GLP-1 Concentrations Research Articles

Study of the influence of GLP-1 receptor agonists on the metabolic activity of the intestinal microbiota in patients with type 2 DM

The aim: to investigate the peculiarities of the metabolic activity of the intestinal microbiota in patients with type 2 diabetes under the influence of glucagon-like peptide-1 receptor agonist therapy. Materials and methods: 21 patients with type 2 diabetes mellitus were included in the study, the average age was 57.2±8.53 years (M±SD), the HbA1c level was 8.29±0.88 % (M±SD). Patients were prescribed raGLP-1 at the maximum tolerated dose for 6 months. Before and after the course of treatment, indicators of body composition were determined by the bioelectrical impedance method (TANITA BC-545N analyzer, Japan), characteristics of carbohydrate metabolism and the lipid spectrum of blood serum, as well as the concentration of GLP-1, trimethylamine-N-oxide (TMAO) by the immunoenzymatic method, of short-chain fatty acids (SCFA) by the method of chromatographic research. Results. After 6 months of therapy with liraglutide against the background of a statistically significant decrease in fasting blood glucose and HbA1c levels (p<0.05), a decrease in body mass index and waist circumference (p<0.05), a decrease in the content of visceral (p<0.05 ) and total fat (p<0.05) in patients with type 2 diabetes, there was a decrease in the concentration of TMAO in blood serum (p<0.05) and an increase in the concentration of SCFA: acetic, propionic (p<0.05) in the coprofiltrate and a tendency to increase in the level of butyric acids. Data analysis also established an increase in the concentration of endogenous GLP-1 in the blood (p<0.05). Conclusions. The detected changes in microbial metabolites may indicate a positive effect of raGLP-1 on the composition of the intestinal microbiota and its metabolic activity in patients with T2DM, which in turn contributes to the improvement of endogenous secretion of incretins

Activation of GPBAR1 attenuates vascular inflammation and atherosclerosis in a mouse model of NAFLD-related cardiovascular disease

While patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk to develop clinically meaningful cardiovascular diseases (CVD), there are no approved drug designed to target the liver and CVD component of NAFLD. GPBAR1, also known as TGR5, is a G protein coupled receptor for secondary bile acids. In this study we have investigated the effect of GPBAR1 activation by BAR501, a selective GPBAR1 agonist, in Apolipoprotein E deficient (ApoE−/−) mice fed a high fat diet and fructose (Western diet), a validated model of NAFLD-associated atherosclerosis. Using aortic samples from patients who underwent surgery for abdominal aneurism, and ex vivo experiments with endothelial cells and human macrophages, we were able to co-localize the expression of GPBAR1 in CD14+ and PECAM1+ cells. Similar findings were observed in the aortic plaques from ApoE-/- mice. Treating ApoE-/- mice with BAR501, 30 mg/kg for 14 weeks, attenuated the body weight gain while ameliorated the insulin sensitivity by increasing the plasma concentrations of GLP-1 and FGF15. Activation of GPBAR1 reduced the aorta thickness and severity of atherosclerotic lesions and decreased the amount of plaques macrophages. Treating ApoE-/- mice reshaped the aortic transcriptome promoting the expression of anti-inflammatory genes, including IL-10, as also confirmed by tSNE analysis of spleen-derived macrophages. Feeding ApoE-/- mice with BAR501 redirected the bile acid synthesis and the composition of the intestinal microbiota. In conclusion, GPBAR1 agonism attenuates systemic inflammation and improve metabolic profile in a genetic/dietetic model of atherosclerosis. BAR501 might be of utility in the treatment for NAFLD-related CVD.

Evaluating the In Situ Insulinotropic Effects of Pea Protein Hydrolysates Mediated by Active GLP-1 via a 2D and Dual-Layered Coculture Cell Model.

