Glucagon-like Peptide-1 Concentrations Research Articles

The signalling association of glucagon-like peptide-1 and its receptors in the gastrointestinal tract and GPR40 and insulin receptor in the pancreas of sheep

The present study was aimed at gaining insight into the signalling relationship between glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) in the regulation of glucose metabolism. Further, to assess the role of G-protein-coupled receptor 40 (GPR40) and insulin receptor (INSR) in the pancreas of sheep that were supplemented with calcium salts of long-chain fatty acids (CSFAs). An experiment was carried out over a period of 60 days with eighteen sheep, and they were fed with a standard basal diet. The sheep were divided into three groups: CSFA0 (without CSFAs), while CSFA3 and CSFA5 were supplemented with 3 % and 5 % of CSFAs, respectively. Plasma concentrations of GLP-1, insulin, glucagon, and glucose were assessed every two weeks. At the end of the experiment, sheep were slaughtered, and samples of gastrointestinal tract (GIT) epithelial tissues and pancreas were collected to assess the relative expression of mRNA of GPR40, GLP-1R, and INSR. Postprandial GLP-1 and insulin were increased by 3.7–4.1 and 1.45–1.5 times, respectively, in the CSFAs-supplemented groups compared to CSFA0. Post-feeding, glucagon and glucose levels decreased in CSFA3 and CSFA5 compared to CSFA0. The results indicated that the supplementation of LCFAs increased the expression of GLP-1R in the GIT and pancreas, as well as the mRNA of GPR40 and INSR in the pancreas. Chemosensing of LCFAs by GPR40 in the pancreas triggers signalling transduction, and enhanced GLP-1 and GLP-1R resulted in moderately increased insulin secretion and reduced glucagon levels. These combined effects, along with the glucose-lowering effect of GLP-1, effectively lowered glucose levels in normoglycemic sheep.

Biomolecules of Adipose Tissue in Atherosclerotic Plaques of Men With Coronary Atherosclerosis.

To study metabolic molecules (adiponectin, adipsin, resistin, glucagon-like peptide-1 (GLP-1), glucagon, secretin) of adipose tissue in atherosclerotic plaques (AP) and their associations with AP instability in men with coronary atherosclerosis. Metabolic molecules (adipocytokines and metabolic hormones) of adipose tissue can act as enzymes, hormones or growth factors in modulating insulin resistance and lipid and glucose metabolism and indirectly influence the course of the atherosclerotic process. This study included 48 men from whom 139 coronary artery (CA) samples were collected during coronary artery bypass grafting, after obtaining the informed consent. According to the histological conclusion, 84 (60.4%) CA plaques were stable, 44 (31.7%) were unstable, and 11 histological samples had a conditionally unchanged CA intima (7.9%). The concentrations of adiponectin, adipsin, resistin, GLP-1, glucagon, and secretin were measured in AP homogenates by multiplex analysis using the Human Metabolic Hormone V3 panel (MILLIPLEX, Germany). During the study, demographic and anthropometric characteristics, medical history, and presence of chronic diseases were recorded. The glucagon concentration in the conditionally unchanged intima was 16.7% lower and in the fragments of unstable atherosclerotic plaques 41.2% lower than in fragments of stable APs. However, the glucagon concentration in stable APs was 28% higher than in unstable APs. The secretin concentration in the conditionally unchanged intima was also lower than in stable APs by 41.2%, while in stable APs, the secretin concentration was 20% higher than in unstable APs. The adiponectin concentrations were directly correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations (r=0.286; p=0.002), while the secretin concentrations were inversely correlated with serum HDL-C concentrations (r= -0.199; p=0.038). The probability of having an unstable AP (in relation to conditionally unchanged intima) increases by 35.8% with an increase in the AP glucagon concentration by 1 pg/mg protein. The probability of having a stable AP (in relation to unchanged intima) increases by 29.4% with an increase in the AP glucagon concentration by 1 pg/mg protein and by 10.1% with an increase in the AP secretin concentration by 1 pg/mg protein. The AP adiponectin concentration directly correlates and the AP secretin concentration inversely correlates with the serum concentration of HDL-C. The presence of both stable and unstable APs is directly associated with the AP glucagon concentration in men with coronary atherosclerosis. The AP secretin concentration is directly associated with plaque stability in men with coronary atherosclerosis. Further thorough study of the identified markers in atherosclerotic lesions will allow using them as potential targets for therapy.

