Glucagon-like Peptide-1 Levels Research Articles

Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study.

Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank. We used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development. Obesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10-12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (β 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (β 0.504; 95% CI 0.03, 0.98; n=11; p=0.04). Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits. All coding is available through https://github.com/nicwin98/UK-Biobank-GCG.

Achyranthes bidentata polysaccharide ameliorates type 2 diabetes mellitus by gut microbiota-derived short-chain fatty acids-induced activation of the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway

Gut microbiota variances reflecting the severity type 2 diabetes mellitus (T2DM). Achyranthes bidentata polysaccharide (ABP) can regulate gut microbiota. However, the hypoglycemic effect and underlying mechanism of ABP remain unclear. Herein, we characterized the structure of ABP and revealed the hypoglycemic effect of ABP in mice with T2DM. ABP repaired the intestinal barrier in T2DM mice and regulated the composition and abundance of gut microbiota, especially increasing bacteria which producing short-chain fatty acids (SCFAs), then increasing glucagon-like peptide-1 (GLP-1) level. The abundance of these bacteria was positively correlated with blood lipid and INS levels, negatively correlated with FBG levels. Colon transcriptome data and immunohistochemistry demonstrated that the alleviating T2DM effect of ABP was related to activation of the GLP-1/GLP-1 receptor (GLP-1R)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB)/INS pathway. Fecal microbiota transplantation (FMT) confirmed the transmissible efficacy of ABPs through gut microbiota. Overall, our research shows that ABP plays a hypoglycemic role by increasing gut microbiota-derived SCFAs levels, and activating the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway, emphasizing ABP as promising T2DM therapeutic candidates.

The Association of Circulating Glucagon-Like Peptide-1 with Cognitive Functions and Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro. In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro. Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD.

High temperature and humidity in the environment disrupt bile acid metabolism, the gut microbiome, and GLP-1 secretion in mice.

High temperature and humidity in the environment are known to be associated with discomfort and disease, yet the underlying mechanisms remain unclear. We observed a decrease in plasma glucagon-like peptide-1 levels in response to high-temperature and humidity conditions. Through 16S rRNA gene sequencing, alterations in the gut microbiota composition were identified following exposure to high temperature and humidity conditions. Notably, changes in the gut microbiota have been implicated in bile acid synthesis. Further analysis revealed a decrease in lithocholic acid levels in high-temperature and humidity conditions. Subsequent in vitro experiments demonstrated that lithocholic acid increases glucagon-like peptide-1 secretion in NCI-H716 cells. Proteomic analysis indicated upregulation of farnesoid X receptor expression in the ileum. In vitro experiments revealed that the combination of lithocholic acid with farnesoid X receptor inhibitors resulted in a significant increase in GLP-1 levels compared to lithocholic acid alone. In this study, we elucidate the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature and humidity condition.

Associations of adupocutokine and metaboliv hormone level in young people aged 25-44 years with type 2 diabetes mellitus and abdominal obesity

BACKGROUND: Diabetes mellitus and obesity are two closely related diseases that are a global public health problem. Obesity is characterized by an increase in the volume of adipose tissue and a change in the production and function of adipocytokines, which leads to a violation of the regulation of insulin sensitivity and glucose metabolism, contributing to the development of insulin resistance and diabetic pathology.AIM: The aim of this study was to evaluate the concentrations of individual adipocytokines and metabolic hormones in patients with DM2 and without diabetes, depending on the presence/absence of abdominal obesity (AO).MATERIALS AND METHODS: A single-center observational cross-sectional study was conducted. A population subsample of men and women aged 25–44 years was examined. Socio-demographic data were collected, anthropometric measurements were performed. The levels of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, were determined in blood serum by multiplex analysis using a set of reagents Human Metabolic Hormone V3 (USA) and Human Adipokine Panel 1 (USA) on a Luminex MAGPIX flow fluorimeter (USA). interleukin 6, insulin, leptin, monocytic chemotactic factor 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor-1 (PAI-1) and resistin.RESULTS: The study included 105 people. The main group consisted of 35 people with diabetes mellitus, 11 of them without AO and 24 with AO, the control group consisted of 70 people without diabetes mellitus (35 people with AO and 35 without AO), comparable in gender and age with the main group. In individuals with abdominal obesity, regardless of the presence of type 2 diabetes mellitus, the levels of C-peptide, GLP-1, insulin, leptin and TNF-alpha are higher than in individuals without abdominal obesity. The chance of having diabetes mellitus and AO is associated with an increase in leptin levels (OR=1.367, 95% CI: 1.050–1.779, p=0.020).CONCLUSION: The results of our study show that the indicators of the adipocytokine profile differ significantly in individuals with the presence/absence of abdominal obesity. According to our data, leptin makes the greatest contribution to the development of SD2 against the background of AO. Further research is needed to identify causal relationships and determine whether treatment that regulates adipocytokine levels can help in personalized approaches to the prevention and treatment of type 2 diabetes mellitus.

