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Thomas A. Lutz - One of the best experts on this subject based on the ideXlab platform.
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whole brain mapping of amylin induced neuronal activity in receptor activity modifying protein 1 3 knockout mice
European Journal of Neuroscience, 2021Co-Authors: Grethe Skovbjerg, Thomas A. Lutz, Christelle Le Foll, Urmas Roostalu, Henrik H Hansen, Casper Gravesen Salinas, Jacob Lercke Skytte, Jacob Jelsing, Niels Vrang, Jacob HeckshersorensenAbstract:The Pancreatic Hormone amylin plays a central role in regulating energy homeostasis and glycaemic control by stimulating satiation and reducing food reward, making amylin receptor agonists attractive for the treatment of metabolic diseases. Amylin receptors consist of heterodimerized complexes of the calcitonin receptor and receptor-activity modifying proteins subtype 1-3 (RAMP1-3). Neuronal activation in response to amylin dosing has been well characterized, but only in selected regions expressing high levels of RAMPs. The current study identifies global brain-wide changes in response to amylin and by comparing wild type and RAMP1/3 knockout mice reveals the importance of RAMP1/3 in mediating this response. Amylin dosing resulted in neuronal activation as measured by an increase in c-Fos labelled cells in 20 brain regions, altogether making up the circuitry of neuronal appetite regulation (e.g., area postrema (AP), nucleus of the solitary tract (NTS), parabrachial nucleus (PB), and central amygdala (CEA)). c-Fos response was also detected in distinct nuclei across the brain that typically have not been linked with amylin signalling. In RAMP1/3 knockout amylin induced low-level neuronal activation in seven regions, including the AP, NTS and PB, indicating the existence of RAMP1/3-independent mechanisms of amylin response. Under basal conditions RAMP1/3 knockout mice show reduced neuronal activity in the hippocampal formation as well as reduced hippocampal volume, suggesting a role for RAMP1/3 in hippocampal physiology and maintenance. Altogether these data provide a global map of amylin response in the mouse brain and establishes the significance of RAMP1/3 receptors in relaying this response.
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Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism.
Comprehensive Physiology, 2020Co-Authors: Christelle Le Foll, Thomas A. LutzAbstract:This article in the Neural and Endocrine Section of Comprehensive Physiology discusses the physiology and pathophysiology of the Pancreatic Hormone amylin. Shortly after its discovery in 1986, amylin has been shown to reduce food intake as a satiation signal to limit meal size. Amylin also affects food reward, sensitizes the brain to the catabolic actions of leptin, and may also play a prominent role in the development of certain brain areas that are involved in metabolic control. Amylin may act at different sites in the brain in addition to the area postrema (AP) in the caudal hindbrain. In particular, the sensitizing effect of amylin on leptin action may depend on a direct interaction in the hypothalamus. The concept of central pathways mediating amylin action became more complex after the discovery that amylin is also synthesized in certain hypothalamic areas but the interaction between central and peripheral amylin signaling remains currently unexplored. Amylin may also play a dominant pathophysiological role that is associated with the aggregation of monomeric amylin into larger, cytotoxic molecular entities. This aggregation in certain species may contribute to the development of type 2 diabetes mellitus but also cardiovascular disease. Amylin receptor pharmacology is complex because several distinct amylin receptor subtypes have been described, because other neuropeptides [e.g., calcitonin gene-related peptide (CGRP)] can also bind to amylin receptors, and because some components of the functional amylin receptor are also used for other G-protein coupled receptor (GPCR) systems. © 2020 American Physiological Society. Compr Physiol 10:811-837, 2020.
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amylin calcitonin receptor mediated signaling in pomc neurons influences energy balance and locomotor activity in chow fed male mice
Diabetes, 2020Co-Authors: Bernd Coester, Thomas A. Lutz, Christina Koesterhegmann, Christelle Le FollAbstract:Amylin, a Pancreatic Hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has recently been shown to act as a neurotrophic factor to control the development of area postrema → nucleus of the solitary tract and arcuate hypothalamic nucleus → paraventricular nucleus axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. For investigation of the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR), was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue. Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.