The aim of this study was to evaluate the in situ insulinotropic effects of pea protein hydrolysates (PPHs) mediated by active glucagon-like peptide-17-36 (active GLP-1) using a 2D and dual-layered coculture cell model. Following this model, a mixed Caco-2 and NCI-H716 cell monolayer was differentiated on the apical side to study the effects of PPHs on active GLP-1 levels; meanwhile, the beta-TC-6 cells were seeded on the basolateral side to investigate the insulin responses induced by active GLP-1. The in situ DPP-4 half-maximal inhibitory concentration (IC50) of PPHs, PPHs-120G, and PPHs-120I was 2.94, 3.43, and 2.26 mg/mL, respectively. They directly stimulated active GLP-1 secretion in NCI-H716 cells by 3.03 ± 0.21, 1.99 ± 0.03, and 2.24 ± 0.02 times, respectively. Insulin release in beta-TC-6 cells was directly stimulated by PPHs but not by PPHs-120G and PPHs-120I. Interestingly, PPHs-120G and PPHs-120I indirectly stimulated insulin release in this coculture cell model by enhancing active GLP-1 concentrations. More importantly, PPHs, PPHs-120G, and PPHs-120I increase active GLP-1 levels by their dual function of stimulating active GLP-1 secretion and DPP-4 inhibition. This study suggests that the 2D and dual-layered coculture cell model supports a more comprehensive assessment of in situ insulinotropic effects of protein hydrolysates mediated by active GLP-1.

Obesity in dogs: dimension of the problem and effects of feed

Obesity in dogs is a growing problem which affects between 30 – 60 % of the pet population world-wide. It is mainly caused by an energy consumption greater than the animal’s requirement; and needs to be detected and faced accordingly because it negatively affects their well-being and longevity. Some important observations are; although it has been reported that depends on the composition of the diet, that dogs fed 2 times a day have lower blood glucose levels, as well as insulin levels showing the same tendency as glucose. Ghrelin and GLP1 concentrations are no different feeding 1 or 2 times a day. Energy expenditure through physical activity is important as it increases the rate of energy utilization and helps to raise the metabolic rate, which contributes to a comprehensive weight reduction program. Metabolic Energy Rate (MER) in sterilized dogs is lower than for intact animals; therefore, sterilization of pets increases the risk of obesity. The level of protein in the diet is important for promoting body protein synthesis and tissue repair. High protein diets work best when feed is offered ad libitum. Omega fatty acids reduce plasma concentrations of C-reactive protein and insulin. Dietary fiber helps to significantly reduce blood cholesterol and triglycerides.

882-P: Effects of YG1699 and Sotagliflozin on Intestinal Glucose Absorption and GLP-1 in Mice

Background and Aims: YG1699, a dual inhibitor of SGLT1 and SGLT2, recently showed greater glucose reduction than dapagliflozin in patients with type 1 diabetes. This study examined whether YG1699 provides gastrointestinal SGLT1 inhibition. Materials and Methods: Male BALB/c mice (n=105) were randomly divided into five groups: vehicle, YG1699 at low (1mg/kg), medium (3mg/kg), and high doses (10mg/kg), and LX4211 (sotagliflozin) 10mg/kg by oral gavage. Animals received a 5g/kg glucose challenge 15 minutes after study drug. Animals were euthanized at various times to examine intestinal plasma GLP-1 and glucose content in small intestine, cecum, and colon. Differences between groups were evaluated by ANOVA. Results (See Table 1): Small intestinal glucose content 1 hour after glucose challenge increased in a dose-related fashion with YG1699 compared to vehicle (p<0.001 for each YG1699 group vs. vehicle). Similar results were found in cecum (p<0.05 for each YG1699 group vs. vehicle). Plasma GLP-1 and PYY concentrations at 1 hour were higher on YG1699 vs. vehicle. Intestinal glucose content in the sotagliflozin group was similar to vehicle and the plasma GLP-1 were only numerically increased in this group. Conclusion: YG1699 delays intestinal glucose absorption and induces an incretin response in BALB/c mice, indicating significant gastrointestinal SGLT1 inhibition. Disclosure J.Li: None. R.W.Xu: Consultant; Youngene Therapeutics. J.He: None. P.Lapuerta: Board Member; 4M Therapeutics, Consultant; Youngene Therapeutics, ViaCyte, Inc., Encuragen, Capsida, Provention Bio, Inc., Decibel Therapeutics, Crinetics, Next Phase Therapeutics.

