Plasma GLP-1 Research Articles

Investigation of fructose consumption on hippocampal insulin and glucagon-like peptide-1 receptors, and metabolic effects in rats.

The detrimental effects of high fructose consumption on metabolic health have been extensively studied. However, limited research has focused on the impact of fructose intake on neuroprotective mechanisms, specifically the expression of insulin receptor (INSR) and glucagon-like peptide-1 receptor (GLP-1R) in the hippocampus. Understanding the effects of fructose on these neuroprotective molecules can provide valuable insights into the potential role of fructose in hippocampal dysfunction. The goal of this study is to aim at the basal plasma levels of lipid profile, insulin, GLP-1, and HOMA-IR, as well as the mRNA and protein expression of neuroprotective molecules such as INSR and GLP-1R in Wistar rats fed a high fructose diet. Rats were separated into control (C) and high fructose (HF) groups. The HF group was given 20% fructose water to drink for 16 weeks. Fructose ingestion significantly increased abdominal fat (C=1.24±0.08 g, HF=1.79±0.19 g, P<0.05) and plasma triglyceride levels (C=179.22±22.85 µg/ml, HF=242.45±14.45 µg/ml, P<0.05), but had no statistically significant effect on body weight and plasma HDL, LDL, total cholesterol, insulin, and GLP-1 levels (P>0.05). Although INSR mRNA expression in the hippocampus was significantly lower in the HF group compared to the control group (P<0.05), GLP-1R mRNA expression did not differ significantly across the groups (P>0.05). Furthermore, whereas INSR and GLP-1R protein levels in the experimental group were on a declining trend, this trend was not substantially different (P>0.05). These data suggest that fructose consumption may be harmful to the hippocampus by lowering the expression of INSR.

Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass

Purpose Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB.MethodWe used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery.ResultsRYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls.ConclusionThe postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery.Graphical abstract

Mangrove fruit (Bruguiera gymnorhiza) increases circulating GLP-1 and PYY, modulates lipid profiles, and reduces systemic inflammation by improving SCFA levels in obese wistar rats

Bruguiera gymnorhiza (BG) has potential as a functional food because of its dietary fibre content and bioactive components such as flavonoids and phenolic compounds. However, it is not studied in the context of diet-related disease prevention. In the present study, we aimed to investigate the effects of Bruguiera gymnorhiza fruit flour (BGF) on satiety hormone, lipid profile, systemic inflammation, body weight, and caecum SCFA levels in diet-induced obese rats. A total of 28 obese male Wistar rats were divided into four groups. Group 1 (K1) was given a standard chow, group 2 (K2) standard chow + orlistat, group 3 (P1) standard chow + BGF 2 g/200 g BW/day, and group 4 (P2) standard chow + BGF 4 g/200 g BW/day for 28 days. The levels of GLP-1, PYY, total cholesterol (TC), triglyceride (TG), HDL, IL-6, TNF-α, and body weight were measured before and after the intervention; meanwhile, the caecum SCFA levels were assessed only after the intervention. In this study, BGF intervention increased the dose-dependent plasma GLP-1 and PYY levels (P < 0.000). In addition, BGF intervention also decreased lipid profiles (TC & TG) (P < 0.000, respectively) and systemic inflammation in a dose-dependent manner. Finally, acetate, propionate, and total SCFA concentrations were higher in the BGF intervention group (P2) compared to the other groups (p < 0.05). The SCFA levels were associated with satiety hormones, lipids, and systemic inflammation (P < 0.05). The BGF intervention improved satiety hormone, lipid profile, systemic inflammation, and SCFA levels.

Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice

Abstract Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3.

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.

Emetic Response to T-2 Toxin Correspond to Secretion of Glucagon-like Peptide-17-36 Amide and Glucose-Dependent Insulinotropic Polypeptide.