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involvement of amylin and leptin in the development of projections from the area postrema to the nucleus of the solitary tract
Frontiers in Endocrinology, 2017Co-Authors: Kathrin Abegg, Thomas A. Lutz, Christina N Boyle, Andreas Hermann, Sebastien G Bouret, Thomas RiedigerAbstract:The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the Pancreatic Hormone amylin. Amylin’s target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived Hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP−/−) and leptin-deficient (ob/ob) mice. Compared to wild-type littermates, postnatal (P10) and adult (P60) IAPP−/− mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14) ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions.
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the area postrema ap and the parabrachial nucleus pbn are important sites for salmon calcitonin sct to decrease evoked phasic dopamine release in the nucleus accumbens nac
Physiology & Behavior, 2017Co-Authors: Lynda Whiting, James E Mccutcheon, Christina N Boyle, Mitchell F Roitman, Thomas A. LutzAbstract:The Pancreatic Hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic 'reward' pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats. Amylin (50μg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50μg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake.
Thomas Riediger - One of the best experts on this subject based on the ideXlab platform.
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involvement of amylin and leptin in the development of projections from the area postrema to the nucleus of the solitary tract
Frontiers in Endocrinology, 2017Co-Authors: Kathrin Abegg, Thomas A. Lutz, Christina N Boyle, Andreas Hermann, Sebastien G Bouret, Thomas RiedigerAbstract:The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the Pancreatic Hormone amylin. Amylin’s target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived Hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP−/−) and leptin-deficient (ob/ob) mice. Compared to wild-type littermates, postnatal (P10) and adult (P60) IAPP−/− mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14) ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions.
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amylin and glp 1 target different populations of area postrema neurons that are both modulated by nutrient stimuli
Physiology & Behavior, 2013Co-Authors: Daniela Zuger, Thomas A. Lutz, Karoline Forster, Thomas RiedigerAbstract:Abstract The area postrema mediates the hypophagic effect of the Pancreatic Hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of amylin-induced c-Fos and CTR (68%), no c-Fos/CTR co-localization occurred after treatment with GLP-1 or the GLP-1R agonist exendin 4 (2 μg/kg ip). Similarly, LiCl (76 mg/kg ip) or AngII (50 μg/kg sc) led to c-Fos expression only in CTR negative AP neurons. In conclusion, our findings support a protein-dependent modulation of behavioral and neuronal amylin responsiveness under equicaloric feeding conditions. Amino acids might contribute to the inhibitory effect of diet-derived protein to reduce amylin-induced neuronal AP activation. Neuronal AP responsiveness to GLP-1 is also increased in the fasted state suggesting that diet-derived nutrients may also interfere with AP-mediated GLP-1 effects. Nevertheless, the primary target neurons for amylin appear to be distinct from cells targeted by GLP-1 and by stimuli producing aversion (LiCl) or contributing to blood pressure regulation (AngII) via the AP. Since amylin and GLP-1 analogs are targets for the treatment of obesity, the nutrient-dependent modulation of AP responsiveness might entail implications for such therapeutic approaches.
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the receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance
Riediger Thomas (2012). The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance. Procee, 2012Co-Authors: Thomas RiedigerAbstract:The hypothalamic arcuate nucleus (ARC) and the area postrema (AP) represent targets for hormonal and metabolic signals involved in energy homoeostasis, e.g. glucose, amylin, insulin, leptin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and ghrelin. Orexigenic neuropeptide Y expressing ARC neurons are activated by food deprivation and inhibited by feeding in a nutrient-dependent manner. PYY and leptin also reverse or prevent fasting-induced activation of the ARC. Interestingly, hypothalamic responses to fasting are blunted in different models of obesity (e.g. diet-induced obesity (DIO) or late-onset obesity). The AP also responds to feeding-related signals. The Pancreatic Hormone amylin acts via the AP to control energy intake. Amylin-sensitive AP neurons are also glucose-responsive. Furthermore, diet-derived protein attenuates amylin responsiveness suggesting a modulation of AP sensitivity by macronutrient supply. This review gives an overview of the receptive function of the ARC and the AP to hormonal and nutritional stimuli involved in the control of energy balance and the possible implications in the context of obesity. Collectively, there is consistency between the neurophysiological actions of these stimuli and their effects on energy homoeostasis under experimental conditions. However, surprisingly little progress has been made in the development of effective pharmacological approaches against obesity. A promising way to improve effectiveness involves combination treatments (e.g. amylin/leptin agonists). Hormonal alterations (e.g. GLP-1 and PYY) are also considered to mediate body weight loss observed in obese patients receiving bariatric surgery. The effects of hormonal and nutritional signals and their interactions might hold the potential to develop poly-mechanistic therapeutic strategies against obesity.