Structural changes of thermally treated starch during digestion and the impact on postprandial glucose homeostasis

Intake of foods upon thermal treatment is typically associated with an elevated postprandial glycemic response, which is one of the risk factors for type 2 diabetes development and progression. In this study, rice starch was thermally treated using aqueous phase (boil), air phase (bake), and lipid phase (fry). Peak blood glucose levels in C57 mice increased by 16.94 %, 12.60 %, and 8.1 % after ingestion of thermally treated starch (20.23, 19.48, and 18.70 mmol/L), compared with raw starch (17.30 mmol/L). The insulin response to the intake of thermally treated starch increased (4.73 %–6.83 % higher than the control), whereas the concentration of GLP-1, a hormone used to promote insulin secretion, decreased (1.54 %–8.56 % lower than the control). Furthermore, thermally treated starch accelerated food absorption by enhancing gastrointestinal digestion, exacerbating postprandial glucose fluctuation at the next meal. Structural characterization showed thermal treatment reduced starch branching density and degree of structure order, which were not conducive to preventing the attack of enzymes. During digestion, they were highly hydrolyzed into low-molecular-weight fragments, and the proportion of ultrashort chains substantially increased. These findings provide a better understanding of the fine structure of starch that promotes hypoglycemia and initially explain how diets high in thermally treated starch impair glucose balance.

Long-term treatment with teduglutide: a 48-week open-label single-center clinical trial in children with short bowel syndrome

BackgroundShort bowel syndrome (SBS) is the main cause of intestinal failure in children. ObjectivesThis single-center study evaluated the safety and efficacy of teduglutide in pediatric patients with SBS–associated intestinal failure (SBS-IF). MethodsChildren with SBS followed at our center with ≥2 y on parenteral nutrition (PN) and with small bowel length <80 cm who had reached a plateau were consecutively included in the study. At baseline, participants underwent a clinical assessment including a 3-d stool balance analysis, which was repeated at the end of the study. Teduglutide was administered subcutaneously 0.05 mg/kg/d for 48 wk. PN dependence was expressed as the PN dependency index (PNDI), which is the ratio PN non-protein energy intake/REE. Safety endpoints included treatment-emergent adverse events and growth parameters. ResultsMedian age at inclusion was 9.4 y (range: 5–16). The median residual SB length was 26 cm (IQR: 12–40). At baseline, the median PNDI was 94% (IQR: 74–119), (median PN intake: 38.9 calories/kg/d, IQR: 26.1–48.6). At week 24, 24 (96%) children experienced a reduction of >20% of PN requirements with a median PNDI = 50% (IQR: 38–81), (PN intake: 23.5 calories/kg/d IQR: 14.6–26.2), P < 0.01. At week 48, 8 children (32%) were weaned completely off PN. Plasma citrulline increased from 14 μmol/L (IQR: 8–21) at baseline to 29 μmol/L (IQR: 17–54) at week 48 (P < 0.001). Weight, height, and BMI z-scores remained stable. The median total energy absorption rate increased from 59% (IQR: 46–76) at baseline to 73% (IQR: 58–81) at week 48 (P = 0.0222). Fasting and postprandial endogenous GLP-2 concentrations increased at weeks 24 and 48 compared with baseline. Mild abdominal pain at the early phase of treatment, stoma changes, and redness at the injection site were commonly reported. ConclusionsIncreased intestinal absorption and PN dependency reduction were observed with teduglutide treatment in children with SBS-IF. Trial registrationClinicalTrials.gov NCT03562130. https://clinicaltrials.gov/ct2/show/NCT03562130?term=NCT03562130&draw=2&rank=1