The T-2 toxin, a major secondary metabolite of Fusarium Gramineae, is considered a great risk to humans and animals due to its toxicity, such as inducing emesis. The mechanism of emesis is a complex signal involving an imbalance of hormones and neurotransmitters, as well as activity of visceral afferent neurons. The T-2 toxin has been proven to induce emesis and possess the capacity to elevate expressions of intestinal hormones glucagon-like peptide-17–36 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are important emetic factors. In addition, the activation of calcium-sensitive receptor (CaSR) and transient receptor potential (TRP) channels are engaged in intestinal hormone release. However, it is unknown whether hormones GLP-1 and GIP mediate T-2 toxin-induced emetic response through activating CaSR and TRP channels. To further assess the mechanism of T-2 toxin-induced emesis, we studied the hypothesis that T-2 toxin-caused emetic response and intestinal hormones GLP-1 and GIP released in mink are associated with activating calcium transduction. Following oral gavage and intraperitoneal injection T-2 toxin, emetic responses were observed in a dose-dependent manner, which notably corresponded to the secretion of GLP-1 and GIP, and were suppressed by pretreatment with respective antagonist Exending9–39 and Pro3GIP. Additional research found that NPS-2143 (NPS) and ruthenium red (RR), respective antagonists of CaSR and TRP channels, dramatically inhibited both T-2 toxin-induced emesis response and the expression of plasma GLP-1 and GIP. According to these data, we observed that T-2 toxin-induced emetic response corresponds to secretion of GLP-1 and GIP via calcium transduction.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36(PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. Single or multiple dose GTS-21 (0.5-8.0mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

Dietary Medium-Chain Triglyceride Decanoate Affects Glucose Homeostasis Through GPR84-Mediated GLP-1 Secretion in Mice.

BackgroundDietary triglycerides are an important energy source; however, their excess intake causes metabolic diseases such as obesity and type 2 diabetes. Medium-chain triglycerides (MCTs) as triglyceride forms of medium-chain fatty acids (MCFAs) are applied to meet the energy demands of athletes, the elderly, and people with stunted growth, because MCFAs are efficiently converted into energy for immediate utilization by the organs and do not accumulate as fat. Although the intake of each MCT type (octanoate; C8:0, decanoate; C10:0, and dodecanoate; C12:0) exhibits beneficial metabolic effects, individual functional differences remain unclear.MethodsMCTs or MCFAs were administrated to male GPR84-deficient mice with a C57BL/6J background and mouse enteroendocrine cell line STC-1, and the effects on glucose homeostasis and gut hormone GLP-1 secretion were evaluated.ResultsC10:0 intake improves glucose metabolism through the MCFA receptor GPR84-mediated GLP-1 secretion. Each MCT intake showed resistance to obesity and improved metabolic parameters compared with lard intake. Moreover, oral administration of MCTs enhanced glucose tolerance, especially C10:0 administration, which sufficiently increased plasma GLP-1 levels. Additionally, C10:0 stimulation promoted GLP-1 secretion via GPR84 in STC-1, enhanced glucose tolerance through GPR84-mediated GLP-1 secretion, and showed resistance to high-fat diet (HFD)-induced obesity in mice.ConclusionsDietary MCT (C10:0) intake efficiently may protect against obesity and improve insulin resistance via GLP-1 secretion.

A randomized placebo-controlled cross-over study on the effects of anthocyanins on inflammatory and metabolic responses to a high-fat meal in healthy subjects

This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.

Efficacy of a meal sequence in patients with type 2 diabetes: a systematic review and meta-analysis

IntroductionThis systematic review investigated the efficacy of a meal sequence, the carbohydrate-later meal pattern (CL), on type 2 diabetes mellitus (T2DM).Research design and methodsWe searched the Cochrane Central Register of...

