OBJECTIVE: To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. METHODS: The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. RESULTS: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). CONCLUSION HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.
Animals ; Glucagon-Like Peptide 1/metabolism* ; Diabetes Mellitus, Type 2/metabolism* ; Glucagon-Like Peptide-1 Receptor/metabolism* ; Insulin-Secreting Cells/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Male ; Blood Glucose/metabolism* ; Insulin/blood* ; Mice ; Intestinal Mucosa/pathology* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Islets of Langerhans/pathology*

OBJECTIVES: To investigate the effects of live combined Bacillus subtilis and Enterococcus faecium (LCBE) on glucose and lipid metabolism in mice with type 2 diabetes mellitus (T2DM) and circadian rhythm disorder (CRD) and explore the possible mechanisms. METHODS: KM mice were randomized into normal diet (ND) group (n=8), high-fat diet (HFD) group (n=8), and rhythm-intervention with HFD group (n=16). After 8 weeks of feeding, the mice were given an intraperitoneal injection of streptozotocin (100 mg/kg) to induce T2DM. The mice in CRD-T2DM group were further randomized into two equal groups for treatment with LCBE (225 mg/kg) or saline by gavage; the mice in ND and HFD groups also received saline gavage for 8 weeks. Blood glucose level of the mice was measured using a glucometer, and serum levels of Bmal1, PER2, insulin, C-peptide and lipids were determined with ELISA. Colon morphology and hepatic lipid metabolism of the mice were examined using HE staining and Oil Red O staining, respectively, and fecal short-chain fatty acids (SCFAs) was detected using LC-MS; GPR43 and GLP-1 expression levels were analyzed using RT-qPCR and Western blotting. RESULTS: Compared with those in CRD-T2DM group, the LCBE-treated mice exhibited significant body weight loss, lowered levels of PER2, insulin, C-peptide, total cholesterol (TC) and LDL-C, and increased levels of Bmal1 and HDL-C levels. LCBE treatment significantly increased SCFAs, upregulated GPR43 and GLP-1 expressions at both the mRNA and protein levels, and improved hepatic steatosis and colon histology. CONCLUSIONS LCBE ameliorates lipid metabolism disorder in CRD-T2DM mice by reducing body weight and improving lipid profiles and circadian regulators possibly via the SCFAs/GPR43/GLP-1 pathway.
Animals ; Mice ; Lipid Metabolism ; Diabetes Mellitus, Type 2/metabolism* ; Enterococcus faecium ; Glucagon-Like Peptide 1/metabolism* ; Bacillus subtilis ; Diabetes Mellitus, Experimental/metabolism* ; Circadian Rhythm ; Blood Glucose/metabolism* ; Receptors, G-Protein-Coupled/metabolism* ; Fatty Acids, Volatile/metabolism* ; Male ; Chronobiology Disorders/metabolism*

This study aims to observe the effects of different doses of Astragali Radix on the expression of glucagon(GLP-1) in se-rum and glucagon receptor(GLP-1R) in cartilage tissue in rats with knee osteoarthritis(KOA), explore the effect of Astragali Radix on the inflammation and apoptosis of KOA by regulating GLP-1/GLP-1R signaling axis, and investigate the mechanism of its action in alleviating KOA. Forty-eight male SD rats were randomly divided into six groups: blank group, model group, low-, medium-, and high-dose Astragali Radix groups(3.125, 6.25, and 12.5 g·kg~(-1)), and glucosamine sulfate group(0.1 g·kg~(-1)). Except for the blank group, rats in other groups were injected with sodium iodoacetate(MIA) into the knee joint to establish KOA models. After successful modeling, the rats were continuously treated for five weeks. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of GLP-1, tumor necrosis factor-alpha(TNF-α), and interleukin-1β(IL-1β) in rat serum. Pathological examination was utilized to observe the pathological changes in knee joint cartilage. The mRNA levels of TNF-α and MMP13 in knee joint cartilage were detected by qRT-PCR, and the protein expression levels of GLP-1R, MMP13, and caspase-8 in knee joint cartilage were detected by Western blot. The expression of GLP-1R and MMP13 in the knee joint was detected by immunohistochemistry. Tunel staining was used to observe the apoptosis of chondrocytes in the knee joint. The above experimental results showed that Astragali Radix may raise the serum levels of GLP-1, reduce serum levels of TNF-α and IL-1, and decrease the relative mRNA expression of TNF-α and MMP13 through the GLP-1/GLP-1R axis. It thus activated GLP-1R, reduced the protein expression of MMP13 and caspase-8 in cartilage, and regulated their related signaling pathways to improve inflammation and apoptosis, so as to protect cartilage and improve KOA.
Animals ; Male ; Rats, Sprague-Dawley ; Osteoarthritis, Knee/genetics* ; Rats ; Drugs, Chinese Herbal/pharmacology* ; Glucagon-Like Peptide 1/metabolism* ; Glucagon-Like Peptide-1 Receptor/metabolism* ; Astragalus propinquus/chemistry* ; Humans ; Matrix Metalloproteinase 13/metabolism* ; Signal Transduction/drug effects* ; Tumor Necrosis Factor-alpha/metabolism* ; Astragalus Plant/chemistry* ; Apoptosis/drug effects*

