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1
Forsyth, Robert J. "The contribution of astrocyte glycogen to brain energy homeostasis." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361387.
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2
Burke, Luke Kennedy. "Neurocircuitry underlying serotonin's effects on energy and glucose homeostasis." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708592.
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3
Matthäus, Dörte. "The role of CADM1 in energy and glucose homeostasis." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16905.
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Mehr als 300 Millionen Menschen sind weltweit von Diabetes betroffen, die Mehrheit davon leidet an Typ-2-Diabetes. Typ-2-Diabetes ist durch eine Insulinresistenz charakterisiert, welche meistens durch Übergewicht und Adipositas verursacht wird. Diese Insulinresistenz kann zunächst durch eine erhöhte pankreatische Insulinsekretion kompensiert werden, jedoch können langfristig die pankreatischen beta-Zellen den erhöhten Insulinbedarf nicht mehr decken. Dies verursacht einen starken Anstieg der Blutglucosespiegel und stellt den Beginn der Typ-2-Diabetes Erkrankung dar. Neben genetischen Veränderungen sind Umweltfaktoren, wie erhöhte Nahrungsaufnahme und reduzierte Bewegung, wichtige Faktoren in der Pathogenese des Typ-2-Diabetes. Frühere Forschungsergebnisse zeigten eine wichtige Rolle von microRNA 375 (miR-375) im Wachstum und in der Funktion der Insulin produzierenden beta-Zellen. Die Genexpression von miR-375 ist in diabetischen Nagetieren und Menschen verändert, was auf eine wichtige Rolle dieser microRNA in der Pathogenese des Typ-2-Diabetes hindeutet. Gene, die durch miR-375 reguliert werden, wurden in den pankreatischen beta-Zellen beschrieben, jedoch ist der Mechanismus wie miR-375 das Wachstum und die Funktion der pankreatischen beta-Zellen beeinflusst noch nicht im Detail verstanden. Das Cell Adhesion Molecule 1 (CADM1) ist ein bekanntes Zielgen der miR-375 und vor allem im Gehirn als Regulator von Anzahl und Funktion der Synapsen bekannt. Da es außerdem in den pankreatischen beta Zellen exprimiert ist, könnte es auch dort an der Regulation von beta-Zellwachstum und –funktion beteiligt sein und die Glucose- und Energiehomöostase verändern. Ziel dieser Arbeit war es, in vollständig oder konditionell Cadm1-defizienten Mäusen den Einfluss von CADM1 in pankreatischen beta-Zellen und neuronalem Gewebe an der Regulation von Glucose- und Energiehomöostase zu untersuchen.<br>More than 300 million people world-wide are affected by diabetes, the majority suffering from type 2 diabetes. Type 2 diabetes is characterized by insulin resistance, usually caused by obesity and overweight. Enhanced pancreatic insulin secretion largely compensates insulin resistance for years. A failure of pancreatic beta-cells to meet increased insulin demands drastically increases blood glucose levels and marks the onset of type 2 diabetes. Besides environmental influences, mainly elevated food intake and reduced physical activity, also genetic mutations are important factors in the pathophysiology of type 2 diabetes. Recent literature highlights the role of microRNA 375 (miR-375) in the growth and function of pancreatic insulin-producing beta-cells. MiR-375 gene expression is regulated in diabetic humans and rodents, suggesting that this microRNA is involved in the pathogenesis of type 2 diabetes. Genes regulated by miR-375 have been described in pancreatic beta-cells. Nevertheless, the exact mechanisms how miR-375 regulates beta-cell growth and insulin secretion have not been understood. Cell adhesion molecule 1 (CADM1) is a known target of miR-375 and has mainly been described as regulator of synapse number and synaptic function in the brain. CADM1 is also expressed in pancreatic beta-cells and might regulate beta-cell growth and function and might be involved in the control of glucose and energy homeostasis. The aim of this work was to investigate whether CADM1 in pancreatic beta-cells or neuronal tissue contributes to the regulation of energy and glucose homeostasis by using total and conditional Cadm1 deficient mice. Total Cadm1 deficient (Cadm1KO) mice showed increased sensitivity to glucose and insulin as well as enhanced glucose-stimulated insulin secretion compared to littermate control mice. Elevated glucose-stimulated insulin secretion after Cadm1 depletion could be confirmed in an in vitro beta-cell model.
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Wang, Xun. "IRF3 is a Critical Regulator of Adipose Glucose and Energy Homeostasis." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10537.
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Obesity is associated with a state of chronic inflammation, which is believed to contribute to insulin resistance. We previously identified interferon regulatory factor 3 (IRF3) as an anti-adipogenic transcription factor with high expression in adipocytes. Because IRF3 is known to drive expression of pro-inflammatory genes in immune cells, we hypothesized that it may also promote inflammation and insulin resistance in adipocytes. Consistent with our expectations, we found that the expression of inflammatory genes in adipocytes was induced by IRF3 overexpression, while knockdown of IRF3 had the opposite effect. Despite this effect on local adipocyte gene expression, we found that \(Irf3^{-/-}\) mice did not show evidence of altered systemic inflammation. Nonetheless, \(Irf3^{-/-}\) mice did display altered metabolism relative to their wild type (WT) littermates. For example, high fat diet (HFD) fed \(Irf3^{-/-}\) mice exhibited increased lean mass and decreased fat mass compared to WT, accompanied by increased food intake and energy expenditure. Further investigation showed that the white adipose tissue (WAT) of \(Irf3^{-/-}\) mice had increased expression of brown adipocyte selective genes compared to WT, and the inguinal WAT of the \(Irf3^{-/-}\) mouse contain multilocular adipocytes that resemble brown adipocytes. These data suggest that IRF3 affects energy homeostasis by regulating the development of brown adipocyte-like cells in WAT. Additionally, \(Irf3^{-/-}\) mice are significantly more insulin sensitive and glucose tolerant compared to WT when kept on HFD. Consistent with in vivo observations, IRF3 knockdown in 3T3-L1 adipocytes resulted in enhanced insulin-stimulated glucose uptake and lipogenesis, while overexpression of constitutively active IRF3 had the opposite effect. Several IRF3 target genes in adipocytes were identified using transcriptional profiling. Interestingly, the expression level of Slc2a4 (encoding the Glut4 protein) was inversely correlated with that of IRF3 in both WAT and cultured adipocytes. Analysis of the Slc2a4 proximal promoter identified a putative IRF3 binding site upstream of the transcription start site, and luciferase assay in 3T3-L1 adipocytes showed that IRF3 negatively regulates Slc2a4 expression via this site. Taken together, these data indicate that IRF3 plays a role in whole body glucose homeostasis by repressing thermogenic gene expression as well as the expression of adipose Glut4.
