Glucagon-like Peptide-1 Production Research Articles

Neuroprotective effects of an engineered Escherichia coli Nissle 1917 on Parkinson's disease in mice by delivering GLP-1 and modulating gut microbiota.

Considerable evidence suggests that insulin resistance is closely linked to Parkinson's disease (PD), leading to agents aiming at treating diabetes can be regarded as new neuroprotective strategies in PD, notably glucagon-like peptide-1 (GLP-1). However, the extremely short half-life of GLP-1 due to degradation by the ubiquitous proteolytic enzyme limits its clinical application. In this study, we engineered the recombinant integrant probiotic strain Escherichia coli Nissle 1917 (EcN) to create a strain EcN-GLP-1 that effectively delivers the heterologous GLP-1 molecule. Subsequently, we assessed its neuroprotective effects on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. We demonstrated that EcN-GLP-1 treatment could improve motor deficits, increase tyrosine hydroxylase-positive neurons, suppress microglia and astrocyte activation, reduce brain and colon inflammation, and ameliorate colonic barrier function damaged by MPTP induction. Meanwhile, we confirmed that the oral administration of EcN-GLP-1 could restore the disturbance of gut microbiota in the MPTP-induced PD mice, by reducing the relative abundances of Akkermansia and Oscillospira, and increasing the level of Prevotella in the gut. These results support further development of an engineered probiotic platform in which production of GLP-1 for gut-brain disorders, such as PD.

844-P: Jatupalathika Extract Acts via G-Protein-Coupled Receptors to Stimulate GLP-1 Secretion in STC-1 Cell Line

One of the most important molecular targets for the prevention and treatment of diabetes is glucagon-like peptide-1 (GLP-1) , a molecule secreted by enteroendocrine L cells in the intestine. It has been reported that nutrients, as well as non-nutritional dietary factors, can activate GLP-1 secretion. Jatupalathika (JPT) is a traditional herbal formulation of four dried fruits: Terminalia bellirica (Gaertn.) Roxb., Terminalia chebula Retz., Terminalia arjuna (Roxb.) Wight & Arn., and Phyllanthus emblica Linn. JPT extracts have traditionally been used for their anti-oxidant, anti-aging, body fat depletion, and weight loss properties. However, its effects on glucose metabolism and GLP-1 are not known. Thus, we evaluated the antidiabetes potential of JPT aqueous extracts by assessing its ability to induce GLP-1 secretion in a mouse intestinal cell line (STC-1) . The MTT assay was used to assess the cytotoxicity, and the LUMINEX multiplex assays were used to assess GLP-1 hormone secretion. When compared to control, JPT extracts (125 µg/ml) increased GLP-1 secretion after 45-120 minutes of incubation without any effects on cell survival. The mechanism of action of GLP-1 secretion activity in cells was studied using real-time PCR. We discovered an increase in expression of six genes related to GLP-1 secretion: SLC5A1 (encoding SGLT1) , FFAR2 (encoding GPR43) , FFAR3 (encoding GPR41) , GPR119, GPBAR1, and CABP1. This finding demonstrated that JTP extract significantly increased GLP-1 hormone production via G-protein-coupled receptor activation, which also promotes Ca2+ release from the endoplasmic reticulum. Phytochemical profiling and molecular docking study revealed that Ellagic acid and Orientin are abundant metabolites with a favorable ability to bind the FFAR2/3 protein, acting as potential agents that aid in GLP-1 production. The findings showed that JPT might be useful in the prevention and treatment of diabetes. However, more research on in vivo effects is required. Disclosure C.Chaichana: None. N.Khumkhana: None. P.Wongshaya: None. W.Deekum: None. P.Pramyothin: Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk.

366-OR: 14-3-3-ζ Contributes to Effect of ß-Cell GLP1 Receptor Signaling to Alter a-Cell Proglucagon Processing