Humans ; Glucagon-Like Peptide-1 Receptor/agonists* ; Diabetic Cardiomyopathies/drug therapy* ; Diabetes Mellitus, Type 2

OBJECTIVES: To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery. METHODS: Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 μg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups. RESULTS: There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (P>0.05). On the 3rd and 7th day after surgery, the levels of serum GAS, MTL, insulin, and GLP-1 in the observation group were higher than those in the control group (P<0.05). In the observation group, the levels of GAS, MTL, insulin, and GLP-1 on the 7th day after surgery were higher than those before surgery and on the 3rd day after surgery (P<0.05), and the levels on the 3rd day after surgery were higher than those before surgery (P<0.05). There was no significant difference in the levels of serum GAS, MTL, and insulin before surgery, on the 3rd day after surgery, and on the 7th day after surgery in the control group (P>0.05). The level of GLP-1 on the 7th day after surgery was higher than that before surgery and on the 3rd day after surgery (P<0.05), and the level on the 3rd day after surgery was higher than that before surgery (P<0.05) in the control group. The observation group had shorter first time of anal exhaust, recovery time of bowel sounds, and first time of defecation after surgery compared to the control group (P<0.05). The incidence of complications after surgery in the observation group was lower than that in the control group (10% vs 33%, P<0.05). CONCLUSIONS Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.
Humans ; Infant ; Critical Illness ; Digestive System Surgical Procedures ; Glucagon-Like Peptide 1 ; Insulin ; Prospective Studies ; Somatostatin/therapeutic use*