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Hall, Jessica Ann. "Thyroid Hormone and Insulin Metabolic Actions on Energy and Glucose Homeostasis." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11663.
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Faced with an environment of constantly changing nutrient availability, mammals have adapted complex homeostatic mechanisms to maintain energy balance. Deviations from this balance are largely corrected through a concerted, multi-organ effort that integrates hormonal signals with transcriptional regulatory networks. When these relationships are altered, as with over-nutrition and insulin resistance, metabolic disease ensues. Here, I present data concerning two distinct transcriptional pathways--one for thyroid hormone (TH) and one for insulin--that confer hormone responsiveness on metabolic gene programs that preserve energy homeostasis.
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Rahman, S. A. "Investigating the role of gut hormones in energy and glucose homeostasis." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1417078/.
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Obesity is associated with type-2 diabetes mellitus. Gut hormones are peptides secreted in response to nutrient intake that act to regulate food intake, energy and glucose homeostasis. Thus, alterations in gut hormone abundance and/or signalling can contribute to the development of the obese and T2DM phenotype. The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic hormone augment glucose-mediated insulin secretion. Peptide YY is released from the gut post-prandially and acts primarily as a satiety signal. Recently studies have highlighted a role for PYY in regulating glucose homeostasis, which to date remains partially understood. Dipeptidyl peptidase-4 is involved in the biological inactivation of the incretins hence; DPP-4 inhibition is used to treat T2DM. DPP-4 also regulates PYY. Thus, DPP-4 inhibition may potentially impact on pancreatic PYY function and signalling and may alter the effects of the PYY system on glucose homeostasis. In addition, gut peptides have been identified as possible contributors to cases of hyperinsulinaemic-hypoglycaemia resulting from bariatric surgery. Therefore, this thesis aimed to (1) determine the contribution of pancreatic PYY deletion to the intra-islet PYY system; glucose homeostasis and body weight phenotype and (2) establish the impact of hyperinsulinism on DPP-4 and its gut hormone substrates. To address the first point, pancreatic-specific Pyy null mice were phenotyped for changes in the pancreatic endocrine system, followed by body weight and glucose metabolism, in vivo. Further investigations measuring gut hormone mRNA suggested the intra-islet system was contributing to the observed reduction in weight gain and hyperinsulinaemia. Finally, patients with congenital forms of HI were evaluated for PYY, the incretins and DPP-4. This study highlighted a role for DPP-4, PYY and GIP in mediating HI. In conclusion, this thesis demonstrates a role for gut hormones in energy and glucose homeostasis. Further work is required to understand the interaction of gut peptides on islet function.
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Stump, Madeliene. "The role of brain PPAR[gamma] in regulation of energy balance and glucose homeostasis." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/6000.
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The Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a master regulator of adipogenesis, has been shown to influence energy balance through its actions in the brain rather than in the adipose tissue alone. Deletion of PPARγ in mouse brain results in resistance to weight gain in response to high fat diet. Activation of PPARγ leads to change in the firing pattern of melanocortin system neurons (POMC and AgRP), which are critical for energy homeostasis. To determine the effects of modulation of brain PPARγ on food intake and energy expenditure we generated a novel transgenic mouse model in which a dominant-negative (DN) mutant form of PPARγ (P467L) or a wild type (WT) form that is conditionally expressed in either the entire central nervous system (CNS) or specifically in POMC or AgRP neurons. Interference with brain PPARγ results in impaired insulin and glucose regulation. This in turn has significant implications in altering the growth rate and metabolic homeostasis. In light of the well-established role of PPARγ in regulating insulin sensitivity, this is the first report implicating brain PPARγ in controlling peripheral insulin levels. Overexpression of the WT PPARγ in the CNS leads to failure to thrive and early death due to microcephaly and severe distortion of brain architecture with notable agenesis of the corpus callosum. Our results show that the levels of PPARγ in the brain are tightly regulated and perturbations leading to “too much” or “too little” functional PPARγ result in major shifts in structural organization of the brain or metabolic balance.
The herein presented data show that chronic interference with the function of neuronal PPARγ affects energy balance only under certain dietary conditions and through specific neuronal populations. We show that POMC, but not AgRP neurons, are particularly sensitive to modulation of PPARγ activity. These observations give support to the notion that cellular adaptations in POMC neurons, driven by PPARγ, represent critical components in the regulation of metabolic homeostasis.
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Aatsinki, S. M. (Sanna-Mari). "Regulation of hepatic glucose homeostasis and Cytochrome P450 enzymes by energy-sensing coactivator PGC-1α". Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526208053.