Effects ofsemaglutide-loaded lipid nanocapsules on metabolic dysfunction-associated steatotic liverdisease.

Metabolic dysfunction-associated steatotic liver disease(MASLD) is a highly prevalent chronic liver disease that can progress to end-stage conditions with life-threatening complications, but no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNC) are very versatile platforms that areeasy to produce and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being studied in clinical trials in the context of MASLD. Our nanosystem provides with increased levels of the native GLP-1 and increased plasmatic absorption of the encapsulated GLP-1 analog (semaglutide). Our goal was touse our strategy to demonstrate a better outcome and a greater impact on the metabolic syndrome associated with MASLD and on liver disease progression with our strategy compared with the oral marketed version of semaglutide, Rybelsus®. Therefore, we studied the effect of our nanocarriers on a dietary mouse model of MASLD, the Western diet model, during a daily chronic treatment of 4weeks. Overall, the results showed a positive impact of semaglutide-loaded lipid nanocapsules towards the normalization of glucose homeostasis and insulin resistance. In the liver, there were no significant changes in lipid accumulation, but an improvement in markers related to inflammation was observed. Overall, our strategy had a positive trend on the metabolic syndrome and atreducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration ofRybelsus®, as a suspension.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Ileum excision partially reverses improvement of glucose metabolism in diabetic rats after biliopancreatic diversion with duodenal switch

BackgroundBile acids can stimulate the secretion of glucagon-like peptide-1 (GLP-1) and be mostly reabsorbed in the ileum. ObjectiveWe aimed to investigate whether ileum excision could reverse the glucose improvement after biliopancreatic diversion with duodenal switch (BPD/DS). SettingPeking Union Medical College Hospital MethodsThirty diabetic rats were randomly divided into the BPD/DS group, BPD/DS plus ileectomy (BDI) group and control group. The fasting blood glucose, bile acids, and glucagon-like peptide-1 levels in plasma samples were analyzed. ResultsIn postoperative week 20, the fasting blood glucose level in the BDI group was significantly higher than that in the BPD/DS group (11.5 ± 1.4 mmol/l vs. 7.6 ± 1.0 mmol/l, P < 0.001), and the AUCOGTT value was also significantly higher than that in the BPD/DS group (2186.1 ± 237.2 mmol/l·min vs. 1551.2 ± 136.9 mmol/l·min, P < 0.001). The plasma level of bile acids in the BDI group was lower than that in the BPD/DS group (P = 0.012) and was not significantly different from that in the control group (P = 0.629). The plasma level of GLP-1 in the BDI group was lower than that in the BPD/DS group (P = 0.009) and was not significantly different from that in the control group (P = 0.530). Moreover, the intestinal TGR5 expression in the BDI group was significantly lower than that in the BPD/DS group (P < 0.001). ConclusionsThe results show that excision of the ileum can partially reverse the improvement in glucose metabolism after BPD/DS.

Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

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 100mg/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.

Acid-base properties of non-protein nitrogen affect nutrients intake, rumen fermentation and antioxidant capacity of fattening Hu sheep.

This study conducted a comparison of the effects of non-protein nitrogen with different acid-base properties on feed intake, rumen fermentation, nutrient digestion and antioxidant capacity in fattening Hu sheep. Sixteen fattening male sheep (31.43 ± 2.41 kg) with permanent rumen cannulas were randomly assigned to two dietary treatments: 1% urea and 1.78% ammonium chloride (NH4Cl, AC). A 42 days experimental period was conducted, with 14 days for adaptation and 28 days for treatment. Daily feed intake was recorded and various samples including feed, feces, rumen fluid, and blood were collected at different time points during the final week. The results indicated that the urea group had significantly higher dry matter intake, average daily gain, and gain efficiency in comparison to the AC group (p < 0.01). There was no difference in rumen pH and concentration of ammonia nitrogen between different groups (p > 0.05), but the rumen pH of urea group was higher than that of the AC group at 1 and 3 h after feeding (p < 0.05). The urea group exhibited higher concentrations of total volatile fatty acids (VFA) and individual VFAs compared to the AC group at all-time points (p < 0.01). Compared to the urea group, the intake of all nutrients decreased in the AC group (p < 0.01), but the digestibility of dry matter and organic matter increased significantly (p < 0.01), and the digestibility of CP had an increasing trend (p = 0.06) in the AC group. Additionally, the urea group had lower levels of serum glucagon-like peptide-1, peptide YY, Cl, total protein and globulin than the AC group (p < 0.05). The overall levels of HCO3-, superoxide dismutase, glutathione peroxidase, catalase, albumin/globulin, blood urea nitrogen and total cholesterol in the urea group increased significantly compared to the AC group (p < 0.05). It was concluded that adding urea to the high-concentrate diet resulted in increased rumen pH and improved rumen fermentation and growth performance in fattening sheep compared to NH4Cl addition. Furthermore, urea addition improved sheep's antioxidant capacity and maintained their acid-base balance more effectively as compared to NH4Cl.