A New Alternative Nutritional Source Hawthorn Vinegar: How It Interacts with Protein, Glucose and GLP-1.

(1) Background: There is a balance between nutrition, glycemic control, and immune response. Their roles in physiological mechanisms are essential for maintaining life quality. This study aimed to evaluate hawthorn vinegar's metabolic effects, and describe its possible mechanism. We also pointed out several vinegar production methods to clarify the antioxidant features. (2) Methods: In the study, three vinegar techniques were applied to vinegar: traditional production of hawthorn vinegar (N), thermal pasteurization (P), and ultrasound method (U). Thirty-two female adult Wistar albino rats were randomly separated into four groups: Control, N1 (regular vinegar; 1 mL/kg bw), P1 (pasteurized vinegar; 1 mL/kg bw), and U1(ultrasound treated vinegar; 1 mL/kg bw). Vinegar was administered by oral gavage daily for 45 days. Initial and final weights, the percentage changes of body weight gains, and Gamma-Glutamyl Transferase (GGT) values of plasma and liver were measured. The total protein, globulin, and albumin values of plasma, liver, and intestinal tissue were determined. In addition, plasma glucagon-like peptide-1 (GLP-1) and glucose concentrations were evaluated. (3) Results: There was a statistical increase in total intestinal protein value and an increasing tendency in total protein in plasma and liver in group U1 compared to group Control. However, the GGT concentrations in plasma and liver were slightly lower in group U1 than in group Control. In addition, there were significant increases in plasma GLP-1 values in all experimental groups compared to the Control group (p: 0.015; 576.80 ± 56.06, 773.10 ± 28.92, 700.70 ± 17.05 and 735.00 ± 40.70; respectively groups control, N1, P1, and U1). Also, liver GLP-1 concentrations in groups P1 and U1 were higher than in group Control (p: 0.005; 968.00 ± 25.54, 1176 ± 17.54 and 1174.00 ± 44.06, respectively groups control, P1 and U1). On the other hand, significant decreases were found in plasma glucose concentrations in groups N1 and U1 as to the Control group (p: 0.02; Control: 189.90 ± 15.22, N1: 133.10 ± 7.32 and U1: 142.30 ± 4.14). Besides, liver glucose levels were lower in all experimental groups than in group Control statistically (p: 0.010; 53.47 ± 0.97, 37.99 ± 1.46, 44.52 ± 4.05 and 44.57 ± 2.39, respectively groups control, N1, P1, and U1). (4) Conclusions: The findings suggest that hawthorn vinegar can balance normal physiological conditions via intestinal health, protein profiles, and glycemic control. Additionally, ultrasound application of vinegar may improve the ability of hawthorn vinegar, and have positive effects on general health.

Preclinical pharmacokinetics, pharmacodynamics, and toxicity of novel small-molecule GPR119 agonists to treat type-2 diabetes and obesity

The escalating global prevalence of type-2 diabetes (T2D) and obesity necessitates the development of novel oral medications. Agonism at G-protein coupled receptor-119 (GPR119) has been recognized for modulation of metabolic homeostasis in T2D, obesity, and fatty liver disease. However, off-target effects have impeded the advancement of synthetic GPR119 agonist drug candidates. Non-systemic, gut-restricted GPR119 agonism is suggested as an alternative strategy that may locally stimulate intestinal enteroendocrine cells (EEC) for incretin secretion, without the need for systemic drug availability, consequently alleviating conventional class-related side effects. Herein, we report the preclinical acute safety, efficacy, and pharmacokinetics (PK) of novel GPR119 agonist compounds ps297 and ps318 that potentially target gut EEC for incretin secretion. In a proof-of-efficacy study, both compounds demonstrated glucagon-like peptide-1 (GLP-1) secretion capability during glucose and mixed-meal tolerance tests in healthy mice. Furthermore, co-administration of sitagliptin with investigational compounds in diabetic db/db mice resulted in synergism, with GLP-1 concentrations rising by three-fold. Both ps297 and ps318 exhibited low gut permeability assessed in the in-vitro Caco-2 cell model. A single oral dose PK study conducted on healthy mice demonstrated poor systemic bioavailability of both agents. PK measures (mean ± SD) for compound ps297 (Cmax 23 ± 19 ng/mL, Tmax range 0.5 – 1 h, AUC0–24 h 19.6 ± 21 h*ng/mL) and ps318 (Cmax 75 ± 22 ng/mL, Tmax range 0.25 – 0.5 h, AUC0–24 h 35 ± 23 h*ng/mL) suggest poor oral absorption. Additionally, examinations of drug excretion patterns in mice revealed that around 25 % (ps297) and 4 % (ps318) of the drugs were excreted through faeces as an unchanged form, while negligible drug concentrations (<0.005 %) were excreted in the urine. These acute PK/PD assessments suggest the gut is a primary site of action for both agents. Toxicity assessments conducted in the zebrafish and healthy mice models confirmed the safety and tolerability of both compounds. Future chronic in-vivo studies in relevant disease models will be essential to confirm the long-term safety and efficacy of these novel compounds.