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Abstract Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of energy metabolism and mitochondrial biology in high-energy cell types and tissues. The regulation of PGC-1α is versatile, and both transcriptional and post-transcriptional mechanisms play major roles. External stimuli affect PGC-1α-regulation which in turn adapts cellular signals to meet them. For example, conditions like fasting and diabetes mellitus (DM) are known to activate PGC-1α expression in the liver, resulting in enhanced de novo glucose production, gluconeogenesis. In the present study, the mechanisms of hepatic PGC-1α regulation and PGC-1α-regulated functions were elucidated. We found that PGC-1α was induced by oral type 2 diabetes therapeutic metformin, via AMPK and SIRT1, regulating the mitochondrial gene response, against previous assumptions. Simultaneously, gluconeogenesis was repressed by other means. Furthermore, PGC-1α upregulated the anti-inflammatory interleukin 1 receptor antagonist (IL1Rn). PGC-1α also diminished interleukin 1β-mediated inflammatory response in hepatocytes. Novel, xenobiotic and endobiotic metabolizing Cytochrome P450 enzymes regulated by PGC-1α were also identified in this thesis. CYP2A5 was induced by PGC-1α through hepatocyte nuclear factor 4α (HNF-4α) coactivation. Also, vitamin D metabolizing CYP2R1 and CYP24A1 were identified as novel genes regulated by PGC-1α, suggesting a role for PGC-1α in the regulation of active vitamin D levels. The findings presented in this thesis provide insight into the pathology of glucose perturbations such as type 2 diabetes, and stimulate discovery of therapeutic agents to treat this disease. Furthermore, the findings suggest that vitamin D metabolism and energy metabolism are tightly linked, with PGC-1α emerging as a novel mediator<br>Tiivistelmä Peroksisomiproliferaattori-aktivoituvan reseptori γ:n koaktivaattori 1α (PGC-1α) on merkittävä glukoosiaineenvaihdunnan ja mitokondrioiden toiminnan säätelijä korkeaenergisissä soluissa ja kudoksissa. PGC-1α:a säädellään monin tavoin: sekä transkriptionaalisella säätelyllä että transkription jälkeisellä muokkauksella on merkittävä rooli. Monet ulkoiset tekijät säätelevät PGC-1α:n aktiivisuutta, joka puolestaan säätelee solunsisäisiä signaalireittejä vastaamaan tähän signaaliin. Esimerkiksi paasto ja diabetes mellitus (DM) ovat fysiologisia tiloja, jotka lisäävät voimakkaasti PGC-1α:n ilmentymistä maksassa, jolloin glukoosin uudistuotanto eli glukoneogeneesi kiihtyy. Tässä väitöskirjassa tutkittiin PGC-1α:n säätelyä sekä PGC-1α -säädeltyjä signaalireittejä maksassa. Osoitimme, että tyypin 2 diabeteslääke metformiini indusoi PGC-1α:n ilmentymistä maksassa, vastoin aikaisempia käsityksiä. PGC-1α indusoitui AMPK:n ja SIRT1:n välityksellä, säädelleen edelleen mitokondriaalisten geenien aktiivisuutta. Samalla glukoneogeneesi kuitenkin repressoitui muilla mekanismeilla. Lisäksi osoitimme, että PGC-1α indusoi tulehdusreaktiota vaimentavaa interleukiini 1 reseptorin antagonistia (IL1Rn). PGC-1α esti interleukiini 1β:n aiheuttamaa tulehdusvastetta hepatosyyteissä. Lisäksi väitöskirjassa tunnistettiin uusia, PGC-1α -säädeltyjä lääkeaineita ja elimistön sisäisiä yhdisteitä metaboloivia sytokromi P450 -entsyymejä (CYP). Hiiren CYP2A5:n ilmentymisen osoitettiin olevan PGC-1α- ja HNF4α-välitteistä. Lisäksi osoitettiin, että D-vitamiinia metaboloivat CYP2R1 ja CYP24A1 ovat uusia PGC-1α -säädeltyjä geenejä. Tämä löydös viittaa siihen, että PGC-1α:lla on rooli aktiivisen D-vitamiinin säätelyssä. Tämän väitöskirjan löydökset lisäävät tietoa glukoosiaineenvaihdunnan häiriöiden kuten tyypin 2 diabeteksen molekulaarisista mekanismeista, joita voidaan hyödyntää mahdollisten uusien lääkeaineiden kehittämisessä. Lisäksi väitöskirjassa osoitettiin, että D-vitamiinimetabolia on kytköksissä energia-aineenvaihduntaan ja että PGC-1α:lla on tässä rooli, jota ei aiemmin ole tunnettu
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Eftychidis, Vasileios. "Elucidating the principal role of cholecystokinin neurons of the ventromedial hypothalamic nucleus in energy homeostasis." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:906a0aa6-847a-43b8-a527-458252aca825.
