexin A was assayed by radioimmunoassay. Serum leptin was assayed by enzyme linked immunosorbent assay. The expression of Prepro-OX mRNA and OX1R mRNA of hypothalamus were measured by reverse transcription polymerase chain reaction, and expression of orexin A, OX1R and ob-R by immunohistochemistry. Automatic biochemical analyzer was used to measure the serum creatinine.

<b>RESULTSb>Hypothalamus orexin A levels were negatively correlated (r = -0.63, P < 0.001) with serum leptin levels in the rats. The expression of hypothalamus Prepro-OX mRNA in CRF rats was significantly lower than that of sham-operation at week 12 (P < 0.01). Hypothalamus Prepro-OX mRNA levels were negatively correlated (r = -0.81, P < 0.001) with the levels of serum leptin and serum creatinine (r = -0.68, P < 0.05) in the rats at week 12. The expression of hypothalamus OX1R mRNA in CRF rats was lower than that of sham-operation at week 12 (P > 0.05). Specific immunoreactivity for orexin A was present in perikeryon of the hypothalamus neuron. Specific OX1R-like immunoreactivity was observed in some nerve fibres. Specific immunoreactivity for ob-R was present in membranes of the hypothalamus neuron. Hypothalamus neurons of orexin A-like specific immunoreactivity in CRF rats were significantly fewer than those in shamoperated rats at week 8. Hypothalamus neurons of OX1R-like specific immunoreactivity in CRF rats were similar to those in sham-operated rat at week 8. Hypothalamus neurons of ob-R-like specific immunoreactivity in CRF rats were significantly more than those in sham-operated rats at week 8.

<b>CONCLUSIONSb>The lower hypothalamus orexin A levels may be induced by high serum leptin level in CRF rats. The lower expression of hypothalamus Prepro-OX mRNA in CRF rats may be one of the main causes inducing lower hypothalamus orexin A. The expression of OX1R in hypothalamus neurons is somewhat reduced and the expression of ob-R in hypothalamus neurons is somewhat raised in CRF rats. These remain to be studied further.

Animals ; Carrier Proteins ; genetics ; metabolism ; Hypothalamus ; metabolism ; Intracellular Signaling Peptides and Proteins ; Kidney Failure, Chronic ; metabolism ; Leptin ; genetics ; metabolism ; Male ; Neuropeptides ; genetics ; metabolism ; Neurotransmitter Agents ; genetics ; metabolism ; Orexin Receptors ; Orexins ; Protein Precursors ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Cell Surface ; genetics ; metabolism ; Receptors, G-Protein-Coupled ; Receptors, Leptin ; Receptors, Neuropeptide ; genetics ; metabolism

BACKGROUND AND PURPOSE: The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity. METHODS: Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was also quantified by real-time reverse-transcription PCR in the remaining 15 patients. RESULTS: RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression. CONCLUSIONS: The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy.
Biopsy* ; Diabetes Mellitus ; Diabetic Nephropathies ; Diabetic Neuropathies* ; Dyslipidemias ; Glycosylation End Products, Advanced* ; Humans ; Michigan ; Polymerase Chain Reaction ; Prediabetic State ; Rage ; RNA, Messenger ; Skin* ; Sural Nerve ; Up-Regulation* ; Advanced Glycosylation End Product-Specific Receptor