Fermented red pepper paste (kochujang) modulates glucose metabolism and gut microbiota in parasympathetic suppression: Network pharmacology and In vivo study

We aimed to explore the relationship between Korean fermented red pepper paste, kochujang compounds, and the genes associated with type 2 diabetes (T2DM) and parasympathetic nervous system (PNS) dysfunction by network pharmacology. The study aimed to validate the kochujang efficacy on glucose metabolism in PNS-suppressed rats. Male Sprague-Dawley rats were intraperitoneally injected with scopolamine at 2 mg/kg body weight daily for 8 weeks. They were divided into four groups according to kochujang types: 1% traditionally-made kochujang (TMK) in 43% fat diets based on the capsaicin content and factory-made kochujang (FMK). The control and normal-C groups received a 43% fat diet. In the network pharmacology analysis, kochujang contained 26 chemical compounds: carotenoids, isoflavonoids, capsaicin-related compounds, and phytosterols. It highlighted critical genes, including AKT1, B-cell lymphoma-2(BLC2), catenin beta-1(CTNNB1), and caspase-3(CASP3) as the primary targets for treating T2DM and PNS suppression. Functional enrichment analysis indicated the involvement of kochujang compounds in endopeptidase activity and G-protein-coupled receptor activity relevant to diabetes and neuropathy. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed associations with cancer, infection and inflammation, lipid metabolism, and diabetic complication-related pathways. FMK and TMK consumption improved glucose homeostasis and lipid profiles by modulating serum insulin and glucagon-like peptide-1 concentration and insulin resistance in scopolamine-induced rats. Oral glucose tolerance tests showed reduced glucose intolerance in kochujang-treated groups, especially high capsaicin-containing TMK. Kochujang mitigated liver damage and inflammation and modulated the gut microbiota composition to prevent the inhibition of insulin and neurotransmitter secretion through potentiating cAMP and calcium signaling pathways. In conclusion, high capsaicin-containing kochujang exhibited promising therapeutic effects against T2DM induced by PNS suppression through gut microbiota modulation.

Effects of Breaking Up Sitting on Gut Hormone Responses and Subsequent Compensatory Behaviors in Physically Inactive Adults.

The effects of breaking up sitting on gut hormone responses and free-living energy compensatory behaviors are still unclear in people of Asian ethnicity. Twenty-six Asians including 13 lean individuals (Lean) and 13 individuals with centrally overweight/obesity (OW), aged between 20 and 45 yr, completed a randomized crossover study with either 5.5-h uninterrupted sitting (SIT) or 5.5-h sitting with 2-min walking at 6.4 km·h -1 every 20 min (ACTIVE) in the laboratory. Blood samples were collected at regular time points to examine postprandial glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and glucose-dependent insulinotropic polypeptide (GIP) concentrations. Free-living physical activity and energy intake were recorded using wearable devices and weighed food diaries outside the laboratory until midnight. Paired t -tests were conducted to compare responses between trials. Postprandial GLP-1 and PYY incremental area under the curve values were higher in the ACTIVE trial versus SIT in both Lean and OW groups (all, P < 0.05), but there was no difference in GIP in either group (both, P > 0.05). There were no differences in free-living physical activity (volume and intensity) or energy intake (total and macronutrients) between trials in either group (all, P > 0.05), resulting in greater total physical activity over the 24-h monitoring period in ACTIVE trial versus SIT trial (both, P < 0.05). Breaking up sitting increases postprandial GLP-1 and PYY concentrations in Asians, but does not induce subsequent behavioral compensation, resulting in greater 24-h physical activity levels and lower relative energy intake, in inactive individuals irrespective of bodyweight status.