De novo phosphatidylcholine synthesis in the small intestinal epithelium is required for normal dietary lipid handling and maintenance of the mucosal barrier

Cytidine triphosphate:phosphocholine cytidylyltransferase-α (CTα) is the rate limiting enzyme in the major pathway for de novo phosphatidylcholine (PC) synthesis. When CTα is deleted specifically in intestinal epithelial cells of adult mice (CTαIKO mice) fed a high-fat diet they present with weight loss, lipid malabsorption, and high postprandial GLP-1 levels. The current study aimed to characterize the changes that occur in the small intestines of CTαIKO mice using transcriptomics and to determine whether intestinal function could be rescued in CTαIKO mice. We found that impaired de novo PC synthesis in the gut is linked to lower abundance of transcripts related to lipid metabolism and higher abundance of transcripts related to ER stress and cell death, together with loss of goblet cells from the small intestinal epithelium. Furthermore, impaired movement of fatty acids from the intestinal lumen into enterocytes was observed in isolated intestinal sacs derived from CTαIKO mice, a model that excludes factors such as bile, gastric emptying, the nervous system, and circulating hormones. Antibiotic treatment prevented acute weight loss and normalized jejunum TG concentrations after refeeding but did not prevent ER stress or loss of goblet cells in CTαIKO mice. Dietary PC supplementation partially prevented loss of goblet cells but was unable to normalize jejunal TG concentrations after refeeding in CTαIKO mice. High postprandial plasma GLP-1 levels were present in CTαIKO mice regardless of antibiotic treatment, dietary PC content, or dietary fat content. Together, these data show that there is a specific requirement from de novo PC synthesis in maintaining small intestinal homeostasis, including dietary lipid uptake, normal hormone secretion, and barrier function.

Hnf4g invalidation prevents diet-induced obesity via intestinal lipid malabsorption.

Changes in dietary habits have occurred concomitantly with a rise of type 2 diabetes (T2D) and obesity. Intestine is the first organ facing nutrient ingestion and has to adapt its metabolism with these dietary changes. HNF-4γ, a transcription factor member of the nuclear receptor superfamily and mainly expressed in intestine, has been suggested to be involved in susceptibility to T2D. Our aim was to investigate the role of HNF-4γ in metabolic disorders and related mechanisms. Hnf4g-/- mice were fed high-fat/high-fructose (HF-HF) diet for 6 weeks to induce obesity and T2D. Glucose homeostasis, energy homeostasis in metabolic cages, body composition and stool energy composition, as well as gene expression analysis in the jejunum were analyzed. Despite an absence of decrease in calorie intake, of increase in locomotor activity or energy expenditure, Hnf4g-/- mice fed with HF-HF are protected against weight gain after 6 weeks of HF-HF diet. We showed that Hnf4g-/- mice fed HF-HF display an increase in fecal calorie loss, mainly due to intestinal lipid malabsorption. Gene expression of lipid transporters, Fatp4 and Scarb1 and of triglyceride-rich lipoprotein secretion proteins, Mttp and ApoB are decreased in gut epithelium of Hnf4g-/- mice fed HF-HF, showing the HNF-4γ role in intestine lipid absorption. Furthermore, plasma GLP-1 and jejunal GLP-1 content are increased in Hnf4g-/- mice fed HF-HF, which could contribute to the glucose intolerance protection. The loss of HNF-4γ leads to a protection against a diet-induced weight gain and to a deregulated glucose homeostasis, associated with lipid malabsorption.

Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats.

The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats. OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development. There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose. The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.

Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia.

Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (Ldlr-/-), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.