To explore the application value of serum Gal-13, GLP-1 and VEGF in the prevention and guidance of adverse pregnancy outcomes in gestational diabetes (GDM). A retrospective study with case-control method was used to select 1 012 GDM patients from Haikou Maternal and Child Health Hospital from January 2019 to December 2022 as the study objects, and they were divided into poor pregnancy outcome group (n=342) and good pregnancy outcome group (n=670) according to whether they had adverse pregnancy outcomes. The medical records of 521 healthy women with normal glucose metabolism were selected as the control group. Serum Gal-13 and GLP-1 were detected by enzyme-linked immunosorbent assay and VEGF was determined by IAMMGE specific protein analyzer. After comparing the differences of the above factors among the three groups, multivariate logistic regression model was used to analyze the influencing factors of adverse pregnancy outcomes in GDM patients, and ROC curve was drawn to analyze the predictive value of serum Gal-13, GLP-1 and VEGF levels on adverse pregnancy outcomes in GDM patients. The results showed that Fasting blood glucose (FPG), glycosylated hemoglobin (HbA1c) and fasting insulin (FINS) in the adverse pregnancy outcome group were 5.92(4.98, 6.41) mmol/L, 5.32(4.96, 5.47)%, 62.56(49.21,99.50) pmol/L, VEGF was 495.47(389.14, 567.13) ng/L, TSH was 1.48(1.34, 1.58) mIU/L, right ventricular myocardial work index (Tei index) was 0.59(0.45, 0.67), 89 cases of elderly parturients; FPG was 4.45(4.16, 5.03) mmol/L, HbA1c was 5.04(4.86, 5.29)%, FINS was 57.41(46.90, 74.08) pmol/L, VEGF was 405.84(348.02, 462.68) ng/L, TSH was 1.42(1.25, 1.50) mIU/L, Tei index was 0.50(0.47, 0.64), there were 142 cases of old women. In the control group, FPG was 4.33(4.05, 4.75) mmol/L, HbA1c was 5.01(4.13, 5.18)%, FINS was 38.48(36.76, 41.72) pmol/L and VEGF was 302.45(283.14, 336.56) ng/L, TSH was 1.32(1.24, 1.47)mIU/L, Tei index was 0.48(0.39, 0.59), and there were 106 elderly parturiencies. The levels of FPG, HbA1c, FINS, VEGF, TSH and Tei index in the adverse pregnancy outcome group and the good pregnancy outcome group were higher than those in the control group, and the proportion of elderly parturients was higher than that in the control group, and the adverse pregnancy outcome group was higher than that in the good pregnancy outcome group. The differences were statistically significant (H=8.620, P<0.001, H=2.616, P=0.014, H=6.156, P<0.001, H=3.051, P<0.001, H=4.892, P=0.044, χ²=2.548, P=0.045). In the adverse pregnancy outcome group, Gal-13 was 15.27(8.35, 24.45)pg/ml, GLP-1 was 9.27(8.26, 12.35) pmol/L and FT4 was 11.59(9.67, 13.48) pmol/L. In the group with good pregnancy outcome, Gal-13 was 25.34(20.14, 29.73) pg/ml, GLP-1 was 12.38(10.25, 15.63) pmol/L and FT4 was 13.86(10.67, 15.10) pmol/L. In the control group, Gal-13 was 31.21(27.48, 34.45) pg/ml, GLP-1 was 11.34(10.40, 14.37) pmol/L and FT4 was 14.15(10.75, 15.43)pmol/L. The levels of Gal-13, GLP-1 and FT4 in the adverse pregnancy outcome group and the good pregnancy outcome group were significantly lower than those in the control group, and the adverse pregnancy outcome group was lower than that in the good pregnancy outcome group. The differences were statistically significant (H=6.458, P=0.011, H=8.445, P<0.001, H=5.694, P<0.001). The levels of Gal-13 and GLP-1 in normal blood glucose recovery group were higher than those in non-normal blood glucose recovery group, and the levels of VEGF were lower than those in non-normal blood glucose recovery group (P<0.05).In multivariate logistic regression analysis, Gal-13, GLP-1, VEGF, TSH, FT4 and Tei indexes were independent influencing factors for adverse pregnancy outcomes with GDM (P<0.05). ROC curve analysis showed that the AUC of Gal-13, GLP-1 and VEGF alone in predicting adverse pregnancy were 0.779, 0.761 and 0.615, respectively. The value of the combined diagnosis was the highest (AUC=0.912), the sensitivity was 90.1%, and the specificity was 80.0%. In conclusion, Gal-13, GLP-1 and VEGF may be independent influencing factors for adverse pregnancy outcomes in GDM patients, and the combined detection of the three may help to improve the auxiliary diagnostic efficacy for predicting adverse pregnancy outcomes.
Aged ; Child ; Female ; Humans ; Pregnancy ; Blood Glucose ; Diabetes, Gestational ; Glucagon-Like Peptide 1 ; Glycated Hemoglobin ; Pregnancy Outcome ; Retrospective Studies ; Thyrotropin ; Vascular Endothelial Growth Factor A