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identification of central projections from amylin activated neurons to the lateral hypothalamus
Brain Research, 2010Co-Authors: Catarina Soares Potes, Thomas A. Lutz, Thomas RiedigerAbstract:Abstract The ability of the Pancreatic Hormone amylin to inhibit food intake relies on a direct activation of the area postrema (AP). This activation is synaptically transmitted to the nucleus of the solitary tract (NTS), the lateral parabrachial nucleus (LPB), the central amygdaloid nucleus (Ce) and the lateral bed nucleus of stria terminalis (BSTL). Interestingly, neurons of the rostro-dorsal lateral hypothalamic area (dLHA), which are activated during fasting, are inhibited by peripheral amylin, although they lack amylin receptors. Using the retrograde tracer cholera toxin-B (Ctb) we analyzed whether the dLHA receives neuronal projections from amylin-activated brain areas. The anterograde tracer biotinylated dextran-amine (BDA) was used to confirm the projections and to identify further neuronal pathways potentially involved in amylin signaling. We identified dense projections from the amylin activated neurons in the LPB and sparse projections from the NTS to the dLHA. LPB fiber efferents were found in close proximity to dLHA nuclei activated by 24 h of fasting. The AP and the Ce showed no projections to the dLHA. Dense efferents were also observed from the LPB to other hypothalamic areas, namely to the ventromedial, dorsomedial, paraventricular and arcuate nuclei. This study provides neuroanatomical evidence that among the amylin activated areas, the LPB provides the strongest input to the dLHA, thus it may mediate the amylin-induced inhibition of the dLHA.
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diet derived nutrients modulate the effects of amylin on c fos expression in the area postrema and on food intake
Neuroendocrinology, 2007Co-Authors: Signe Michel, Thomas A. Lutz, Csilla Becskei, Elif Erguven, Thomas RiedigerAbstract:The Pancreatic Hormone amylin decreases food intake via activation of area postrema (AP) neurons. We investigated whether amylin’s potency to reduce food intake and to induce c-Fos expression in the A
Jens J Holst - One of the best experts on this subject based on the ideXlab platform.