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

BackgroundProlonged high fat feeding negatively impacts pancreatic and intestinal morphology. In this regard, direct effects of PYY(3–36) on intestinal cell and pancreatic islet morphometry are yet to be fully explored in the setting of obesity. MethodsWe examined the influence of 21-days twice daily treatment with PYY(3–36) on these parameters in mice fed a high fat diet (HFD). ResultsPYY(3–36) treatment decreased food intake, body weight and circulating glucose in HFD mice. In terms of intestinal morphology, crypt depth was restored to control levels by PYY(3–36), with an additional enlargement of villi length. PYY(3–36) also reversed HFD-induced decreases of ileal PYY, and especially GLP-1, content. HFD increased numbers of PYY and GIP positive ileal cells, with PYY(3–36) fully reversing the effect on PYY cell detection. There were no obvious differences in the overall number of GLP-1 positive ileal cells in all mice, barring PYY(3–36) marginally decreasing GLP-1 villi cell immunoreactivity. Within pancreatic islets, PYY(3–36) significantly decreased alpha-cell area, whilst islet, beta-, PYY- and delta-cell areas remained unchanged. However, PYY(3–36) increased the percentage of beta-cells while also reducing percentage alpha-cell area. This was related to PYY(3-36)-induced reductions of beta-cell proliferation and apoptosis frequencies. Co-localisation of islet PYY with glucagon or somatostatin was elevated by PYY(3–36), with GLP-1/glucagon co-visualisation increased when compared to lean controls. ConclusionPYY(3–36) exerts protective effects on pancreatic and intestinal morphology in HFD mice linked to elevated ileal GLP-1 content. General significanceThese observations highlight mechanisms linked to the metabolic and weight reducing benefits of PYY(3–36).

Circulating levels of gastrointestinal hormones in prediabetes reversing to normoglycemia or progressing to diabetes in a year–A cross-sectional and prospective analysis

AimsWe aimed to compare the concentrations of GLP-1, glucagon and GIP (established regulators of glucose homeostasis) and glicentin (emerging new metabolic marker)during an OGTT in patients with normal glucose tolerance (NGT), prediabetes and diabetes at onset, and one-year before, when all had prediabetes. MethodsGLP-1, glucagon, GIP and glicentin concentrations were measured and compared with markers of body composition, insulin sensitivity and β-cell function at a 5-timepoint OGTT in 125 subjects (30 diabetes, 65 prediabetes, 30 NGT) and in 106 of them one-year before, when all had prediabetes. ResultsAt baseline, when all subjects were in prediabetic state, hormonal levels did not differ between groups. One year later, patients progressing to diabetes had lower postprandial increases of glicentin and GLP-1, lower postprandial decrease of glucagon, and higher levels of fasting GIP compared to patients regressing to NGT. Changes in glicentin and GLP-1 AUC within this year correlated negatively with changes in Glucose AUC of OGTT and with changes in markers of beta cell function. ConclusionIncretins, glucagon and glicentin profiles in prediabetic state cannot predict future glycemic traits, but prediabetes progressing to diabetes is accompanied by deterioration of postprandial increases of GLP-1 and glicentin.

Wei-Tong-Xin exerts anti-inflammatory effects through TLR4-mediated macrophages M1/M2 polarization and affects GLP-1 secretion.

The present study was undertaken to explore the effects and mechanisms of Wei-Tong-Xin (WTX) in inhibiting lipopolysaccharide (LPS)-induced inflammatory response of macrophages, in turn, to study the influences on GLP-1 secretion of GLUTag cells. We first evaluated the activation of Raw 264.7 cells and measured the intracellular ROS, CD86 and CD206 levels by flow cytometry. The expressions of proteins were detected by western blot and immunofluorescence. GLP-1 levels were detected by ELISA kits. TLR4 siRNA was used to investigate the role of TLR4 in the regulation of macrophage polarization by WTX. The results showed that WTX inhibited LPS-induced polarization of macrophages toward the M1 phenotype, but promoted the M2 phenotype. Meanwhile, WTX inhibited the TLR4/MyD88 pathway. The polarization of M1 phenotype promoted GLP-1 secretion by GLUTag cells, which was inhibited by WTX. The results of siRNA showed that WTX exhibited anti-inflammatory effects through targeting TLR4. Overall, WTX inhibited polarization of macrophages towards M1 phenotype but promoted the amounts of M2 phenotype, further the macrophages regulated by WTX alleviated GLP-1 content secreted by GLUTag cells. The aforementioned results were produced by WTX-mediated TLR4.