Efficacy of a Novel Low-Glycemic-Index Medical Food on Satiety and Gut Hormone Responses in the Normal-Weight and Obese

Low glycemic index medical food (LGI) has been utilized as a meal replacement for patients with type 2 diabetes, obesity, and improving other metabolic outcomes. However, since the impact of this diet on hormones and satiety is unclear, this study determined the effect of a novel LGI on satiety and gut hormone responses in normal-weight and obese adults. Methods: The study was a randomized, cross-over, single-blind controlled trial. Healthy adults aged 20–45 years consisting of 20 normal weight (NW) and 20 obese (OB) as classified by % body fat. Each subject was assigned to drink the soybean milk (SB) as a control and the novel LGI breakfast (ONCE PROⓇ) as a test meal in a random order, with a seven-day washout period. Their satiety was assessed with a visual analog scale (VAS) questionnaire before and every 30 minutes after each breakfast for 240 minutes. Plasma GLP-1, ghrelin, and total PYY were measured at baseline, 30, 60, 120, and 240 minutes after breakfast. After 240 minutes, subjects were given a buffet lunch to eat until satiated and total lunch intake was recorded. Results: Both NW and OB had significantly higher GLP-1 and PYY AUCs and significantly lower ghrelin AUCs (both NW and OB; GLP-1 pConclusions: The novel low glycemic index medical food had superior effects on gut hormones and satiety improvement over soybean milk in both NW and OB subjects. Furthermore, OB tended to be more influenced by the novel LGI than NW on the hormonal changes and decreased eating.

Abstract 9769: Bicarbonate Treatment Before Reperfusion Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibition of Spleen-Mediated Inflammatory Response

Introduction: The spleen plays an important role in mediating myocardial ischemia/reperfusion injury (IRI). Sodium bicarbonate (NaHCO 3 ) administration is reported to inhibit spleen-mediated inflammatory responses via vagus nerve activation. Hypothesis: NaHCO 3 treatment attenuates myocardial IRI in a spleen dependent-manner. Methods: C57BL/6 mice underwent 40 minutes of LCA occlusion followed by 60 minutes of reperfusion. PBS (control), NaHCO 3 (1 mEq/ml), or 5.8% NaCl of equivalent osmolality were administered intravenously (IV) 10 minutes before reperfusion at a dose of 1 μl/g. Intraperitoneal (IP) NaHCO 3 was administered 10 minutes before reperfusion at low dose (0.25 mEq/ml, 20 μl/g), high dose (0.5 mEq/ml, 20 μl/g), or as a localized topical rinse of the spleen or liver (1 mEq/ml, 1μl/g). Infarct size (IF), denoted as percentage of risk region (RR, % of LV), was measured by TTC-Phthalo blue staining. Additional groups (n=4) without IRI received IV PBS, IV NaHCO 3 , or IP NaHCO 3 splenic rinse and underwent plasma and spleen harvest 10 minutes after treatment. Results: RR was comparable among all groups with IRI. Among IV-treated groups (Figure A), IF was similar with PBS and 5.8% NaCl (51±4% and 46±3%), while IV NaHCO 3 significantly reduced IF to 25±3% (p&lt;0.05 vs. PBS &amp; 5.8% NaCl). Among IP-treated groups (Figure B), low-dose NaCO3, high-dose NaHCO 3 , and topical NaHCO 3 spleen rinse equally attenuated IF compared to control (p&lt;0.05), while topical NaHCO 3 liver rinse did not reduce IF (51±2%, p = NS vs. control). IV NaHCO 3 administration elevated base excess and HCO 3 - without changing pH, pO 2 or pCO 2 . IV and topical splenic NaHCO 3 elevated plasma GLP-1 and enhanced splenic monocyte M2 polarization. Conclusions: Both IV and IP NaHCO 3 treatment attenuated IF via inhibiting spleen-mediated inflammatory responses. Sodium bicarbonate administered prior to reperfusion may a potential therapeutic adjunct for ischemia/reperfusion injury in acute coronary syndrome.