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entero Pancreatic Hormone secretion gastric emptying and glucose absorption after frequently sampled meal tests
The Journal of Clinical Endocrinology and Metabolism, 2021Co-Authors: Simon Veedfald, Jens F Rehfeld, Gerrit Van Hall, Lars Bo Svendsen, Jens J HolstAbstract:CONTEXT Entero-Pancreatic Hormone secretion has been reported during the pre-absorptive cephalic and gastric meal phases, but never with a blood sampling frequency providing a temporal resolution that allows close scrutiny and correlations with gastric emptying and glucose-absorption. OBJECTIVE We hypothesized that entero-Pancreatic Hormone secretion after nutrient ingestion would be rapid and correlate with gastric emptying and glucose absorption. DESIGN AND SETTING Two visits in a clinical research facility. PARTICIPANTS Ten healthy young men. INTERVENTIONS A 75g glucose drink (OG) and a liquid mixed meal (LMM) were ingested (t 0-2 min) on separate days. Acetaminophen and 3-O-methyl-D-glucopyranose (3-OMG) were added to the drinks to evaluate gastric emptying and glucose absorption, respectively. Arterialized venous blood was sampled (t -30,-20,-18,-16,-14,-12,-10,-8,-6,-4,-2, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30 min). MAIN OUTCOME MEASURES Plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), gastrin, cholecystokinin (CCK), glucagon, Pancreatic polypeptide (PP), 3-OMG and glucose. Serum insulin, C-peptide and acetaminophen. RESULTS Acetaminophen increased 8min after OG(p<0.001) and LMM(p<0.05). 3-OMG; 8min after LMM(p<0.0001), 10min after OG(p=0.04). PP; 4min after LMM(p<0.03). Gastrin; 6min after LMM(p<0.003) and OG(p<0.003). CCK; 6min after LMM(p=0.0001). GIP; 8min after OG(p<0.05) and LMM(p<0.03). Glucose; 8min after OG(p<0.001), 12min after LMM(p<0.02). GLP-1; 12min after OG(p<0.01), 10min after LMM (p<0.01).. Insulin; 12min after LMM(p=0.02) and OG(p=0.002). C-peptide; 12min after OG(p=0.002) and LMM(p=0.04). CONCLUSIONS Early postprandial Hormone responses show characteristic differences with regards to timing and amplitude, but also great individual differences. This should be considered when interpreting mean responses and designing study protocols. CLINICALTRIALS.GOV NUMBER NCT03543423.
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normal insulin sensitivity glucose tolerance gut incretin and Pancreatic Hormone responses in adults with atopic dermatitis
Diabetes Obesity and Metabolism, 2020Co-Authors: Lise Gether, Jens J Holst, Jacob P Thyssen, Mette Gyldenlove, Bolette Hartmann, Signe Foghsgaard, Tina VilsbollAbstract:Aims Epidemiological studies show increased occurrence of type 2 diabetes in adults with atopic dermatitis (AD) compared to the general population. We examined whether adults with AD have reduced insulin sensitivity and/or exhibit other gluco-metabolic disturbances that could explain this association. Materials and methods Sixteen adult, non-obese, non-diabetic patients with mild to moderate AD and 16 gender, age and body mass index (BMI)-matched, healthy controls underwent a hyperinsulinemic euglycemic clamp (insulin infusion rate: 40 mU/m2 /min) and an oral glucose tolerance test (OGTT) with frequent blood sampling for gut and Pancreatic Hormones. Results The two groups were similar in age (33±3 vs. 33±3 years, mean ± standard error of the mean (SEM)), gender (56% women), BMI (24.5±0.7 vs. 24.4±0.7 kg/m2 ), physical activity level, fasting plasma glucose and HbA1c. Patients with AD had a mean Eczema Area and Severity Index score of 8.5±1.0 (moderate disease) and a mean AD duration of 28±3 years. During the OGTT, circulating glucose, insulin, C-peptide, glucagon and glucose-dependent insulinotropic polypeptide, respectively, were similar in the two groups, except glucagon-like peptide-1 which was higher in patients with AD. The clamp showed no differences in insulin sensitivity between groups (M-value 9.2 ± 0.6 vs. 9.8 ± 0.8, P=0.541, 95% CI -1.51;2.60), or circulating insulin, C-peptide and glucagon levels. Conclusions Using OGTT and the hyperinsulinemic euglycemic clamp technique, we found no difference in insulin sensitivity or other gluco-metabolic characteristics between patients with mild to moderate AD and matched healthy controls; suggesting that the inflammatory skin disease AD has little or no influence on glucose metabolism. ClinicalTrials.gov (NCT03003793) This article is protected by copyright. All rights reserved.