Citrus pectin protects mice from burn injury by modulating intestinal microbiota, GLP-1 secretion and immune response

Water-soluble rhamnogalacturonan-I enriched citrus pectin (WRP) has promising effect on antimicrobial defense. We aim to determine whether the modified acidic (A) or neutral (B) WRP solutions can improve intestinal microbial dysbiosis in burn-injured mice. Male Balb/c mice were gavaged with WRPs at 80, 160, 320 mg/kg. Body weight daily for 21 days before exposed to thermal injury of 15 % total body surface area and mortality was monitored. Mice with 80 mg/kg WRPs were also subjected to fecal DNAs and T cell metabonomics analysis, intestinal and plasma glucagon-like peptide 1 (GLP-1) detection, plasma defensin, immunoglobin and intestinal barrier examinations at 1 and 3d postburn (p.b.). Burn-induced mortality was only improved by low dose WRP-A (P = 0.039). Both WRPs could prevent the dysbiosis of gut microbiota in burn injury by reducing the expansion of inflammation-promoting bacteria. Both WRPs suppressed ileum GLP-1 production at 1d p.b. (P = 0.002) and plasma GLP-1 levels at 3d p.b. (P = 0.013). Plasma GLP-1 level correlated closely with ileum GLP-1 production (P = 0.019) but negatively with microbiota diversity at 1d p.b. (P = 0.003). Intestinal T cell number was increased by both WRPs in jejunum at 3d p.b. However, the exaggerated splenic T cell metabolism in burn injury was reversed by both WRPs at 1d p.b. The burn-increased plasma defensin β1 level was only reduced by WRP-B. Similarly, the intestinal barrier permeability was only rescued by WRP-B at 1d p.b. WRP-A rather than WRP-B could reduce burn-induced mortality in mice by suppressing intestinal GLP-1 secretion, restoring gut microbiota dysbiosis and improving adaptive immune response.

Indole-3-carboxyaldehyde does not reverse the intestinal effects of fiber-free diet in mice.

Fiber-free diet impairs intestinal and colonic health in mice, in parallel with a reduction in glucagon like peptide-1 (GLP-1) levels. Endogenous GLP-1 is important for intestinal growth and maintenance of the intestinal integrity. We aimed to investigate whether fiber-free diet reduces luminal content of metabolites which, upon supplementation, could increase GLP-1 secretion and restore the adverse effects of fiber-free diet. Untargeted metabolomics (LC-MS) was performed on colonic content of mice fed a fiber-free diet, identifying a metabolite of particular interest: indole-3-carboxyaldehyde (I3A). We exposed cultured GLUTag cells to I3A, and measured cumulative GLP-1 secretion. Isolated colon perfusions were performed in male C57BL/6JRj mice and Wistar rats. I3A was administered luminally or vascularly, and GLP-1 was measured in portal vein effluent. Finally, female C57BL/6JRJ mice were fed chow or fiber-free diet, with I3A or vehicle by oral gavage. After 10 days, plasma GLP-1 (ELISA) and intestinal permeability (FITC-dextran) were measured, animals were sacrificed and organs removed for histology. Mice fed a fiber-free diet had significantly lower I3A in their colonic content compared to a control diet (7883 ± 3375 AU, p=0.04). GLP-1 secretion from GLUTag cells was unchanged after five minutes of exposure to I3A. However, GLP-1 levels increased after 120 minutes of exposure to 1 mM (60% increase, p=0.016) and 5 mM (89% increase, p=0.0025) I3A. In contrast, 48h exposure to 1 mM decreased GLP-1 secretion (51% decrease, p<0.001) and viability. In isolated perfused mouse and rat colon, I3A applied into the luminal or vascular side did not affect GLP-1 secretion. Mice fed a fiber-free diet tended to weigh less compared to chow fed mice; and the small intestine and colon were significantly smaller. No differences were seen in crypt depth, villus length, mucosal area, and intestinal permeability. Supplementing I3A did not affect body weight, morphology or plasma GLP-1 levels. Fiber-free diet lowered colonic content of I3A in mice. I3A stimulates GLP-1 secretion in vitro, but not in animal studies. Moreover, it has no evident beneficial effect on intestinal health when administered in vivo.

GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota

ObjectivesGut microbiota increases energy availability through fermentation of dietary fibers to short-chain fatty acids in conventionally raised mice. Energy deficiency in germ-free (GF) mice increases glucagon-like peptide-1 (GLP-1) levels, which slows intestinal transit. To further analyze the role of GLP-1-mediated signaling in this model of energy deficiency, we re-derived mice lacking GLP-1 receptor (GLP-1R KO) as GF. MethodsGLP-1R KO mice were rederived as GF through hysterectomy and monitored for 30 weeks. Mice were subjected to rescue experiments either through feeding an energy-rich diet or colonization with a normal cecal microbiota. Histology and intestinal function were assessed at different ages. Intestinal organoids were assessed to investigate stemness. ResultsUnexpectedly, 25% of GF GLP-1R KO mice died before 20 weeks of age, associated with enlarged ceca, increased cecal water content, increased colonic expression of apical ion transporters, reduced number of goblet cells and loss of colonic epithelial integrity. Colonocytes from GLP-1R KO mice were energy-deprived and exhibited increased ER-stress; mitochondrial fragmentation, increased oxygen levels and loss of stemness. Restoring colonic energy levels either by feeding a Western-style diet or colonization with a normal gut microbiota normalized gut phenotypes and prevented lethality. ConclusionsOur findings reveal a heretofore unrecognized role for GLP-1R signaling in the maintenance of colonic physiology and survival during energy deprivation.

Large Yellow Tea Polysaccharide Alleviates HFD-Induced Intestinal Homeostasis Dysbiosis via Modulating Gut Barrier Integrity, Immune Responses, and the Gut Microbiome.

Long-term high-fat diet (HFD) will induce dysbiosis and a disturbance of intestinal homeostasis. Large yellow tea polysaccharide (LYP) has been shown to improve obesity-associated metabolic disease via modulation of the M2 polarization. However, the contribution of LYP to intestinal barrier impairment and improvement mechanisms in obesity caused by an HFD are still not clear. In this study, we evaluated the impacts of LYP on the mucosal barrier function and microbiota composition in HFD-feeding mice. Results exhibited that dietary LYP supplement could ameliorate the physical barrier function via maintaining intestinal mucosal integrity and elevating tight-junction protein production, strengthen the chemical barrier function via up-regulating the levels of glucagon-like peptide-1 and increasing mucin-producing goblet cell numbers, and enhance the intestinal immune barrier function though suppressing immune cell subsets and cytokines toward pro-inflammatory phenotypes. Moreover, LYP reshaped the constitution and metabolism of intestinal flora by enriching probiotics that produce short-chain fatty acids. Overall, LYP might be used as a critical regulator of intestinal homeostasis to improve host health by promoting gut barrier integrity, modulating intestinal immune response, and inhibiting bowel inflammation.

Effect of Single Oral Coingestion of GABA and Malic Acid on Postprandial GLP-1, Glucose, and Insulin Responses in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

This study examines whether coingestion of γ-aminobutyric acid (GABA) and malic acid (MA) before meals enhances glucagon-like peptide-1 (GLP-1) secretion, and which affects subsequent insulin and glycemic responses in humans. Initially, a murine enteroendocrine STC-1 cell line is used to verify coadministration of GABA and MA synergistically induces GLP-1 secretion. Next, 22 healthy adults are given water (50mL) containing 400mg GABA and 400mg MA (Test), or only 400mg citric acid (CA) (Placebo) 20min before meal tolerance test (MTT). Interval blood samples are taken postprandially over 180min to determine GLP-1, insulin, and glucose responses. By comparison to preload of Placebo, preload of Test significantly increases plasma GLP-1 (total/active) levels (incremental area under the curve by 1.2- and 1.6-fold), respectively. However, there are no significant differences in postprandial blood glucose and insulin. Coingestion of GABA and MA before meals enhances postprandial GLP-1 secretion. Future studies should explore optimal dosage regimens to find the efficacy of the mixture on insulin and glycemic response.

Acute and Chronic Exposure to Linagliptin, a Selective Inhibitor of Dipeptidyl Peptidase-4 (DPP-4), Has an Effect on Dopamine, Serotonin and Noradrenaline Level in the Striatum and Hippocampus of Rats.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

Fasting GLP-1 Levels and Albuminuria Are Negatively Associated in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16-10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17-1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria.

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 29.9kg/m² and 62 individuals with obesity with BMI ≥30kg/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.

Effects of dipeptidyl peptidase-4 inhibition in vivo: Dipeptidyl peptidase-4 inhibitor/gut microbiome crosstalk suggests novel therapeutic options for diabetes management.

Wang etal. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroidesgenus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance.