Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.
Diabetes Mellitus, Type 2/drug therapy* ; Glucagon-Like Peptide-1 Receptor/therapeutic use* ; Glucagon-Like Peptides ; Humans ; Hypoglycemic Agents/therapeutic use* ; Motivation ; Obesity/drug therapy*

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

Intestinal adaptation is a spontaneous compensation of the remanent bowel after extensive enterectomy, which improves the absorption capacity of the remanent bowel to energy, fluid and other nutrients. Intestinal adaptation mainly occurs within 2 years after enterectomy, including morphological changes, hyperfunction and hyperphagia. Intestinal adaptation is the key factor for patients with short bowel syndrome to weaning off parenteral nutrition dependence and mainly influenced by length of remanent bowel, type of surgery and colon continuity. In addition, multiple factors including enteral feeding, glucagon-like peptide 2 (GLP-2), growth hormone, gut microbiota and its metabolites regulate intestinal adaptation via multi-biological pathways, such as proliferation and differentiation of stem cell, apoptosis, angiogenesis, nutrients transport related protein expression, gut endocrine etc. Phase III clinical trials have verified the safety and efficacy of teduglutide (long-acting GLP-2) and somatropin (recombinant human growth hormone) in improving intestinal adaptation, and both have been approved for clinical use. We aim to review the current knowledge about characteristics, mechanism, evaluation methods, key factors, clinical strategies of intestinal adaptation.
Humans ; Adaptation, Physiological ; Glucagon-Like Peptide 2/therapeutic use* ; Intestines/surgery* ; Parenteral Nutrition ; Short Bowel Syndrome/surgery*

Type 2 diabetes is a high-profile global public health problem, particularly in Asia. The young age of onset, low body mass index, and early appearance of pancreatic islet dysfunction are characteristics of Asian patients with T2DM. Metabolic surgery has become the standard treatment for T2DM patients and can significantly improve T2DM through a variety of mechanisms including modulation of energy homeostasis and reduction of body fat mass. Indeed, restoration of islet function also plays an integral role in the remission of T2DM. After metabolic surgery, islet function in Asian T2DM patients has improved significantly, with proven short-term and long-term effects. In addition, islet function is an important criterion and reference for patient selection prior to metabolic surgery. The mechanism of islet function improvement after metabolic surgery is not clear, but postoperative anatomical changes in the gastrointestinal tract leading to a number of hormonal changes seem to be the potential cause, including glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, ghrelin, and cholecystokinin. The authors analyzed the current retrospective and prospective studies on the effect of metabolic surgery on the islet function of Asian T2DM patients with a low BMI and its mechanism, summarized the clinical evidence that metabolic surgery improved islet function in Asian T2DM patients with a low BMI, and discussed its underlying mechanism. It is of great significance for realizing personalized and precise treatment of metabolic surgery and further improving its clinical benefits.
Bariatric Surgery ; Body Mass Index ; Cholecystokinin/therapeutic use* ; Diabetes Mellitus, Type 2/surgery* ; Gastric Inhibitory Polypeptide/therapeutic use* ; Ghrelin/therapeutic use* ; Glucagon-Like Peptide 1/therapeutic use* ; Humans ; Peptide YY/therapeutic use* ; Prospective Studies ; Retrospective Studies ; Treatment Outcome

Child ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; physiopathology ; Glucagon-Like Peptide 1 ; metabolism ; therapeutic use ; Humans ; Incretins ; therapeutic use ; Treatment Outcome

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Mice ; Animals ; Glucagon-Like Peptide 1/metabolism* ; Receptors, Glucagon/therapeutic use* ; Xenopus laevis/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Glycopeptides/therapeutic use* ; Obesity/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Peptides/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

OBJECTIVETo investigate the protective effect of recombinant glucagons like peptide-2 (GLP-2) on intestinal mucosa of rats with severe burns.

METHODSSD rats of either sex were randomly divided into 4 groups: normal control (N, n = 6), burn control group (C, n = 6), recombinant GLP-2 group (Gr, n = 6, with subcutaneous injection of 100 nmol x kg(-1) x d(-1) recombinant GLP-2 at 4 post-burn hours (PBH) and synthesized GLP-2 group (G, n = 6, with subcutaneous injection of 100 nmol x kg(-1) x d(-1) synthesized GLP-2 at 4 PBH). Except the normal control group, all animals in the other groups received a 30% TBSA third degree burns, the rats were sacrificed on 7 postburn days (PBD) and the following indexes were determined: pathological examination of intestinal mucosa, mucosa permeability of intestinal mucosa, the ratio of mucosa wet weight and bowel mass or carcase weight, and the protein content of intestinal mucosa.