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The central nervous system (CNS) has a crucial role in the maintenance of energy homeostasis by orchestrating a plethora of signals from peripheral organs about the state of energy stores and the current energy intake needed to match energy expenditure. These signals converge into the hypothalamic regions and its complex local circuitry. CNS-derived cholecystokinin (CCK) is acting at central level to modulate energy balance by regulating the neuronal activity of hypothalamic neuronal populations that regulate food intake, energy storage and consumption. Moreover, our recent published work identifies CCK neurons as key integrators of the neuroendocrine negative feedback of glucocorticoids to the PVN. Glucose sensing neurons of the Ventromedial Hypothalamus (VMH) are integrating energy signals and are essential for mounting a counter-regulatory response and glucose homeostasis. VMH is also important in energy expenditure by regulating body weight and thermogenesis. CCK neurons are present in high density in the VMH.The source of endogenous CCK that acts on distinct neuronal components has not been elucidated. The research so far does not address the purpose of CCK neurons in the hypothalamus and their potential role in the network dynamics regarding energy homeostasis. In this study, we untangle the role of CCK neurons in the VMH nucleus by employing stereotactic intracranial delivery of adeno-associated viruses that result in cell-type specific chemogenetic inhibition or ablation of these neurons. Acute silencing of their neurotransmission with the cre-dependent AAV expression of the chemogenetic tool of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) increases their daily food intake due to increased meal numbers and eating frequency without meal size or meal duration being affected. CCK ablation by a newly generated double-recombinase-mediated Diphtheria Toxin Receptor (DTR) mouse line or AAV-DTA-mediated ablation resulted in hyperphagia, obesity and hyperglycaemia. We conclude that CCK<sup>VMH</sup> neurons are implicated in the regulation of food intake, body weight and glucose homeostasis in the adult brain.
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Birkenfeld, Andreas L. [Verfasser]. "The role of natriuretic peptides in the regulation of energy metabolism, lipid- and glucose homeostasis / Andreas L. Birkenfeld." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1035182424/34.
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Meyer, Cornelius [Verfasser], and Rey Adriana [Akademischer Betreuer] del. "Effects of interleukin-1 on glucose uptake and energy homeostasis in lymphocytes / Cornelius Meyer ; Betreuer: Adriana del Rey." Marburg : Philipps-Universität Marburg, 2020. http://d-nb.info/1224046765/34.
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Matthäus, Dörte [Verfasser], Thomas [Akademischer Betreuer] Sommer, Mathias [Akademischer Betreuer] Treier, and Susanne [Akademischer Betreuer] Klaus. "The role of CADM1 in energy and glucose homeostasis / Dörte Matthäus. Gutachter: Thomas Sommer ; Mathias Treier ; Susanne Klaus." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://d-nb.info/104785273X/34.
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13
Weigt, Carmen. "Impact of estradiol, estrogen receptor subtype-selective agonists and genistein on energy homeostasis." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-127919.
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The prevalence of obesity is dramatically increasing and thus constitutes a major risk factor for developing chronic diseases such as type 2 diabetes, dyslipidemia, cardiovascular diseases, and certain forms of cancer. High-caloric nutrition and a lack of physical activity are the main contributing factors for this global epidemic. Estrogen receptors (ERs) are recognized to be involved in many processes related to the control of energy homeostasis. In my studies, I investigated the impact of estrogens (17beta-estradiol (E2)) on energy homeostasis. Special emphasis was given to the effects of two synthetic ER subtype-selective agonists, 16alpha-LE2 (Alpha) and 8beta-VE2 (Beta), to determine to what extend the two distinct ER subtypes are involved in the underlying molecular mechanisms. Because of its estrogenic activity and also its widespread use as a nutritional supplement the influence of the isoflavone genistein (Gen) was examined. For this purpose two different female rat models were used: Wistar rats with nutrition-induced obesity and leptin resistant Zucker diabetic fatty (ZDF) rats. In both experiments, the animals were ovariectomized (OVX) and treated with vehicle (untreated controls) or the estrogenic compounds. The most important finding was that treatment of OVX animals with Beta enlarges soleus muscle fiber sizes in both animal models compared to untreated OVX animals. This anabolic effect may in turn improve the muscle/fat ratio of the body that enhances muscular uptake and utilization of fuels. By contrast, in the gastrocnemius muscle of OVX ZDF rats substitution with Alpha increased expression and distribution of the insulin-dependent glucose transporter 4 (GLUT4). Consequently, systemic insulin sensitivity in both animal models was improved by treatment with estrogenic compounds compared to untreated OVX animals. The strongest effect was observed in E2-treated rats that indicate an additive effect through activation of both pathways. In all OVX rats, treatment with either ER subtype-selective agonist showed an anti-lipogenic effect in adipose tissue, liver, and skeletal muscle of nutrition-induced obese Wistar rats in comparison to OVX animals without treatment. Decreased visceral fat mass, adipocyte sizes, serum leptin levels, triglyceride accumulation in liver and muscle as well as mRNA expression of genes that are involved in lipo-/adipogenesis reflected this. Therefore, the lower visceral fat mass as well as decreased accumulation of triglycerides in non-adipose tissues such as liver and skeletal muscle most likely contributes to the improved insulin sensitivity in such treated animals. Gen exerted effects similar to those of the ER beta-selective agonist (except on adipose tissue in Wistar rats). Especially, the