Glucagon like peptide 1 (GLP1) , a classically gut derived hormone, potentiates insulin secretion. New evidence suggests that α cells can produce GLP1 under certain conditions, which may offer a novel therapeutic modality for treating diabetes; however, the mechanisms regulating α cell GLP1 production are unknown. We previously found that enhanced β cell GLP1 receptor (GLP1R) signaling activates α cell GLP1 by activating prohormone convertase 1/3 (Pcsk1) expression. We tested the hypothesis that enhanced β cell GLP1R signaling activates α cell GLP1 production through paracrine factors. We studied the impact of conditioned media (CM) generated from β cell GLP1R WT and KO islets of saline (CTRL) and liraglutide (LIRA) treated mice on α cell gene expression and function. CM from LIRA treated islets increased α cell Pcsk1 expression and active GLP-1 secretion only if β cells expressed the GLP1R (Pcsk1 expression (AU) : CTRL WT=1.0±0.1, LIRA WT=2.0±0.3, CTRL KO=1.1±0.2, LIRA KO=1.1±0.2, P<0.01; active GLP-1 (pg/mL) : CTRL WT=124±44, LIRA WT=682±247, CTRL KO=173±101, LIRA KO=116±30, P<0.05) . Subsequent identification of the proteome secreted by mouse and human islets in response to LIRA and CTRL revealed 14-3-3-ζ as a lead candidate in the regulation of α cell Pcsk1 expression. To assess the role of 14-3-3-ζ, islets from LIRA treated mice were treated with and without 14-3-3-ζ, and islets from CTRL treated mice were treated with and without the 14-3-3 inhibitor, R18. Addition of 14-3-3-ζ ablated the effect of CM from LIRA treated islets to increase α cell Pcsk1 expression, while inhibition of 14-3-3 with R18 in CTRL islets resulted in CM that mimicked the effect of CM from LIRA treated islets to stimulate α cell Pcsk1 expression (Pcsk1 expression: CTRL=1.1±0.2, R18=2.0±0.2, LIRA=2.4±0.3, LIRA+14-3-3-ζ=1.3±0.1, P<0.05) . These data refine our understanding of α cell GLP1 regulation and identify 14-3-3-ζ as a potential target with which to enhance α cell GLP1 production for diabetes treatment. Disclosure M.Holter: None. B.Cummings: None. D.Phuong: None. I.S.H.Lee: None. M.Saikia: None. L.A.Weikert: Stock/Shareholder; Merck & Co., Inc., Oramed Pharmaceuticals. E.T.Anderson: None. Q.Fu: None. S.Zhang: None. K.Sloop: Employee; Eli Lilly and Company. Funding NIH/NIDDK (F30 DK126538) Department of Defense (W81XWH-18-1-0206) The Hartwell Foundation NIH/NIDDK (R56DK124853)

108-OR: The Effect of Human Pregnancy on Morphology of the Endocrine Pancreas

In animal models, pregnancy is associated with distinct morphological and functional adaptations in the endocrine pancreas, particularly characterized by β cell hyperplasia and hypertrophy. Failed islet adaptation to increased metabolic demands in pregnancy contributes to the development of gestational diabetes. However, the effects of pregnancy on the remodeling of human endocrine pancreas remain largely unknown. To address this, we used human pancreatic autopsy specimens from 8 women who died during pregnancy or within 6 weeks postpartum (P/PP) , and 16 women who were matched by age and body mass index (BMI) to serve as controls (CON) who were not pregnant at death. Subjects had a complete autopsy with pancreatic tissue of adequate quality/quantity stored and a corresponding medical record. Consecutive pancreatic sections were co-immunostained for key islet cell markers including Insulin, Glucagon and Glucagon-Like Peptide-1 (GLP-1) as well as a marker of cell proliferation (Ki-67) . Although the pancreatic fractional insulin area (β cell area) was comparable between P/PP and CON groups, the glucagon and the GLP-1 positive areas were substantially increased ∼2-fold in the P/PP group (p<0.05) . Our analysis also revealed an increase in the proportion of GLP-1/glucagon double positive islet cells (p<0.05) in PP/P subjects, suggesting a modulatory effect of pregnancy in favor of increased islet GLP-1 production in α cells. Consistently, P/PP subjects demonstrated an increase in α cell expression of prohormone convertase 1/3 (PC1/3) (p<0.05) , an enzyme responsible for the proteolytic cleavage of GLP-1 from proglucagon. Finally, the frequency of both β and α cell proliferation was comparable between groups (p>0.05) . While prior pre-clinical studies have focused solely on functional and morphological changes in pancreatic β cells, our data suggest that proglucagon gene products (glucagon and GLP-1) may play an underappreciated role in (or serve as markers of) the metabolic changes impacting human pregnancy. Disclosure A.M.Egan: None. T.K.Her: None. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. A.Matveyenko: None. Funding National Institutes of Health (K12 HD065987/HD/NICHD)

The impact of binge-like palatable food intake on the endogenous glucagon-like peptide-1 system in female rats