Non-altered incretin secretion in women with impaired fasting plasma glucose in the early stage of pregnancy: a case control study

BackgroundsGlucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) may be involved in pathogenesis of gestational diabetes mellitus (GDM). The aim was to compare GLP-1 and GIP production in fasting state and during 3 h mixed meal tolerance test (MMTT) measured by mean area under the curve (AUC) between pregnant women with normal and impaired fasting glucose in an early phase of pregnancy, and healthy non-pregnant controls.MethodsThis study was undertaken as a case–control study. Repeated measurement of fasting plasma glucose ≥ 5.1 mmol/L and < 7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes according to IADSPG criteria was used to find women with impaired fasting glucose (n = 22). Age-matched controls consisted of healthy pregnant (n = 25) and non-pregnant (n = 24) women. In addition to incretins, anthropometric parameters and markers of insulin resistance and beta-cell function were assessed. Variables were summarized as median (interquartile range).ResultsFasting GLP-1 and GIP concentration or their AUC during MMTT did not significantly differ between pregnant women with impaired fasting plasma glucose [GLP-1AUC 19.0 (53.1) and GIPAUC 302 (100) pg/mL/min] and healthy pregnant women [GLP-1AUC 16.7 (22.3) and GIPAUC 297 (142) pg/mL/min] or non-pregnant controls [GLP-1AUC 16.8 (9.8) and for GIPAUC 313 (98) pg/mL/min]. Although women with impaired fasting glucose were more obese and showed decreased beta-cell function, there were not significant correlations between incretin production and parameters of insulin secretion, insulin resistance, or obesity.ConclusionsWomen with impaired fasting plasma glucose did not show altered incretin production in the first trimester of pregnancy. In contrast to type 2 diabetes, impaired incretin secretion does not seem to play a major role in the early development of GDM.

Mumefural prevents insulin resistance and amyloid-beta accumulation in the brain by improving lowered interstitial fluid pH in type 2 diabetes mellitus.

The present study tried to clarify if mumefural would prevent hyperglycemia, one of the typical symptoms of type 2 diabetes mellitus (T2DM), since mumefural is an extract from Japanese apricots preventing hyperglycemia. To clarify if mumefural would prevent T2DM pathogenesis, we used Otsuka Long-Evans Tokushima fatty (OLETF) rats, T2DM model. Mumefural diminished hyperglycemia, HOMA-IR and plasma triglyceride concentration in OLETF rats under fasting conditions. In addition, mumefural elevated protein expression of sodium-coupled monocarboxylate transporter 1 (SMCT1) in the distal colon participating in absorption of weak organic acids, which behave as bases but not acids after absorption into the body. Mumefural also increased the interstitial fluid pH around the brain hippocampus lowered in OLETF rats compared with non-T2DM LETO rats used as control for OLETF rats. Amyloid-beta accumulation in the brain decreased in accordance with the pH elevation. On the one hand, mumefural didn't affect plasma concentrations of glucagon, GLP-1, GIP or PYY under fasting conditions. Taken together, these observations indicate that: 1) mumefural would be a useful functional food improving hyperglycemia, insulin resistance and the lowered interstitial fluid pH in T2DM; 2) the interstitial fluid pH would be one of key factors influencing the accumulation of amyloid-beta.

Enteroendocrine peptides, growth, and the microbiome during the porcine weaning transition

BackgroundGrowth rate in pigs can be affected by numerous factors that also affect feeding behavior and the microbiome. Recent studies report some communication between the microbiome and the enteroendocrine system. The present study examined if changes in the piglet microbiome between birth and during the weaning transition can be correlated either positively or negatively with growth rate and plasma concentrations of enteroendocrine peptides.ResultsDuring the post-weaning transition, a 49% reduction in average daily gain was observed at day 24 (P < 0.05) relative to day 21. Pigs recovered by day 28 with body weight and average daily gain increases of 17% and 175%, respectively relative to day 24 and the highest rate of gain was measured at day 35 (462 g/day). The time interval between day 21–24 had the highest number of correlations (n = 25) between the relative abundance differences in taxa over time and corresponding percent weight gain. Amplicon sequence variants with the greatest correlation with percent weight gain between day 21–24 belonged to families Prevotellaceae NK3B31 (ρ = 0.65, P < 0.001), Veillonellaceae (ρ = 0.63, P < 0.001) and Rikenellaceae RC9 (ρ = 0.62, P < 0.001). Seven taxa were positively correlated with percent weight gain between day 24–28. Eight taxa were positively correlated with percent weight gain between day 28–35, of which four were Clostridia. Only Lactobacillus reuteri was positively correlated across both day 24–28 and day 28–35 analyses. Insulin-like growth factor 1 (IGF-1; R2 = 0.61, P < 0.001), glucose-dependent insulinotropic polypeptide (GIP; R2 = 0.20, P < 0.001), glucagon-like peptide 1 (GLP-1; R2 = 0.51, P < 0.001), and glucagon-like peptide 2 (GLP-2; R2 = 0.21, P < 0.001) were significantly associated with the piglet fecal community NMDS, while serotonin showed no significant association (R2 = 0.03, P = 0.15). Higher concentrations of GLP-1 and GLP-2 characterized day 1 fecal communities, while GIP levels had the strongest relationship primarily with samples ordinated with the day 21 cluster.ConclusionsDemonstration of an association of certain taxa with individual gut peptides at specific ages suggests the potential for the microbiome to elicit changes in the gut enteroendocrine system during early postnatal development in the pig.

Arabinoxylan as well as β-glucan in barley promotes GLP-1 secretion by increasing short-chain fatty acids production

Barley is rich in soluble dietary fiber including β-glucan and arabinoxylan. Barley β-glucan is fermented by gut bacteria and, thereby contributes to an effect on intestinal bacterial composition and short-chain fatty acids (SCFAs). It also increases GLP-1 secretion via SCFAs receptor. However, few studies have focused on barley arabinoxylan. Therefore, we have investigated the effects of arabinoxylan from barley on intestinal fermentability and GLP-1 secretion. C57BL/6J mice were fed a high-fat diet containing arabinoxylan-dominant barley flour without β-glucan (bgl) and high β-glucan-containing barley flour (BF) for 12 weeks. We conducted oral glucose tolerance test (OGTT) to measure insulin and GLP-1 concentrations. The concentration of SCFAs in the cecum contents was also determined. Furthermore, we measured mRNA expression assay GLP-1 secretion using real-time PCR. The OGTT result showed that GLP-1 concentrations at 60 min were increased in mice fed bgl and BF. Acetic acid and total SCFAs concentrations in the cecum contents were increased in both the barley groups, and butyric acid was increased in the bgl group. Furthermore, the bgl and BF groups had increased Gpr43, a receptor for SCFAs, and NeuroD which is involved in L cell differentiation. These results show arabinoxylan as well as β-glucan is involved in the SCFAs-mediated increase in GLP-1 secretion upon barley consumption.

The Levels of Ghrelin, Glucagon, Visfatin and Glp-1 Are Decreased in the Peritoneal Fluid of Women with Endometriosis along with the Increased Expression of the CD10 Protease by the Macrophages.