Impact of high energy oral nutritional supplements consumed in the late afternoon on appetite, energy intake and cardio-metabolic risk factors in females with lower BMI

Background/ObjectiveMorning consumption of a single dose of high-energy oral nutritional supplement (ONS) in females with a lower BMI displaces some of the food eaten at breakfast but increases overall daily energy intake. This study investigated the effectiveness of ONS intake in the late afternoon and for longer duration.Subjects/MethodsTwenty-one healthy females (mean ± SD, age 25 ± 5 years; BMI 18.7 ± 1.2 kg/m2) participated in a randomised, crossover study with two experimental trials. In the afternoon of days 1–5, participants consumed either ONS (2.510 MJ) or low-energy PLACEBO drink (0.377 MJ) and recorded food eaten at home. On day six, energy intake was measured during buffet meals, and energy expenditure, appetite measurements and blood samples were collected throughout the day.ResultOver the 5-day period, in the ONS trial energy intake from evening meals was lower (ONS, 2.7 ± 0.25 MJ; Placebo, 3.6 ± 0.25 MJ, P = 0.01) but averaged total daily energy intake was higher (ONS, 9.2 ± 0.3 MJ; PLACEBO, 8.2 ± 0.4 MJ, P = 0.03). On day six, energy intake, appetite scores, plasma GLP-1 and PYY, and energy expenditure were not significantly different between the two trials but fasting insulin concentration and HOMAIR, were higher (P < 0.05) and insulin sensitivity score based on fasting insulin and TAG lower (P < 0.05) in ONS trial.ConclusionLate afternoon consumption of ONS for five consecutive days by females with a lower BMI has only a partial and short-lived energy intake suppression and thus increases daily energy intake but reduces insulin sensitivity.

Effects of co-administration of metformin and evogliptin on cerebral infarct volume in the diabetic rat

Patients with diabetes suffer more severe ischemic stroke. A combination of metformin and dipeptidyl peptide-4 inhibitors is commonly prescribed to treat diabetes. Therefore, we aimed to determine if pretreatment with a combination of metformin and evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce cerebral infarct volume in rats with streptozotocin-induced diabetes. After confirming diabetes induction, the rats were treated with vehicle, evogliptin, metformin, or evogliptin/metformin combination for 30 days. Then, stroke was induced by transient middle cerebral artery occlusion (tMCAO). Infarct volume, oxidative stress, levels of methylglyoxal-modified protein, glucagon-like peptide-1 receptor (GLP-1R), AMPK, and Akt/PI3K pathway-related proteins, and post-stroke pancreatic islet cell volume were evaluated. Compared to vehicle, only the co-administration group had significantly reduced infarct volume from the effects of tMCAO; the regimen also improved glycemic control, whereas the individual treatments did not. Co-administration also significantly reduced methylglyoxal-modified protein level in the core of the brain cortex, and the expression of 4-HNE and 8-OHdG was reduced. Co-administration increased p-Akt levels in the ischemic core and mitigated the suppression of Bcl-2 expression. Plasma GLP-1 and dipeptidyl peptidase-4 levels and brain GLP-1R expression remained unaltered. In the pancreas, islet cell damage was reduced by co-administration. These results reveal that metformin and evogliptin co-administration ameliorates cerebral infarction associated with prolonged glycemic control and pancreatic beta cell sparing. Other potential protective mechanisms may be upregulation of insulin receptor signaling or reduction of methylglyoxal-induced neurotoxicity. The combination of metformin and evogliptin should be tested further for its potential against focal cerebral ischemia in diabetes patients.

Hemp and buckwheat are valuable sources of dietary amino acids, beneficially modulating gastrointestinal hormones and promoting satiety in healthy volunteers