Food temperature altered macronutrients induced changes in satiety hormones; glucagon - like peptide -1 and cholecystokinin and their correlation with subjective satiety.

The benefits of dietary macronutrients for weight management depend on the integrity of gut hormones. The role of food temperature in the release of satiety hormones and satiety needs elucidation. We aimed to determine the impact of different food temperatures with varying macronutrient compositions on satiety-related gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) and find the correlation of satiety hormones with appetite scores and remainder-day food (energy) intake. Thirteen healthy participants (eight males and five females) aged 25-35 years with body mass index 18.5-24.9 kg/m2 with no medical illnesses or eating disorders consumed three compositions of meals (high carbohydrate, high fat, and high protein meals) each at three temperatures (cold, warm, and hot) in a randomized, double-blinded, controlled crossover design. Plasma concentrations of peptide hormones were determined at 0, 30, and 240 minutes by enzyme-linked immunosorbent assay, and 24-hours food recall was used for remainder-day food intake (remainder energy). Data were analyzed using SPSS version 27.0. The change in plasma levels of gut hormones with time was assessed using Friedman test; Kruskal-Wallis test was employed to compare GLP-1 and CCK hormonal levels across nine meals. A comparison of the three meals at the three temperatures (total of nine groups), showed that the GLP-1 and CCK plasma concentrations were significantly different (P < 0.001). GLP-1 and CCK responses increased more after hot meals than cold meals. Overall, high-fat meals had more effective gut hormone secretions. The area under the curve was increased for GLP-1 in high-fat meals and for CCK in hot meals. The peptide hormones (GLP-1 and CCK) were positively correlated with satiety scores and inversely with remainder food intake. The temperature of food was found to be an effective stimulus for the regulation of CCK and GLP-1 secretion. Hot food temperature increased satiety hormones (CCK and GLP-1), independent of food macronutrient composition.

Investigation of glucagon-like peptide-1 response to six oral carbohydrates in ponies

Glucagon-like peptide-1 (GLP-1), the principal incretin in horses, may play a role in the pathophysiology of insulin dysregulation (ID). This study aimed to describe its concentration in response to three preserved forages and four dynamic tests for ID in ponies. Twelve adult ponies of mixed ID status were given a meal of hay, soaked hay or haylage, an in-feed oral glucose test (OGT), oral sugar test (OST), an oral test using a proprietary breakfast cereal (WEET) or a combined glucose-insulin tolerance test (CGIT) weekly in a randomised cross-over study. Glucose, insulin and GLP-1 concentrations were measured before and following each intervention. Ponies were designated ID or non-ID and insulin resistant (IR) or non-IR according to OGT and CGIT results, respectively.All interventions apart from the CGIT provoked a GLP-1 response within 30 min. The OGT and WEET interventions, (containing the greatest dose of non-structural carbohydrate, 1.06 and 1 g/kg BW, respectively), resulted in a greater area under the curve (AUC) for GLP-1 compared to all other interventions (P < 0.001). No difference in GLP-1 response was detected according to ID or IR status, despite there being strong positive correlations (rs [95 % CI]) between GLP-1 and insulin concentrations measured at individual time points (0.67 [0.62 – 0.71]; P < 0.001) and as AUC (0.66 [0.49–0.79], P < 0.001). These data do not support of the use of GLP-1 as an adjunctive diagnostic test for ID or IR, as defined by conventional intravenous or oral dynamic tests.

Effect of vegetable consumption with chewing on postprandial glucose metabolism in healthy young men: a randomised controlled study

Although thorough chewing lowers postprandial glucose concentrations, research on the effectiveness of chewing vegetables in different forms on postprandial glucose metabolism remains limited. This study examined the effects of vegetables consumed in solid versus puree forms on postprandial glucose metabolism. Nineteen healthy young men completed two 180-min trials on separate days in a random order: the chewing trial involved the consumption of shredded cabbage with chewing and the non-chewing trial involved the consumption of pureed cabbage without chewing. Energy jelly was consumed immediately after the consumption of shredded or puree cabbage. Blood samples were collected at 0, 30, 45, 60, 90, 120 and 180 min. Circulating concentrations of glucose, insulin, total glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) concentrations were measured from the plasma. Although plasma glucose concentrations did not differ between the trials, the plasma insulin and GIP incremental area under the curve values were higher in the chewing than in the non-chewing trial. Postprandial total GLP-1 concentrations were higher in the chewing than in the non-chewing trial at 45, 60 and 90 min. This study demonstrates that consuming shredded cabbage while chewing enhances postprandial incretin secretion but has no effect on postprandial glucose concentration.Trial registration: Clinical trial registration ID.: UMIN000052662, registered 31 October 2023.