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gip 3 30 nh2 is a potent competitive antagonist of the gip receptor and effectively inhibits gip mediated insulin glucagon and somatostatin release
Biochemical Pharmacology, 2017Co-Authors: Alexander Hovard Sparreulrich, Jens J Holst, Berit Svendsen, Bolette Hartmann, Maria Buur Nordskov Gabe, Laerke S Gasbjerg, Charlotte B Christiansen, Mette M RosenkildeAbstract:Alternative processing of the precursor protein pro-GIP results in endogenously produced GIP(1-30)NH2, that by DPP-4 cleavage in vivo results in the metabolite GIP(3-30)NH2. We showed previously that GIP(3-30)NH2 is a high affinity antagonist of the human GIPR in vitro. Here we determine whether it is suitable for studies of GIP physiology in rats since effects of GIP agonists and antagonists are strictly species-dependent. Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation or assayed in competition binding using human 125I-GIP(1-42) as radioligand. In isolated perfused rat pancreata, insulin, glucagon, and somatostatin-releasing properties were evaluated. Competition binding demonstrated that on the rat GIP receptor (GIPR), rat GIP(3-30)NH2 bound with high affinity (Ki of 17nM), in contrast to human GIP(3-30)NH2 (Ki of 250nM). In cAMP studies, rat GIP(3-30)NH2 inhibited GIP(1-42)-induced rat GIPR activation and schild-plot analysis showed competitive antagonism with a pA2 of 13nM and a slope of 0.9±0.09. Alone, rat GIP(3-30)NH2 displayed weak, low-potent partial agonistic properties (EC50>1μM) with an efficacy of 9.4% at 0.32μM compared to GIP(1-42). In perfused rat pancreata, rat GIP(3-30)NH2 efficiently antagonized rat GIP(1-42)-induced insulin, somatostatin, and glucagon secretion. In summary, rat GIP(3-30)NH2 is a high affinity competitive GIPR antagonist and effectively antagonizes GIP-mediated G protein-signaling as well as Pancreatic Hormone release, while human GIP(3-30)NH2, despite a difference of only one amino acid between the two (arginine in position 18 in rat GIP(3-30)NH2; histidine in human), is unsuitable in the rat system. This underlines the importance of species differences in the GIP system, and the limitations of testing human peptides in rodent systems.
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the vgf derived neuropeptide tlqp 21 shows no impact on Hormone secretion in the isolated perfused rat pancreas
Hormone and Metabolic Research, 2015Co-Authors: Charlotte Bayer Christiansen, Berit Svendsen, Jens J HolstAbstract:TLQP-21 is a VGF-derived neuropeptide proposed to be involved in regulation of metabolism. More specifically it has been suggested that TLQP-21 has the ability to enhance glucose stimulated insulin secretion, making it a candidate for treatment of patients with type 2 diabetes. In this study, we investigated the impact of TLQP-21 on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. We found that administration of 5 and 50 nM TLQP-21 had no impact on Pancreatic Hormone secretion at 3.5 or 8 mM glucose levels. Increasing TLQP-21 (200 nM) and glucose concentration (3.5 and 16 mM) led to a nonsignificant decrease in glucagon secretion, though insulin and somatostatin secretory patterns remained unaffected. In a final set of experiments, perfusions were performed with infusion of 50 and 1 000 nM TLQP-21 to ensure sufficient stimulation. However, administration of TLQP-21 under this setup showed no impact on the Pancreatic Hormone secretion either. In conclusion, the outcome of this study does not concur with previous findings, suggesting that the effect of TLQP-21 does not directly involve silent Hormone secretion.
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cellular regulation of islet Hormone secretion by the incretin Hormone glucagon like peptide 1
Pflügers Archiv: European Journal of Physiology, 1998Co-Authors: Jesper Gromada, Jens J Holst, Patrik RorsmanAbstract:Glucagon-like peptide 1 is a gastrointestinally derived Hormone with profound effects on nutrient-induced Pancreatic Hormone release. GLP-1 modulates insulin, glucagon and somatostatin secretion by binding to guanine nucleotide binding protein-coupled receptors resulting in the activation of adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP). In the B-cell, cAMP, via activation of protein kinase A, interacts with a plethora of signal transduction processes including ion channel activity, intracellular Ca2+ handling and exocytosis of the insulin-containing granules. The stimulatory action of GLP-1 on insulin secretion, contrary to that of the currently used hypoglycaemic sulphonylureas, is glucose dependent and requires the presence of normal or elevated concentrations of the sugar. For this reason, GLP-1 attracts much interest as a possible novel principle for the treatment of human type-2 diabetes. Here we review the actions of GLP-1 on islet cell function and attempt to integrate current knowledge into a working model for the control of Pancreatic Hormone secretion.