similar ability to induce anabolic activity in the soleus muscle might be highly relevant. Gen-treated animals might have a more effective utilization of fuels compared to untreated OVX animals because they showed a lower TG content in muscle and liver as well as improved glucose metabolism. In conclusion, because of my studies and the fact that ER beta signaling is not involved in proliferation of uterus and mammary gland, an effective way to treat obesity and co-morbidities in postmenopausal women might be substances that only activate ER beta. A combination with physical activity may support the therapy of obesity and co-morbidities. The isoflavone Gen is able to activate both ER-subtypes. This compound is already placed on the market for treatment of postmenopausal complaints, although adverse effects of Gen cannot be excluded so far (e.g., increased risk of breast cancer). However, Gen might be a natural alternative – not only to the conventional hormone replacement therapy, but also as a strategy for treatment of obesity and co-morbidities – that deserves further research with respect to these new data<br>Die dramatisch zunehmende Prävalenz der Adipositas und das damit verbundene Risiko für Folgeerkrankungen wie Diabetes mellitus, Hypertonie, Dyslipidämie und koronare Herzkrankheiten stellt eine große Herausforderung für das Gesundheitswesen dar. Als Hauptursache wird ein chronisches Missverhältnis der Energiehomöostase aufgrund permanenter Überernährung und Bewegungsmangel postuliert. Estrogene beeinflussen den Glukose- und Lipidstoffwechsel und sind somit in die Regulation des Energiehaushaltes involviert. Estrogene vermitteln ihre Effekte über zwei Estrogenrezeptor (ER)-Subtypen, den ER alpha und den ER beta. Ziel der vorliegenden Arbeit war es mittels tierexperimentellen Studien den Einfluss von Estrogenen, speziell 17beta-Estradiol, auf den Energiehaushalt zu untersuchen. Um einen tieferen Einblick in die zugrundeliegenden molekularen Mechanismen zu erhalten, wurden zwei Subtyp-selektive ER-Agonisten, 16alpha-LE2 (Alpha) and 8beta-VE2 (Beta), synthetischer Herkunft eingesetzt. Aufgrund der estrogenen Aktivität und der Verfügbarkeit als Nahrungsergänzungsmittel wurde des Weiteren der Einfluss des Isoflavons Genistein untersucht. Für die Studien wurden zwei Tiermodelle genutzt: zum einen weibliche Wistar-Ratten mit ernährungsinduzierter Adipositas und zum anderen weibliche leptinresistente „Zucker diabetic fatty“ (ZDF)-Ratten. Die Tiere wurden ovarektomiert (OVX) und entweder mit einem Vehikel (unbehandelte Kontrolltiere) oder mit der entsprechenden estrogenen Substanz behandelt. Die interessanteste Erkenntnis war, dass im Vergleich zu unbehandelten OVX-Tieren beider Tiermodelle die Behandlung mit Beta zur Vergrößerung der Faserquerschnitte im Soleusmuskel führte. Dieser anabole Effekt könnte die muskuläre Aufnahme und Verwertung von Brennstoffmolekülen verbessern und sich insgesamt positiv auf die Körperzusammensetzung auswirken. Den stärksten Effekt hinsichtlich einer erhöhten Expression und Translokation des insulinabhängigen Glukosetransporters 4 (GLUT4) in die Zellmembran des Gastrocnemiusmuskels zeigte sich dagegen durch die Behandlung von OVX ZDF-Ratten mit Alpha. Im Endergebnis zeigten die Tiere beider Modelle durch die Behandlung mit estrogenen Substanzen eine verbesserte systemische Insulinsensitivität im Vergleich zu unbehandelten Kontrolltieren. E2-behandelte Tiere tolerierten die Glukose am besten und lassen einen additiven Effekt aufgrund der Aktivierung beider Signalwege vermuten. Im Vergleich zu unbehandelten OVX Wistar-Ratten führte die Behandlung mit E2 oder mit jeweils einem der beiden ER-Subtyp-selektiven Agonisten zu einer geringeren viszeralen Fettmasse, kleineren Fettzellen, niedrigeren Leptinspiegeln im Serum und geringeren Triglyzeridwerten in Leber und Muskel. Auf der Ebene der Genexpression waren zudem geringere mRNA-Spiegel von lipo- und adipogenen Genen messbar. Somit scheinen beide ER-Subtypen in die antilipogene Wirkung von E2 involviert zu sein. Sowohl die reduzierte viszerale Fettmasse als auch die geringere Anreicherung von Triglyzeriden in Leber und Muskel tragen sehr wahrscheinlich ebenfalls zur verbesserten Insulinsensitivität bei. Die Behandlung von OVX Tieren mit Gen führte zu ähnlichen Ergebnissen wie die Behandlung mit Beta. Eine alleinige Ausnahme stellte das Fettgewebe dar, da hier eine Gen-Behandlung keine antilipogenen/-adipogenen Effekte zeigte. Speziell die Fähigkeit von Gen ebenfalls anabol zu wirken, könnte die molekulare Grundlage sein, weshalb Gen-behandelte Tiere im Vergleich zu unbehandelten Tiere eine verbesserte Toleranz gegenüber Glukose und eine geringere Anreicherung von Triglyzeriden in Muskel und Leber zeigten. Der ER beta ist nicht in die estrogenvermittelte Proliferation von Uterus und Brustdrüse involviert. Vor diesem Hintergrund lassen meine Ergebnisse vermuten, dass eine Behandlung mit ER beta-selektiven Substanzen eine effektive Möglichkeit darstellt, um Adipositas und deren Folgeerkrankungen in postmenopausalen Frauen zu behandeln, ohne deren Risiko für estrogenabhängige Krebsformen zu erhöhen. Eine Kombination mit regelmäßiger körperlicher Aktivität könnte die Erfolge bei der Behandlung von Adipositas und deren Folgeerkrankungen noch maximieren bzw. eine geringere Dosierung der verwendeten Substanz bei gleichbleibendem Behandlungserfolg ermöglichen. Das Isoflavon Gen mit seiner Fähigkeit beide ERs zu aktivieren ist eine bereits auf dem Markt befindliche Substanz und wird zur Behandlung von postmenopausalen Beschwerden eingesetzt, obwohl mögliche negative Effekte (z.B. ein erhöhtes Brustkrebsrisiko) noch nicht abschließend geklärt sind. Falls diese Risiken von Gen ausgeräumt werden können, könnte diese Substanz eventuell eine kostengünstige Alternative darstellen, um sowohl postmenopausale Beschwerden als auch Adipositas und deren Folgekrankheiten zu behandeln
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Hillier, Sarah Elizabeth. "The effects of fluctuations in oestrogen and progesterone during the menstrual cycle on glucose homeostasis, energy balance, exercise and premenstrual syndrome." Thesis, Oxford Brookes University, 2014. https://radar.brookes.ac.uk/radar/items/95a77132-ec7c-487b-8dde-11f3b7f57b2f/1/.