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson’s disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.

Exploring the modulatory effects of sotagliflozin on dyslipidemia in mice: The role of glucagon, fibroblast growth factor 21 and glucagon-like peptide 1.

Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2 inhibition is observed to potentiate the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1). The current preclinical research sought to investigate the effect of sotagliflozin on the secretion of fat-regulating peptides such as GLP-1, glucagon and fibroblast growth factor 21 (FGF21) and their prospective association with sotagliflozin's potential beneficial effects on dyslipidaemia. During an oral fat tolerance test in mice, sotagliflozin substantially increased GLP-1 and insulin concentrations. Although sotagliflozin alone did not ameliorate postprandial lipemia, its combination with linagliptin (DPP-IV inhibitor) significantly improved lipid tolerance comparable to orlistat (lipase inhibitor). In a triton-induced hypertriglyceridemia model, sotagliflozin, along with other medications (fenofibrate, exenatide and linagliptin) reduced fat excursion; however, co-administration with linagliptin provided no extra advantage. Furthermore, sotagliflozin stimulated glucagon secretion in the alpha TC1.6 cells and healthy mice, which resulted in an increased circulating FGF21 and β-hydroxybutyrate concentration. Finally, chronic treatment of sotagliflozin in high-fat diet (HFD)-fed obese mice resulted in reduced body weight gain, liver triglyceride, cholesterol, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels compared with the placebo group. However, the addition of linagliptin did not provide any additional benefit. In conclusion, sotagliflozin was found to have an effect on GLP-1 and also stimulate the release of glucagon and FGF21, which are important for regulating fat metabolism. Therefore, sotagliflozin might represent a potential therapeutic approach for the treatment of diabetic dyslipidemia and steatohepatitis.

The acute effect of a β-glucan-enriched oat bread on gastric emptying, GLP-1 response, and postprandialglycaemia and insulinemia: a randomised crossover trial in healthy adults.

The cereal fibre β-glucan reduces postprandial glycaemia, however, the underlying mechanisms are not fully understood. Thus, the aim of this study was to investigate the acute effect of a β-glucan-enriched oat bread on gastric emptying half-time (T1/2), gastric emptying lag phase (Tlag), and gastric emptying rate (GER), and the secretion of glucagon-like peptide-1 (GLP-1) as potential means to influence postprandial glycaemia. A randomised crossover trial was conducted in 22 healthy adults (age 24.6 ± 3.1years, BMI 23.1 ± 2.7kg/m2) receiving 25g available carbohydrates from a β-glucan-enriched oat bread or a control whole-wheat bread at two non-consecutive days. T1/2, Tlag, and GER were determined based on ultrasound measures of the cross-sectional gastric antrum area in the fasting state and 15, 30, 45, 60, 90, and 120min postprandially. Capillary glucose, serum insulin, and plasma GLP-1 concentrations were measured at the same time points. A biphasic pattern of gastric emptying with a distinct Tlag before the commencement of emptying was observed in most subjects for both bread types. While no differences in GER were evident (p = 0.562), consumption of the oat bread significantly increased T1/2 by 18min and Tlag by 14min compared with the whole-wheat bread (p = 0.005 and p = 0.010, respectively). In addition, the oat bread significantly reduced iAUC2h for glucose and insulin responses compared with the whole-wheat bread (p = 0.001 and p < 0.001, respectively). There were no significant differences in GLP-1 response between the two breads (p = 0.892). The increased T1/2 and Tlag could offer a potential mechanism for the observed attenuation of postprandial glycaemia and insulinemia after consumption of the β-glucan-enriched oat bread compared with the whole-wheat bread. The study is registered at clinicaltrails.gov (NCT04571866).

Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.

Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms. A total of 24 healthy men with regular sleep schedules were examined for 24h at the hospital ward with 15h of wakefulness and 9h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included. Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26h), GLP-1 (p < 0.0001, peak time 17:28h), GIP (p < 0.0001, peak time 18:01h), C-peptide (p < 0.0001, peak time 17.59h), and glucose (p < 0.0001, peak time 23:26h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP. Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity. ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023.

Fasting and post prandial pancreatic and enteroendocrine hormone levels in obese and non-obese participants

Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.

Chitosan and sodium alginate nanocarrier system: Controlling the release of rapeseed-derived peptides and improving their therapeutic efficiency of anti-diabetes

Rapeseed-derived peptides (RPPs) can maintain the homeostasis of human blood glucose by inhibiting Dipeptidyl Peptidase-IV (DPP-IV) and activating the calcium-sensing receptor (CaSR). However, these peptides are susceptible to hydrolysis in the gastrointestinal tract. To enhance the therapeutic potential of these peptides, we developed a chitosan/sodium alginate-based nanocarrier to encapsulate two RPP variants, rapeseed-derived cruciferin peptide (RCPP) and rapeseed-derived napin peptide (RNPP). A convenient three-channel device was employed to prepare chitosan (CS)/sodium alginate (ALG)-RPPs nanoparticles (CS/ALG-RPPs) at a ratio of 1:3:1 for CS, ALG, and RPPs. CS/ALG-RPPs possessed optimal encapsulation efficiencies of 90.7 % (CS/ALG-RNPP) and 91.4 % (CS/ALG-RCPP), with loading capacities of 15.38 % (CS/ALG-RNPP) and 16.63 % (CS/ALG-RCPP) at the specified ratios. The electrostatic association between CS and ALG was corroborated by zeta potential and near infrared analysis. 13C NMR analysis verified successful RPPs loading, with CS/ALG-RNPP displaying superior stability. Pharmacokinetics showed that both nanoparticles were sustained release and transported irregularly (0.43 < n < 0.85). Compared with the control group, CS/ALG-RPPs exhibited significantly increased glucose tolerance, serum GLP-1 (Glucagon-like peptide 1) content, and CaSR expression which play pivotal roles in glucose homeostasis (*p < 0.05). These findings proposed that CS/ALG-RPPs hold promise in achieving sustained release within the intestinal epithelium, thereby augmenting the therapeutic efficacy of targeted peptides.

Differences in the levels of the appetite peptides ghrelin, peptide tyrosine tyrosine, and glucagon-like peptide-1 between obesity classes and lean controls.

This study was designed to compare basal concentrations of the gastrointestinal appetite modulators ghrelin, peptide tyrosine tyrosine (PYY), and glucagon-like peptide 1 (GLP-1) between obesity classes and obesity classes and controls. The study included 49 healthy controls with body mass index (BMI) between 18.5 and 29.9 kg/m² and 62 individuals with obesity with BMI ≥30 kg/m². Basal ghrelin, PYY, and GLP-1 concentrations of the samples were analyzed by an enzyme-linked immunosorbent assay commercial kit (SunRed Human). Other biochemical parameters were measured by a clinical chemistry autoanalyzer (Beckman Coulter AU 5800) in the biochemistry laboratory. Compared with the control group, ghrelin, PYY, and GLP-1 levels were significantly lower in the obese group (P < .05). The PYY concentration was significantly different between obese groups (P < .05). The PYY and GLP-1 levels were significantly different between obesity class I and obesity class III. In addition, ghrelin levels were significantly different between obesity class II and obesity class III. Correlation analysis revealed a negative correlation between BMI and serum ghrelin, GLP-1, and PYY concentrations. Low basal ghrelin, GLP-1, and PYY hormones in the obese group compared with the control group indicate impaired appetite regulation in this population. The significant difference in PYY levels between obese groups was associated with increasing obesity grade.

Insulin resistance prior to term age in very low birthweight infants: a prospective study

ObjectiveTo explore the glucose-related hormone profile of very low birthweight (VLBW) infants and assess the association between neonatal hyperglycaemia and insulin resistance during the admission period.DesignA prospective observational study—the Very...