PurposeThis study evaluated the postprandial effects following consumption of buckwheat, fava bean, pea, hemp and lupin compared to meat (beef); focussing on biomarkers of satiety, gut hormones, aminoacids and plant metabolites bioavailability and metabolism.MethodsTen subjects (n = 3 men; n = 7 women; 42 ± 11.8 years of age; BMI 26 ± 5.8 kg/m2) participated in six 1-day independent acute interventions, each meal containing 30 g of protein from buckwheat, fava bean, pea, hemp, lupin and meat (beef). Blood samples were collected during 24-h and VAS questionnaires over 5-h.ResultsVolunteers consumed significantly higher amounts of most amino acids from the meat meal, and with few exceptions, postprandial composition of plasma amino acids was not significantly different after consuming the plant-based meals. Buckwheat meal was the most satious (300 min hunger scores, p < 0.05).Significant increase in GLP-1 plasma (AUC, iAUC p = 0.01) found after hemp compared with the other plant-based meals. Decreased plasma ghrelin concentrations (iAUC p < 0.05) found on plant (hemp) vs. meat meal. Several plasma metabolites after hemp meal consumption were associated with hormone trends (partial least squares-discriminant analysis (PLS-DA): 4-hydroxyphenylpyruvic acid, indole 3-pyruvic acid, 5-hydoxytryptophan, genistein and biochanin A with GLP-1, PYY and insulin; 3-hydroxymandelic acid and luteolidin with GLP-1 and ghrelin and 4-hydroxymandelic acid, benzoic acid and secoisolariciresinol with insulin and ghrelin. Plasma branched-chain amino acids (BCAAs), (iAUC, p < 0.001); and phenylalanine and tyrosine (iAUC, p < 0.05) were lower after buckwheat comparison with meat meal.ConclusionPlants are valuable sources of amino acids which are promoting satiety. The impact of hemp and buckwheat on GLP-1 and, respectively, BCAAs should be explored further as could be relevant for aid and prevention of chronic diseases such as type 2 diabetes.Study registered with clinicaltrial.gov on 12th July 2013, study ID number: NCT01898351.

The enteroinsular axis during hospitalization in newborn foals

The enteroinsular axis (EIA) is an energy regulatory system that modulates insulin secretion through the release of enteroendocrine factors (incretins). Despite the importance of energy homeostasis in the equine neonate, information on the EIA in hospitalized foals is lacking. The goals of this study were to measure serum insulin and plasma incretin (glucose-dependent insulinotropic polypeptide [GIP], glucagon-like peptide-1 [GLP-1] and glucagon-like peptide-2 [GLP-2]) concentrations, to determine the insulin and incretin association, as well as their link to disease severity and outcome in hospitalized foals. A total of 102 newborn foals ≤72 h old were classified into hospitalized (n = 88) and healthy groups (n = 14). Hospitalized foals included septic (n = 55) and sick non-septic (SNS; n = 33) foals based on sepsis scores. Blood samples were collected over 72 h to measure serum insulin and plasma GIP, GLP-1 and GLP-2 concentrations using immunoassays. Data were analyzed by nonparametric methods and univariate logistic regression. At admission, serum glucose and insulin and plasma GIP were significantly lower in hospitalized and septic compared to healthy foals (P < 0.01), while plasma GLP-1 and GLP-2 concentrations were higher in hospitalized and septic foals than healthy and SNS foals, and decreased over time in septic foals (P < 0.05). As a percent of admission values, GLP-1 and GLP-2 concentrations dropped faster in healthy compared to hospitalized foals. Serum insulin concentrations were lower in hospitalized and septic non-survivors than survivors at admission (P < 0.01). Hospitalized foals with serum insulin < 5.8 µIU/mL, plasma GLP-1 >68.5 pM, and plasma GLP-2 >9 ng/mL within 24 h of admission were more likely to die (OR = 4.2; 95% CI = 1.1–16.1; OR = 13.5, 95% CI = 1.4–123.7; OR = 12.5, 95% CI = 1.6–97.6, respectively; P < 0.05). Low GIP together with increased GLP-1 and GLP-2 concentrations indicates that different mechanisms may be contributing to reduced insulin secretion in critically ill foals, including impaired intestinal production (GIP, proximal intestine) and pancreatic endocrine resistance to enhanced incretin secretion (GLP-1, GLP-2; distal intestine). These imbalances could contribute to energy dysregulation in the critically ill equine neonate.