To explore the application value of serum Gal-13, GLP-1 and VEGF in the prevention and guidance of adverse pregnancy outcomes in gestational diabetes (GDM). A retrospective study with case-control method was used to select 1 012 GDM patients from Haikou Maternal and Child Health Hospital from January 2019 to December 2022 as the study objects, and they were divided into poor pregnancy outcome group (n=342) and good pregnancy outcome group (n=670) according to whether they had adverse pregnancy outcomes. The medical records of 521 healthy women with normal glucose metabolism were selected as the control group. Serum Gal-13 and GLP-1 were detected by enzyme-linked immunosorbent assay and VEGF was determined by IAMMGE specific protein analyzer. After comparing the differences of the above factors among the three groups, multivariate logistic regression model was used to analyze the influencing factors of adverse pregnancy outcomes in GDM patients, and ROC curve was drawn to analyze the predictive value of serum Gal-13, GLP-1 and VEGF levels on adverse pregnancy outcomes in GDM patients. The results showed that Fasting blood glucose (FPG), glycosylated hemoglobin (HbA1c) and fasting insulin (FINS) in the adverse pregnancy outcome group were 5.92(4.98, 6.41) mmol/L, 5.32(4.96, 5.47)%, 62.56(49.21,99.50) pmol/L, VEGF was 495.47(389.14, 567.13) ng/L, TSH was 1.48(1.34, 1.58) mIU/L, right ventricular myocardial work index (Tei index) was 0.59(0.45, 0.67), 89 cases of elderly parturients; FPG was 4.45(4.16, 5.03) mmol/L, HbA1c was 5.04(4.86, 5.29)%, FINS was 57.41(46.90, 74.08) pmol/L, VEGF was 405.84(348.02, 462.68) ng/L, TSH was 1.42(1.25, 1.50) mIU/L, Tei index was 0.50(0.47, 0.64), there were 142 cases of old women. In the control group, FPG was 4.33(4.05, 4.75) mmol/L, HbA1c was 5.01(4.13, 5.18)%, FINS was 38.48(36.76, 41.72) pmol/L and VEGF was 302.45(283.14, 336.56) ng/L, TSH was 1.32(1.24, 1.47)mIU/L, Tei index was 0.48(0.39, 0.59), and there were 106 elderly parturiencies. The levels of FPG, HbA1c, FINS, VEGF, TSH and Tei index in the adverse pregnancy outcome group and the good pregnancy outcome group were higher than those in the control group, and the proportion of elderly parturients was higher than that in the control group, and the adverse pregnancy outcome group was higher than that in the good pregnancy outcome group. The differences were statistically significant (H=8.620, P<0.001, H=2.616, P=0.014, H=6.156, P<0.001, H=3.051, P<0.001, H=4.892, P=0.044, χ²=2.548, P=0.045). In the adverse pregnancy outcome group, Gal-13 was 15.27(8.35, 24.45)pg/ml, GLP-1 was 9.27(8.26, 12.35) pmol/L and FT4 was 11.59(9.67, 13.48) pmol/L. In the group with good pregnancy outcome, Gal-13 was 25.34(20.14, 29.73) pg/ml, GLP-1 was 12.38(10.25, 15.63) pmol/L and FT4 was 13.86(10.67, 15.10) pmol/L. In the control group, Gal-13 was 31.21(27.48, 34.45) pg/ml, GLP-1 was 11.34(10.40, 14.37) pmol/L and FT4 was 14.15(10.75, 15.43)pmol/L. The levels of Gal-13, GLP-1 and FT4 in the adverse pregnancy outcome group and the good pregnancy outcome group were significantly lower than those in the control group, and the adverse pregnancy outcome group was lower than that in the good pregnancy outcome group. The differences were statistically significant (H=6.458, P=0.011, H=8.445, P<0.001, H=5.694, P<0.001). The levels of Gal-13 and GLP-1 in normal blood glucose recovery group were higher than those in non-normal blood glucose recovery group, and the levels of VEGF were lower than those in non-normal blood glucose recovery group (P<0.05).In multivariate logistic regression analysis, Gal-13, GLP-1, VEGF, TSH, FT4 and Tei indexes were independent influencing factors for adverse pregnancy outcomes with GDM (P<0.05). ROC curve analysis showed that the AUC of Gal-13, GLP-1 and VEGF alone in predicting adverse pregnancy were 0.779, 0.761 and 0.615, respectively. The value of the combined diagnosis was the highest (AUC=0.912), the sensitivity was 90.1%, and the specificity was 80.0%. In conclusion, Gal-13, GLP-1 and VEGF may be independent influencing factors for adverse pregnancy outcomes in GDM patients, and the combined detection of the three may help to improve the auxiliary diagnostic efficacy for predicting adverse pregnancy outcomes.
Aged ; Child ; Female ; Humans ; Pregnancy ; Blood Glucose ; Diabetes, Gestational ; Glucagon-Like Peptide 1 ; Glycated Hemoglobin ; Pregnancy Outcome ; Retrospective Studies ; Thyrotropin ; Vascular Endothelial Growth Factor A

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*

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*

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