Insulin sensitivity and beta cell function after duodenal mucosal resurfacing: an open-label, mechanistic, pilot study

Background and AimsThe duodenum has been shown to play a key role in glucose homeostasis. Duodenal mucosal resurfacing (DMR) is an endoscopic procedure for patients with type 2 diabetes (T2D) in which the duodenal mucosa is hydrothermally ablated. DMR improves glycemic control, but the underlying mechanisms remain unclear. Here, we report changes in glucoregulatory hormones and indices of insulin sensitivity and beta cell function after DMR. MethodsWe included 28 patients on non-insulin glucose lowering medications who underwent open-label DMR and a mixed meal test (MMT) in Revita-1 or Revita-2. Inclusion criteria were hemoglobin A1c (HbA1c) 7.6-10.4% and BMI 24-40kg/m2. Baseline and 3-months MMT data included plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations. Glucoregulatory hormones, insulin sensitivity indices (homeostatic model assessment for insulin resistance [HOMA-IR], Matsuda index [MI] and hepatic insulin resistance [HIR]), and beta cell function (insulinogenic index [IGI], disposition index [DI] and insulin secretion rate [ISR]) were assessed. ResultsFasting insulin, glucagon, and C-peptide decreased significantly. Insulin sensitivity (HOMA-IR, MI, and HIR) and beta cell function (DI and ISR) all improved significantly. Decline in postprandial glucose, mainly driven by a decrease in fasting levels, was observed, as well as a decline in postprandial glucagon whereas GLP-1 and GIP did not change. ConclusionsInsulin sensitivity and insulin secretion improved 3 months after DMR. It is unlikely that incretin changes are responsible for improved glucose control after DMR. These data add to the growing evidence validating the duodenum as a therapeutic target for patients with T2D.

Effect of Anagliptin on Vascular Injury in the Femoral Artery of Type 2 Diabetic Rats.

Patients with diabetes mellitus (DM) often experience complications such as peripheral arterial disease (PAD), which is thought to be caused by vascular damage resulting from increased oxidative stress. Dipeptidyl peptidase-4 inhibitors have been reported to reduce oxidative stress, although the exact mechanism remains unclear. This study aimed to investigate the impact of long-term (6 weeks) anagliptin treatment at a dose of 200 mg/kg/d against oxidative stress in the femoral artery of Otsuka Long-Evans Tokushima Fatty (OLETF) rats using a well-established animal model for type 2 DM. Serum toxic advanced glycation end-products concentrations and blood glucose levels after glucose loading were significantly elevated in OLETF rats compared to Long-Evans Tokushima Otsuka (LETO) rats but were significantly suppressed by anagliptin administration. Plasma glucagon-like peptide-1 concentrations after glucose loading were significantly increased in anagliptin-treated rats. Superoxide production and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in femoral arteries were significantly increased in OLETF rats compared to LETO rats but were significantly decreased by anagliptin administration. The expressions of NADPH oxidase components (p22phox in the intima region and p22phox and gp91phox in the media region) in the femoral artery were significantly increased in OLETF rats compared to LETO rats but were significantly suppressed by anagliptin administration. Furthermore, the femoral artery showed increased wall thickness in OLETF rats compared to LETO rats, but anagliptin administration reduced the thickening. This study suggests that long-term anagliptin administration can reduce oxidative stress in femoral arteries and improve vascular injury.

Profiles of Intestinal Flora in Breastfed Obese Children and Selecting Functional Strains Against Obesity.

Breast milk has the potential to prevent childhood obesity by providing probiotics, but there are still instances of obesity in breastfed children. This study investigates the difference in intestinal flora structure between breastfed children with obesity (OB-BF) and normal-weight breastfed children (N-BF). Building upon this foundation, it employs both cell and mouse models to identify an antiobesity strain within the fecal matter of N-BF children and explore its underlying mechanisms. The results reveal a reduction in lactobacillus levels within the intestinal flora of OB-BF children compared to N-BF children. Consequently, Lactobacillus plantarum H-72 (H-72) is identified as a promising candidate due to its capacity to stimulate glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells (ECCs). In vivo, H-72 effectively increases serum GLP-1 concentration, reduces food intake, regulates the expression of genes related to energy metabolism (SCD-1, FAS, UCP-1, and UCP-3), and regulates gut microbiota structure in mice. Moreover, the lipoteichoic acid of H-72 activates toll-like receptor 4 to enhanced GLP-1 secretion in STC-1 cells. L. plantarum H-72 is screened out for its potential antiobesity effect, which presents a potential and promising avenue for future interventions aimed at preventing pediatric obesity in breastfed children.