Binge eating involves consumption of large amounts of food and a loss of control over the amount consumed. The incidence of binge eating disorder is higher in females than males, hinting at important sex differences in binge eating behavior, but the neural underpinnings of binge eating still remain unresolved. Recent work in male rats has shown that a history of binge-like palatable food intake suppresses hindbrain expression of preproglucagon (PPG), the precursor for glucagon-like peptide-1 (GLP-1). Given the roles of GLP-1 in reducing feeding and food reward, this could be a mechanism underlying binge-like eating in rodents. However, whether similar effects occur in female rats is unknown. Here, we tested the hypothesis that a history of binge-like palatable food intake in female rats would reduce PPG expression in the nucleus tractus solitarius (NTS), a key central site of GLP-1 production. Female rats given access to vegetable shortening every fourth day (4D) engaged in binge-like feeding, demonstrated by consuming significantly more shortening during the first hour of fat access compared to counterparts with ad libitum (AL) fat access. After several weeks of fat access under these schedules, PPG and GLP-1 receptor (GLP-1R) expression were measured in the NTS and ileum. Surprisingly, and in contrast to previous findings in male rats, there were no significant differences in expression of PPG or GLP-1R in either site in 4D versus AL rats, nor were there effects on plasma GLP-1 levels. These findings highlight key differences in the effects of binge-like intake on the central GLP-1 system in female compared to male rats.

Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice.

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

Control of water intake by a pathway from the nucleus of the solitary tract to the paraventricular hypothalamic nucleus

Several brain areas have been shown to participate in thirst and control of fluid intake. An understanding of how these circuits interact, and their roles in the activation, maintenance, and termination of fluid intake remains incomplete. Central glucagon-like peptide-1 (GLP-1) receptor activation appears to be an important part of the termination of drinking, but the site(s) of action for this suppression has not yet been determined. In an attempt to use GLP-1 responsiveness as a means to screen targets of hindbrain cells that participate in the termination of thirst and the resultant water intake, we injected the GLP-1 receptor agonist exendin-4 (Ex-4) into three brain areas known to express GLP-1 receptors, and measured subsequent water intake. Ex-4 reduced water consumption when injected into the paraventricular hypothalamic nucleus (PVH) and nucleus of the solitary tract (NTS), but not when injected into the nucleus accumbens (NAc). Using the effective response after injection into the PVH as a guide, we examined the connection between the NTS – the site of endogenous central GLP-1 production – and the PVH. Retrograde tracing combined with Fos immunohistochemistry suggested intake-induced activity in PVH-projecting NTS cells. To test the hypothesis that this pathway is important in the termination of drinking, we chemogenetically activated PVH-projecting hindbrain cells. Interestingly, activation of this population of cells increased water intake, calling into question the heterogeneity of the pathway with respect to the control of fluid intake. Taken together, we conclude that the PVH is a site of action for GLP-1 receptor activation in the inhibition of water intake, but suspect that endogenous GLP-1 in NTS-to-PVH projections may be counterbalanced by a parallel pathway that either activates or maintains already activated water intake.

Yacon-based product improves intestinal hypertrophy and modulates the production of glucagon-like peptide-1 in postmenopausal experimental model

AimsThe progressive decline in estrogen level puts postmenopausal women at a higher risk of developing cardiometabolic diseases. Thus, we evaluated the potential beneficial effects of yacon-based product (YBP) on glycemic profile and intestinal health of postmenopausal rats. MethodsEighty Wistar rats were randomized into 4 ovariectomized (OVX) groups or 4 celiotomized groups treated with a standard diet (SD) or diet supplemented with YBP at 6% of fructooligosaccharide (FOS)/inulin. Key findingsThe continued consumption of YBP at 6% of FOS/inulin did not generate liver damage and gastrointestinal disorders. Rats fed with YBP displayed higher food consumption, but this did not increase the body weight gain, abdominal circumference and body fat percentual of OVX rats. Furthermore, we also found that the FOS/inulin fermentation present in the YBP resulted in cecum, ileum and colon crypts hypertrophy and increased the lactic acid levels in the cecal content. We observed an increase of glucagon-like peptide-1 (GLP-1) immunoreactive cells and there was no change in the glucose and insulin plasma levels of YBP-fed OVX rats. SignificanceOur findings indicated that YBP when consumed previously and after the menopausal period has important effects on the morphology and function of intestinal mucous of rats and has potential to modulate indirectly the glycemic and insulinemic profiles, weight gain and body fat percentual in the hypoestrogenic period through metabolites produced in the fermentation process.

Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity-Nutraceutical Options.

In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin—an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.

Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study

ObjectiveAlthough gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously,...

Unveiling the Metabolic Effects of Glycomacropeptide.