RESULTSCompared with that in burn group [(0.350 +/- 0.040) mg/ml], the mucosa permeability significantly decreased in Gr (0.250 +/- 0.026) mg/ml and G (0.243 +/- 0.008) mg/ml groups, while the ratio of mucosa wet weight and carcase weight, the protein content of intestinal mucosa were significantly increased. In addition, the content of intestinal mucosal protein in Gr group [(57.9 +/- 2.8) mg/g wet weight] was higher than that in G group [(48.9 +/- 4.1) mg/g wet weight]. In contrast to normal controls, the villi of intestinal mucosa in rats on 7 PBD were obviously shortened and exfoliated, with deranged disposition and thinned basal membrane. No obvious difference of the injury was observed between Gr and G groups, and the injury was milder when compared with burn group.

CONCLUSIONRecombinant GLP-2, as well as synthesized GLP-2, exhibits obvious protective effect on intestinal mucosa in alleviating injury to intestinal mucosa in burn rats.

Animals ; Burns ; drug therapy ; pathology ; Disease Models, Animal ; Female ; Glucagon-Like Peptide 2 ; therapeutic use ; Intestinal Mucosa ; drug effects ; metabolism ; pathology ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins ; therapeutic use

OBJECTIVETo investigate the effect of glucagon- like peptide 2 on intestinal mucosa immunity after ischemia/reperfusion injury and explore the possible mechanisms.

METHODSA total of 70 ICR mice were randomly divided into three groups including normal control group(N), I/R group(C) and GLP-2 treatment group(T) (treated with GLP-2,200 microg/kg). The mice were sacrificed on the 1st, 3rd and 5th day after I/R injury. Liver,spleen and mesenteric lymph nodes samples were collected for bacterial culture. The endotoxin levels in plasma were also measured. Small intestine washing were obtained for IgA and the intestine homogenized were analyzed for Th1/Th2 cytokines.

RESULTSThe rate of bacterial translocation and the level of endotoxin in group C were significant higher than those in group T and group N. The IgA level in the lavage of the intestine was significantly decreased on the 1st day after I/R in group C and T compared with that in group N, while there was no difference between group C and T. The IgA level increased on the 3rd day and returned to normal on the 5th day after I/R in group T, while that in group C was still lower than normal. In group C, the levels of Th1-type (IL-2 and IFN-gamma) cytokines increased, the levels of Th2-type (IL-4 and IL-10) decreased significantly on the 1st day and then increased gradually. The change pattern of cytokines levels in group T resembled that in group C, but the levels of IL-4 and IL-10 in group T returned to normal on the 5th day after I/R.

CONCLUSIONSGLP-2 supplementation can partly protect the intestinal mucosal immunity. The mechanism may probably be related to the restitution of the balance of Th1/Th2 cytokines in the intestinal mucosa in mice.

Animals ; Bacterial Translocation ; Cytokines ; immunology ; metabolism ; Disease Models, Animal ; Glucagon-Like Peptide 2 ; therapeutic use ; Immunity, Mucosal ; Immunoglobulin A ; immunology ; metabolism ; Intestinal Mucosa ; immunology ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred ICR ; Reperfusion Injury ; immunology ; metabolism ; pathology

OBJECTIVETo investigate the effects of glucagon-like peptide 2 (GLP-2) on the morphology and functional adaptation of the residual small bowel in rat model of short bowel syndrome.

METHODSTwenty rats with 75% of the midjejunoileum removed were randomly divided into two groups, and received intra-peritoneal injection of GLP-2(250 micro*gd*kg-1*d-1) or subcutaneous injection saline(0.5 ml, twice one day) after operation. On postoperative day 6, the morphological changes of the residual jejunum and ileum, the expression of proliferating cell nuclear antigen(PCNA), and the mRNA expressions of Na-D-glucose cotransporters (SGLT1) and peptide cotransporters (PEPT1) were determined. The intestinal glucose absorption data per unit length as well as per unit weight of ileum were measured by in vivo circulatory perfusion experiment.

RESULTSThe morphological parameters of the residual gut such as the thickness of mucosa, height of villus, depth of crypt, and PCNA positive index were significantly higher, while the apoptosis rate per unit of mucosal square was significantly lower in GLP-2 treatment group than those in the control group. The expressions of mRNA SGTLl and PEPT1 in the residual ileum were significantly higher than those in the control group. There was no significant difference in glucose absorption rate per gram of mucosal wet weight between the two groups (P > 0.05).

CONCLUSIONGLP-2 could improve morphological and functional adaptation of the residual small bowel by stimulating enterocyte proliferation and decreasing enterocyte apoptosis in short bowel syndrome.

Animals ; Disease Models, Animal ; Glucagon-Like Peptide 2 ; therapeutic use ; Ileum ; pathology ; Intestinal Mucosa ; metabolism ; pathology ; physiopathology ; Intestine, Small ; surgery ; Male ; Postoperative Complications ; therapy ; Proliferating Cell Nuclear Antigen ; metabolism ; Rats ; Rats, Wistar ; Short Bowel Syndrome ; pathology ; physiopathology ; therapy