The aim of this study was to evaluate the levels of ten energy metabolism factors: C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1 (total), resistin, and visfatin, and to determine the expression of GLP1R receptors, CD10, CD26 proteases, and pro-inflammatory marker CD86 by macrophages in the peritoneal fluid (PF) in patients with endometriosis. The study included 54 women with endometriosis and a control group of 30 women with uterine myoma without signs of endometriosis. The levels of factors in PF were assessed by a multiplex method. Expression of GLP1R receptors, CD10, CD26 proteases, and CD86 by macrophages was evaluated using flow cytometry. It was found that in women with endometriosis, the concentrations of ghrelin, GLP-1, glucagon, and visfatin in PF were reduced (p = 0.007, p = 0.009, p = 0.002, p = 0.008, respectively). At the same time, there was a noted increase in the CD10 protease expression by peritoneal macrophages (p = 0.044). Correlation analysis showed a positive correlation of ghrelin and GLP-1 levels with CD86 macrophage expression (p = 0.044, p = 0.022, respectively) in the study group; a positive correlation was also found between the levels of GLP-1, glucagon, and visfatin with CD26 macrophage expression (p = 0.041, p = 0.048, p = 0.015, respectively) in PF. No correlations were found in the control group. These results indicate that a decrease in the levels of ghrelin, GLP-1, glucagon, and visfatin in PF may contribute to endometriosis development through their impact on the expression of pro-inflammatory markers of PF macrophages.

The Predictive Value of Glucagon-Like Peptide 1 Plasma Levels on Acute Heart Failure

Acute Heart Failure (AHF) is one of the mechanical complications of Acute Myocardial Infarct (AMI). The diagnostic approach of AHF caused by AMI is based on clinical score, imaging, use of invasive instruments, and laboratory parameters. Glucagon-Like Peptide-I (GLP-1) is an incretin hormone derivate of proglucagon gene transcription, secreted by the L cells from the mucosa of the ileum, colon, and rectum. The cardioprotective effect of GLP-1 through the dependent and independent pathway produces a direct and indirect cardiovascular effect that increases the functional capacity in AHF patients. This study aims to find the predictive value of plasma GLP-1 towards the incidence of AHF in patients with AMI. This study was conducted on 35 patients diagnosed with AMI at Dr. Moewardi General Hospital Surakarta, in October-December 2020. Glucagon-like peptide-I was measured using the ELISA sandwich. The cut-off of plasma GLP-1 was determined using the Receiver Operating Characteristic (ROC) curve. Statistical analysis showed an RR (95% CI) of 2.292 (0.587–8.943) with a p=0.229 for age, 1,143 (0.299–4.367) with a p – 0.127 for a history of type 2 diabetes (T2DM) and plasma GLP-1 concentrations below Cut-Off Value (COV), which was 2.881 (0.729–11.381) with p=0.127. Age, a history of T2DM, and plasma GLP-1 below COV did not significantly affect AHF complications in patients with AMI.

Impact of Vagotomy on Postoperative Weight Loss, Alimentary Intake, and Enterohormone Secretion After Bariatric Surgery in Experimental Translational Models.

Obesity may be treated by bariatric procedures and is related to enterohormone release modulation. Nevertheless, a majority of commonly used surgical procedures have a significant impact on vagus nerve function by breaking the connections with its gastric branches. In the case of an intragastric balloon (BAL), this interaction is unclear. However, BAL-induced weight reduction is not long-lasting. Interestingly, this method has not been used in combination with vagotomy (VAG). Thus, we evaluated, for the first time, the short- and long-term effects of combined BAL and VAG using the animal-based translational model and compared these effects with sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Wistar rats were fed a high-calorie diet for 8weeks to induce obesity before SG, RYGB, BAL + / - VAG. Animals' weight and eating behaviors were monitored weekly. After 90days, serum samples were collected to evaluate postprandial and fasting GLP-1, GIP, PYY, ghrelin, glucagon, insulin, leptin, and pancreatic polypeptide concentrations by fluorescent assay. VAG, SG, RYGB, and BAL + VAG significantly reduced body weight 30 and 90days after surgery. BAL alone induced temporal weight reduction observed after 30days, reversed after 90days. Calories intake was reduced at the first half of the observation period in all groups. Fluid intake was reduced in all groups except SG and BAL. Enterohormone profile for BAL + VAG was comparable to SG and RYGB but not BAL. VAG and BAL + VAG but not BAL alone maintain weight reduction, alimentary intake changes, and enterohormone release after long-term observation. VAG may improve the effectiveness of bariatric procedures for obesity treatment in clinical practice.