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It is widely accepted that the loss of sex hormones after the menopause is strongly linked with cancer, insulin resistance and obesity, with variations in sex hormone concentrations being responsible in part, for the differences reported in energy metabolism and glycaemic control between genders. As such a greater understanding of the effects that oestrogen and progesterone may have on women's health and their potential long term consequences is required. This thesis reports evidence of three studies investigating the effects of oestrogen and progesterone during the menstrual cycle on glucose and insulin response, energy expenditure, substrate oxidation and premenstrual syndrome (PMS). The aim of the first study was to investigate glucose and insulin responses to a 75g glucose load during different phases of the menstrual cycle. Venous blood samples for baseline measurements of oestradiol and progesterone were collected every other week day from eighteen regularly menstruating women for one complete menstrul cycle. An oral glucose tolerance test (OGIT, 75g glucose) was performed on three separate days during the next complete menstrual cycle. The results report an increase in glucose area under the curve (AUC) and insulin AUC during the luteal phase (P < 0.05) compared to the menstrual and follicular phase, but no significant differences in insulin sensitivity between phases. The findings indicate that both oestrogen and progesterone during the luteal phase may affect glycaemic response and this potentially has significant implications for the development of type 2 diabetes over prolonged periods of time. The second study investigated energy expenditure and substrate oxidation at rest and during a 30 minute moderate intensity walking exercise within the three phases of the menstrual cycle. Sex hormone concentrations were collected in the same manner as study 1. Nineteen women undertook resting measures and ten for exercise. The study reports a decrease in carbohydrate (CHO) oxidation (P < 0.05) and a marginal increase in fat oxidation (P=0.06) during the follicular phase at rest, with no difference in energy expenditure at rest. No difference in energy expenditure or substrate oxidation between phases was reported during exercise. The results indicate high oestrogen concentrations during the follicular phase only may mediate the changes in substrate oxidation response reported at rest. I The final study investigated the effects of a 12 week moderate intensity exercise intervention on symptoms of PMS, quality of life and dietary intake and determined whether any such effect was associated with changes in oestrogen and progesterone concentrations in a randomised control trial. Twenty-five sedentary women, identified as suffering from PMS symptoms, were recruited to the trial spanning four menstrual cycles, the first serving as a baseline followed by three cycles of intervention. Participants were randomly assigned to either an exercise (EX) group (n= l 3), which involved three supervised 30-minute moderate intensity (70-80% HR max) treadmill walking exercise sessions per week, or to a control (CON) group (n=12), which involved attending a 90-minute, one-to-one meeting once per week with the investigator. The results report a reduction in PMS symptoms following the exercise intervention (P < 0.05), with no differences in the control (CON) group. Averaged dietary intake over the three intervention cycles reports a decrease in CHO intake (% total energy intake, TEI) during the luteal phase, compared to the menstrual (45.5% vs. 50. l%) and follicular (45.5 vs. 49.9%) phases in the EX group, with no difference in the CON group. No significant difference was reported in overall energy intake in either group. In addition, no significant difference was reported in plasma oestrogen and progesterone concentrations over the four cycles in either group (EX and CON). The findings indicate that the exercise regime reduces PMS symptoms and CHO intake (%TEI), but that these are not mediated in response to changes in oestrogen and progesterone hormone concentrations. As such exercise may therefore be an effective symptom management tool for women suffering with PMS. Further studies are essential to determine the exact duration and intensity required for the most effective symptom relief. The results reported in this thesis provide evidence that the circulating reproductive hormones oestrogen and progesterone during the menstrual cycle have significant implications for energy regulation, glycaemic control and women suffering from PMS. As such, both hormones need to be investigated further in larger research studies to determine their potential long-term adverse effects on health and well-being in women.
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Qian, Yanrong. "Internalization of Extracellular ATP in Cancer Cells and Development of New Generations of Anticancer Glucose Transport Inhibitors." Ohio University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1416411921.
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Troke, Rachel Clare. "A medical bypass : can the manipulation of gut hormone levels replicate the favourable effects on energy and glucose homeostasis seen following gastric bypass surgery?" Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/47922.