Emmanuel E Baetge - One of the best experts on this subject based on the ideXlab platform.
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production of Pancreatic Hormone expressing endocrine cells from human embryonic stem cells
Nature Biotechnology, 2006Co-Authors: Kevin A Damour, Olivia G Kelly, Ala D Agulnick, Anne G Bang, Susan Eliazer, Nora G Smart, Mark A Moorman, Evert Kroon, Melissa K Carpenter, Emmanuel E BaetgeAbstract:Production of Pancreatic Hormone–expressing endocrine cells from human embryonic stem cells
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production of Pancreatic Hormone expressing endocrine cells from human embryonic stem cells
Nature Biotechnology, 2006Co-Authors: Kevin A Damour, Ala D Agulnick, Anne G Bang, Susan Eliazer, Olivia Kelly, Nora G Smart, Mark A Moorman, Evert Kroon, Melissa K Carpenter, Emmanuel E BaetgeAbstract:Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of Pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the Pancreatic Hormones insulin, glucagon, somatostatin, Pancreatic polypeptide and ghrelin. This process mimics in vivo Pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, Pancreatic endoderm and endocrine precursor--en route to cells that express endocrine Hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.
Gary F Lewis - One of the best experts on this subject based on the ideXlab platform.
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abstract 247 dipeptidyl peptidase 4 inhibition with sitagliptin acutely inhibits intestinal lipoprotein particle secretion in healthy humans
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Changting Xiao, Satya Dash, Cecilia Morgantini, Bruce W Patterson, Gary F LewisAbstract:Postprandial dyslipidemia, in part due to overproduction of triglyceride-rich lipoprotein (TRL) particles from the liver and the intestine, contributes to increased CVD risk. The DPP-4 inhibitor sitagliptin, an anti-diabetic agent, has been shown to reduce postprandial lipid excursion following a mixed meal. The underlying mechanism of this effect, however, has not been examined in humans. This study was designed to examine intestinal and hepatic TRL particle production and clearance in response to a single oral dose of sitagliptin. 15 lean, healthy male volunteers were studied in two occasions, 4-6 weeks apart, receiving sitagliptin (100 mg) or placebo in random order. Kinetics of TRL particles of intestinal and hepatic origin were measured using stable isotope tracer infusion techniques and with control of Pancreatic Hormone levels. Sitagliptin decreased TRL apoB-48 concentration (-32%, P
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sitagliptin a dpp 4 inhibitor acutely inhibits intestinal lipoprotein particle secretion in healthy humans
Diabetes, 2014Co-Authors: Changting Xiao, Satya Dash, Cecilia Morgantini, Bruce W Patterson, Gary F LewisAbstract:The dipeptidyl peptidase-4 inhibitor sitagliptin, an antidiabetic agent, which lowers blood glucose levels, also reduces postprandial lipid excursion after a mixed meal. The underlying mechanism of this effect, however, is not clear. This study examined the production and clearance of triglyceride-rich lipoprotein particles from the liver and intestine in healthy volunteers in response to a single oral dose of sitagliptin. Using stable isotope tracer techniques and with control of Pancreatic Hormone levels, the kinetics of lipoprotein particles of intestinal and hepatic origin were measured. Compared with placebo, sitagliptin decreased intestinal lipoprotein concentration by inhibiting particle production, independent of changes in Pancreatic Hormones, and circulating levels of glucose and free fatty acids. Fractional clearance of particles of both intestinal and hepatic origin, and production of particles of hepatic origin, were not affected. This pleiotropic effect of sitagliptin may explain the reduction in postprandial lipemia seen in clinical trials of this agent and may provide metabolic benefits beyond lowering of glucose levels.