Association between 1,5-anhydro-D-sorbitol, Insulin, and Incretins in Patients with Pre-diabetes and ST-elevation Myocardial Infarction

BACKGROUND: Prediabetes itself could be an independent predictor of such adverse cardiovascular events as myocardial infarction and ischemic stroke. Since prediabetes is linked with hyperinsulinism it could also cause fluctuations of incretins concentration. Another significant fact related to prediabetes is glycemic variability. The impact of these factors on prediabetes and acute myocardial infarction is a promising phenomenon to study.&#x0D; AIM: The study aims to estimate insulin, incretins, and glycemic variability in patients with impaired carbohydrate metabolism and acute myocardial infarction&#x0D; METHODS: The 255 prediabetes patients participated in the observational case-control study. The first group included 85 patients hospitalized for STEMI. The second group included 170 patients without STEMI. Insulin and incretins were measured using a multiplex immunological assay with XMap technology on Bioplex 3D. The high-performance liquid chromatography with mass spectrometry was used to evaluate 1,5-AG concentration. The binary logistic regression was performed to evaluate the association between studying parameters and STEMI. &#x0D; RESULTS: The insulin secretion parameters showed higher insulin and C-peptide level in patients with STEMI. A similar trend was noted for the HOMA-IR index. Among incretin, we revealed a higher level of glucagon and reduced GLP-1 in patients with STEMI. The of 1,5-AG in STEMI patients was significantly lower than in non-STEMI patients. The logistic regression model shows that a lower plasma concentration of 1,5-AG increases the odds of STEMI in patients with prediabetes [OR 2.304 (95% CI 1.980–2.973), p = 0.018]. Reduced GLP-1 concentration also increased the odds of STEMI [OR 1.775 (95% CI 1.460-1.990), p = 0.001].&#x0D; CONCLUSION: We discovered the association between 1,5-AG, GLP-1, and STEMI in patients with prediabetes. It is designating their potential role as cardiovascular risk markers in non-diabetic patients with impaired glucose metabolism.

The Essential Role of Pancreatic α-Cells in Maternal Metabolic Adaptation to Pregnancy.

Pancreatic α-cells are important in maintaining metabolic homeostasis, but their role in regulating maternal metabolic adaptations to pregnancy has not been studied. The objective of this study was to determine whether pancreatic α-cells respond to pregnancy and their contribution to maternal metabolic adaptation. With use of C57BL/6 mice, the findings of our study showed that pregnancy induced a significant increase of α-cell mass by promoting α-cell proliferation that was associated with a transitory increase of maternal serum glucagon concentration in early pregnancy. Maternal pancreatic GLP-1 content also was significantly increased during pregnancy. Using the inducible Cre/loxp technique, we ablated the α-cells (α-null) before and during pregnancy while maintaining enteroendocrine L-cells and serum GLP-1 in the normal range. In contrast to an improved glucose tolerance test (GTT) before pregnancy, significantly impaired GTT and remarkably higher serum glucose concentrations in the fed state were observed in α-null dams. Glucagon receptor antagonism treatment, however, did not affect measures of maternal glucose metabolism, indicating a dispensable role of glucagon receptor signaling in maternal glucose homeostasis. However, the GLP-1 receptor agonist improved insulin production and glucose metabolism of α-null dams. Furthermore, GLP-1 receptor antagonist Exendin (9-39) attenuated pregnancy-enhanced insulin secretion and GLP-1 restored glucose-induced insulin secretion of cultured islets from α-null dams. Together, these results demonstrate that α-cells play an essential role in controlling maternal metabolic adaptation to pregnancy by enhancing insulin secretion.

A double-blind, randomized, placebo and positive-controlled study in healthy volunteers to evaluate pharmacokinetic and pharmacodynamic properties of multiple oral doses of cetagliptin.

This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin. Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study. Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied. Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.