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The obesity crisis has reached epidemic proportions. Medical therapies are few and far between, offering only modest benefit, with maximal weight loss at one year in the region of 5-6%. Gastric bypass surgery and specifically Roux-en-Y gastric bypass (RYGB) is the only obesity treatment which has shown a marked and sustained weight loss, with initial remission of diabetes in up to 75% of patients. An increase in the post-prandial secretion of satiety gut hormones glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and oxyntomodulin (OXM) following gastric bypass may mediate these favourable effects. GLP-1 promotes insulin secretion in response to an oral glucose load. PYY also increases insulin sensitivity in rodents, and OXM increases energy expenditure (EE). All three hormones increase satiety. Work in this thesis investigates the contributions of these hormones both alone and in combination on the favourable effects on food intake, body weight, and glycaemic control following gastric bypass surgery. Acute co-infusion of GLP-1 and glucagon (as a surrogate for OXM) as well as glucagon alone increased EE by around 150Kcal per day, an effect that was mediated via the glucagon receptor. GLP-1 did not increase EE but was able to partially counter the hyperglycaemia induced by high doses of glucagon. Acute co-infusion of GLP-1 and glucagon at subanorectic doses reduced food intake by 13% compared to placebo, with no effect seen following administration of either peptide alone. GLP-1 neutralised the hyperglycaemic effect of glucagon at these subanorectic doses. Acute infusion of GLP-1 and PYY(3-36) alone and in combination demonstrated that GLP-1 augments the acute insulin response to glucose (AIRg) as assessed by an intravenous glucose tolerance test. PYY did not modify the AIRg, and neither hormone alone or in combination had any effect on insulin sensitivity or glucose disposal. Chronic administration of long acting analogues of GLP-1, PYY and OXM in combination to diet induced obese (DIO) mice resulted in a marked and sustained reduction in body weight of approximately 16% compared to placebo. This was independent of a reduction in food intake suggesting an increase in EE, possibly mediated via fibroblast growth factor-21. In addition, the combination of analogues improved glucose tolerance compared to placebo. These results suggest that a combination of the gut hormones GLP-1, PYY and OXM, or analogues thereof, offers potential as a novel obesity therapy and may be able to mimic the beneficial metabolic effects seen after gastric bypass.
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Chretien, Chloé. "Un nouvel acteur dans la détection hypothalamique du glucose : les canaux Transient Receptor Potential Canonical (TRPC)." Thesis, Dijon, 2015. http://www.theses.fr/2015DIJOS027/document.
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L’hyperglycémie est détectée et intégrée au niveau de l’hypothalamus médio-basal (MBH) qui inhibe la prise alimentaire et déclenche la sécrétion d’insuline. Le MBH renferme des neurones spécialisés gluco-sensibles (GS) qui détectent directement ou indirectement des variations de la concentration extracellulaire en glucose. Dans une première étude, nous suggérons que la détection indirecte du glucose par les neurones GS hypothalamiques repose sur la libération d’endozépines par les astrocytes, un gliotransmetteur connu pour inhiber la prise alimentaire en réponse à l’hyperglycémie. Nous travaux montrent que les endozépines activent spécifiquement les neurones à pro-opiomélanocortine (POMC) du MBH pour générer leur effet anorexigène. Dans une seconde étude, nous montrons que la détection directe de l’hyperglycémie implique les neurones hypothalamiques dits « high gluco-excited » (HGE). Grâce à des approches pharmacologiques et génétiques, nous mettons en évidence que les canaux redox sensibles Transient Receptor Potential Canonical 3 et 4 (TRPC3/4) sont fondamentaux pour la détection du glucose par les neurones HGE in vitro, la stimulation de la sécrétion d’insuline et la diminution de la prise alimentaire en réponse à l’hyperglycémie cérébrale in vivo. De plus, nos travaux démontrent que les canaux TRPC3 du MBH jouent un rôle clef dans le contrôle de l’homéostasie énergétique. Les travaux de cette thèse permettent de mettre en évidence deux nouveaux mécanismes de détection hypothalamique de l’hyperglycémie : l’un reposant sur l’implication des canaux TRPC3/4 dans les neurones HGE et l’autre proposant les endozépines astrocytaires comme relai du signal « glucose » aux neurones POMC<br>Hyperglycemia is detected and integrated by the mediobasal hypothalamus (MBH) which, in turn, inhibits food intake and triggers insulin secretion. The MBH houses specialized glucose-sensitive (GS) neurons, which directly or indirectly modulate their electrical activity in response to changes in glucose level. In a first study, we hypothesized that indirect detection of glucose by MBH GS neurons involves the secretion of endozepine by astrocytes, a gliotransmitter known to inhibit food intake in response to hyperglycemia. The present work shows that endozepines selectively activate anorexigenic MBH pro-opiomelanotortine (POMC) neurons. In the second study, we show that the direct detection of increased glucose level involves hypothalamic glucose-excited (HGE) neurons. Using pharmacological and genetic approaches, we demonstrate that the redox-sensitive Transient Receptor Potential Canonical 3 et 4 (TRPC3/4) channels are involved in MBH HGE response to glucose in vitro and increased insulin secretion and decreased food intake in response to cerebral hyperglycemia in vivo. We also obtained evidences that MBH TRPC3 channel is a critical new player for energy homeostasis. This thesis work identifies two new mechanisms involved in hypothalamic detection of hyperglycemia: the first based on the involvement of TRPC3/4 channels in HGE neurons and the second highlighting the astroglial endozepines as a relay of the “glucose” signal to POMC neurons
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Desmoulins, Lucie. "Détection hypothalamique du glucose chez le rat soumis à un régime gras enrichi en saccharose : rôle de la dynamique mitochondriale et des espèces actives de l'oxygène d'origine mitochondriale." Thesis, Dijon, 2016. http://www.theses.fr/2016DIJOS024/document.