For many years, the main nitrogen source for patients with phenylketonuria (PKU) was phenylalanine-free amino acid supplements. Recently, casein glycomacropeptide (GMP) supplements have been prescribed due to its functional and sensorial properties. Nevertheless, many doubts still persist about the metabolic effects of GMP compared to free amino acids (fAA) and intact proteins such as casein (CAS). We endeavour to compare, in rats, the metabolic effects of different nitrogen sources. Twenty-four male Wistar rats were fed equal energy density diets plus CAS (control, n = 8), fAA (n = 8) or GMP (n = 8) for 8 weeks. Food, liquid intake and body weight were measured weekly. Blood biochemical parameters and markers of glycidic metabolism were assessed. Glucagon-like peptide-1 (GLP-1) was analysed by ELISA and immunohistochemistry. Food intake was higher in rats fed CAS compared to fAA or GMP throughout the treatment period. Fluid intake was similar between rats fed fAA and GMP. Body weight was systematically lower in rats fed fAA and GMP compared to those fed CAS, and still, from week 4 onwards, there were differences between fAA and GMP. None of the treatments appeared to induce consistent changes in glycaemia, while insulin levels were significantly higher in GMP. Likewise, the production of GLP-1 was higher in rats fed GMP when compared to fAA. Decreased urea, total protein and triglycerides were seen both in fAA and GMP related to CAS. GMP also reduced albumin and triglycerides in comparison to CAS and fAA, respectively. The chronic consumption of the diets triggers different metabolic responses which may provide clues to further study potential underlying mechanisms.

Berberine activates the β-catenin/TCF4 signaling pathway by down-regulating miR-106b to promote GLP-1 production by intestinal L cells

Berberine facilitates the production of glucagon-like peptide-1 (GLP-1) by intestinal L cells. Here, we aimed to reveal the mechanism of berberine facilitating the production of GLP-1 by intestinal L cells. In this study, we confirmed that the 100 mg/kg berberine daily through diet decreased the miR-106b expression and elevated the expressions of β-catenin and T-cell factor 4 (TCF4) in colon tissues of high-fat diet mice; berberine decreased the concentrations of triglycerides, total cholesterol and the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in mouse serum samples; berberine decreased the blood glucose in the mouse tail vein blood and promoted GLP-1 production by intestinal L cells in mouse serum samples and elevated the GLP-1 expression in mouse colon tissues. Meanwhile, the mechanism analysis demonstrated that a dose of 100 μM berberine down-regulated the miR-106b expression by elevating the methylation levels of miR-106b in STC-1 cells and miR-106b bound to TCF4 in 293T cells. Moreover, the 100 mg/kg berberine daily through diet activated the β-catenin/TCF4 signaling pathway by decreasing miR-106b, thereby facilitating GLP-1 production in intestinal L cells through the in vivo assays. Conclusively, our experimental data illustrated that berberine decreased miR-106b expression by increasing its methylation levels and then activated the β-catenin/TCF4 signaling pathway, thereby facilitating GLP-1 production by intestinal L cells.

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.

Enzymatically-Synthesized Glycogen Induces Cecal Glucagon-Like Peptide-1 Production and Suppresses Food Intake in Mice.

It is well known that dietary fiber stimulates the release of satiety hormones such as glucagon-like peptide-1 (GLP-1), which in turn suppresses appetite. In order to evaluate appetite regulating role of enzymatically synthesized glycogen (ESG, one of the resistant starch), we examined the effects of dietary supplementation of ESG on food intake and cecal proglucagon gene expression in normal and high fat diet-fed mice. Twenty four male ICR mice were weighed and assigned to four groups: normal diet group; normal diet containing 25% ESG group; high-fat diet (HFD) group; HFD containing 25% ESG group. Each group was fed the relevant diets for 3 wk. All data were analyzed by a two-way ANOVA with the main effects of HFD and ESG. ESG significantly decreased food intake and increased the weight of the cecum and cecal content. Plasma total short chain fatty acids concentration was significantly elevated by ESG. The mRNA levels of proglucagon in the cecum and plasma total GLP-1 concentration were significantly increased by ESG. The mRNA levels of appetite regulating neuropeptides such as neuropeptide Y, agouti-related protein, proopiomelanocortin, and cocain- and amphetamine-regulating transcript in the hypothalamus were not influenced by ESG. There is no significant interaction between diet and ESG in any parameters. These results suggest that ESG-induced upregulation of GLP-1 production in the cecum suppresses food intake in mice and that fecal fermentation may be involved in the anorexigenic effect.

The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100–1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells.

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

Effects of Dietary Butyrate on Diet-Induced Obesity and Lipid Metabolism

Abstract Objectives We examined the effects of dietary butyrate, a short-chain fatty acids (SCFAs) on body weight control and metabolism in a diet-induced obesity rat model. Methods Male Sprague-Dawley rats fed with high-fat diet for 14 weeks. Sodium butyrate was administrated through diet supplementation at 3% wt/wt for long-term (14 weeks) or drinking water at 1% for short-term (2 weeks). Serum and feces were collected. Colon and liver tissues used for analyzing mRNA expression. To assess the effects of butyrate on lipid metabolism, 3T3-L1 cells were treated with sodium butyrate and sodium-3-hyroxybutyrate during adipogenic differentiation. Results On the high-fat diet, dietary supplementation of butyrate protected against body weight gain. Interestingly, food intake was increased and consistently colonic Proglucagon (Gcg), encoding Glucagon-like Peptide-1 (GLP-1) involved in appetite-suppression, was decreased. In contrast, short-term administration of butyrate did not affect body weight and food intake. Free fatty acid receptor 2 (Ffar2), a G-protein coupled receptor recognizing SCFAs and stimulating GLP-1 production, was decreased in colon. The colonic Hydroxycarboxylic acid receptor 2 (Hcar2) and Tight junction protein-1 (Tjp1) marginally increased but expression of inflammatory cytokines was not altered, implicating that anti-obesity effects of butyrate were not primarily through colon. In the liver, butyrate showed significantly decreased Ffar2 and Peroxisome proliferator–activated receptor-γ (Ppar-γ). In the butyrate group, aberrant phenotypes were observed including hyperlipidemia and alteration of serum level of adiponectin without change in fecal energy density. Intriguingly, in the 3T3-L1 cell line, fat accumulation was significantly stimulated at lower concentration of butyrate with elevated expression of Ffar2 and Ppar-γ. High concentration of butyrate reduced Ffar2 and Ppar-γ and suppressed adipocytic fat accumulation. Conclusions Our results suggested that dietary butyrate prevented diet-induced obesity despite increased food intake. Moreover, butyrate may regulate lipid metabolism in a dose-dependent manner. Funding Sources This research was supported by Basic Science Research Program through the NRF funded by the Ministry of Education. J.S is grateful for financial support from Hyundai Motor Chung Mong-Koo Foundation.

Glucagon Shows Higher Sensitivity than Insulin to Grapeseed Proanthocyanidin Extract (GSPE) Treatment in Cafeteria-Fed Rats.

The endocrine pancreas plays a key role in metabolism. Procyanidins (GSPE) targets β-cells and glucagon-like peptide-1 (GLP-1)-producing cells; however, there is no information on the effects of GSPE on glucagon. We performed GSPE preventive treatments administered to Wistar rats before or at the same time as they were fed a cafeteria diet during 12 or 17 weeks. We then measured the pancreatic function and GLP-1 production. We found that glucagonemia remains modified by GSPE pre-treatment several weeks after the treatment has finished. The animals showed a higher GLP-1 response to glucose stimulation, together with a trend towards a higher GLP-1 receptor expression in the pancreas. When the GSPE treatment was administered every second week, the endocrine pancreas behaved differently. We show here that glucagon is a more sensitive parameter than insulin to GSPE treatments, with a secretion that is highly linked to GLP-1 ileal functionality and dependent on the type of treatment.

The effects of glucagon like peptide-1 (GLP-1) on cardiac remodeling: exploring the role of medication and physiological modulation after metabolic surgery.

Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.

Glucagon-Like Peptide 1 and Taste Perception: From Molecular Mechanisms to Potential Clinical Implications.

Preclinical studies provided some important insights into the action of glucagon-like peptide 1 (GLP-1) in taste perception. This review examines the literature to uncover some molecular mechanisms and connections between GLP-1 and the gustatory coding. Local GLP-1 production in the taste bud cells, the expression of GLP-1 receptor on the adjacent nerves, a functional continuum in the perception of sweet chemicals from the gut to the tongue and an identification of GLP-1 induced signaling pathways in peripheral and central gustatory coding all strongly suggest that GLP-1 is involved in the taste perception, especially sweet. However, the impact of GLP-1 based therapies on gustatory coding in humans remains largely unaddressed. Based on the molecular background we encourage further exploration of the tongue as a new treatment target for GLP-1 receptor agonists in clinical studies. Given that pharmacological manipulation of gustatory coding may represent a new potential strategy against obesity and diabetes, the topic is of utmost clinical relevance.