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L’hypothalamus participe au contrôle de l’homéostasie énergétique en détectant les signaux circulants tels que le glucose. L’hypothalamus médiobasal (MBH) en particulier, est capable de détecter l’hyperglycémie afin d’initier des réponses physiologiques adaptées, comme par exemple la sécrétion d’insuline via le système nerveux autonome (par un contrôle vagal). Notre équipe a récemment montré que la détection du glucose nécessite la production d’espèces actives de l’oxygène d’origine mitochondriale (mROS), fortement dépendante de la dynamique mitochondriale (fusion et fission). Récemment, l’étude de modèles génétiques ont permis de faire un lien entre ces évènements dynamiques dans le MBH et le développement de pathologies métaboliques. L’objectif de ma thèse a été tout d’abord été de mettre en place un modèle expérimental présentant uniquement une altération de la détection hypothalamique du glucose induite par l’exposition à un régime gras enrichi en saccharose (HFHS) chez le rat. Après avoir caractérisé ce modèle, nos objectifs ont été de déterminer si l’exposition à ce régime hypercalorique avait un impact sur la dynamique mitochondriale ainsi que la signalisation mROS, via la fonction respiratoire de la mitochondrie dans l’hypothalamus. Nous avons finallement réversé quelques acteurs métaboliques dérégulés, potentiellement impliqués dans la dynamique mitochondriale, dans le but de réverser le phénotype observé chez les rats HFHS. Nos résultats montrent qu’après 3 semaines d’exposition au régime HFHS, les rats ont un poids corporel normal malgré l’augmentation de leur masse grasse, comparés aux rats contrôles. Les rats HFHS présentent aussi une intolérance au glucose et une augmentation de la glycémie basale sans modification de leur insulinémie. La sécrétion d’insuline en réponse à la détection hypothalamique du glucose, mesurée après une injection intra-carotidienne de glucose en direction du cerveau qui induit une hyperglycémie uniquement cérébrale, a été fortement diminuée. Cependant, la capacité sécrétoire des îlots pancréatiques est normale chez les rats HFHS. Ces défauts sont associés à une diminution de la production de ROS dans le MBH en réponse au glucose, sans modification du status redox. L’efficacité de la respiration mitochondriale hypothalamique a été mesurée par oxygraphie, et les résultats montrent une déficience de la respiration mitochondriale chez les rats HFHS. La translocation de la protéine de fission DRP1 à la mitochondrie est diminuée en réponse au glucose, suggérant une diminution de la fission mitochondriale. L’augmentation de l’activation de l’AMPK dans l’hypothalamus n’est pas responsable de l’altération de la détection hypothalamique du glucose car sa réversion avec une injection intracérébroventriculaire (ICV) de composé C, n’a pas permis de restaurer la sécrétion d’insuline en réponse à l’hyperglycémie cérébrale. De même, une injection ICV de leptine induisant l’activation de STAT3 n’a pas permis de restaurer la sécrétion d’insuline en réponse à l’hyperglycémie cérébrale. Enfin, la diminution de l’activation d’AKT suggère une résistance centrale à l’insuline. Ces résultats démontrent pour la première fois que l’altération hypothalamique de la signalisation ROS, de la fission et de la respiration mitochondriale, sont présent chez les rats exposés pendant 3 semaines à un régime HFHS. Ces défauts précoces hypothalamiques pourraient ainsi participer à un défaut primaire du contrôle de la sécrétion d’insuline, et finallement, à l’installation d’un phénotype diabétique<br>The hypothalamus participates in the control of energy homeostasis by detecting circulating nutrients, such as glucose. The mediobasal hypothalamus (MBH), in particular, senses hyperglycemia and initiates physiological responses, e.g., insulin secretion via the autonomous (vagal) nervous system. We have recently demonstrated that glucose sensing requires mitochondrial reactive oxygen species (mROS) signaling heavily dependant on mitochondrial fusion and fission (dynamics). Recently, genetic models have associated some of these dynamics within the MBH to their obesogenic susceptibility. The aims of my thesis were first to establish a model that only presents a hypothalamic glucose sensing defect induced by a high fat high sucrose (HFHS) feeding in rats. After caracterizing this model, our objectives were to determine whether modulating the diet affects mitochondrial dynamics, and thus, mROS signaling, through the mitochondrial respiratory function in the hypothalamus. We finally reversed some dysregulated metabolic signalings potentially involved in mitochondrial dynamics in order to reverse the phenotype observed in HFHS fed rats. Our results demonstrate that after 3 weeks of HFHS feeding, rats had a normal body weight despite an increase in the fat mass compared to control rats. HFHS fed rats displayed also a glucose intolerance, increased fasting glycemia but no modification of fasting insulinemia. Hypothalamic glucose sensing induced insulin secretion, measured after an intra-carotid glucose injection towards the brain that only increases brain glycemia without alteration in peripheral glycemia, was drastically decreased. However, glucose stimulated insulin secretion in isolated islets was not different compared to controls. These defects correlate with a decrease of MBH ROS production in response to glucose, with no modification in the redox status. Efficiency of hypothalamic mitochondrial respiration was evaluated using oxygraphy, and results showed mitochondrial respiratory deficiencies in HFHS fed rats. The fission protein DRP1 exhibited decreased mitochondrial translocation in the MBH in response to glucose, suggesting decreased mitochondrial fission. The increase of AMPK activation in the hypothalamus was not responsible for the alteration of hypothalamic glucose sensing since its reversal with an intracerebroventricular (ICV) injection of compound C failed to restore brain hyperglycemia induced insulin secretion. Likewise, an ICV injection of leptin that induced STAT3 activation also failed to restore brain hyperglycemia induced insulin secretion. Finally, the decrease in AKT activation suggested a central insulin resistance. These results demonstrate for the first time that hypothalamic alteration of mitochondrial ROS signaling, fission and respiration were present in rats exposed to a 3 weeks HFHS diet. Such hypothalamic glucose sensing defects are early events preceding those in islets. These early but drastic hypothalamic modifications could participate in a primary nervous defect of the control of insulin secretion, and finally, the etablishment of a diabetic phenotype
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Allard, Camille. "Les astrocytes et la détection hypothalamique du glucose : rôle métabolique et implication des connexines astrocytaires." Phd thesis, Université de Bourgogne, 2012. http://tel.archives-ouvertes.fr/tel-00935261.
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L'hypothalamus est fortement impliqué dans la régulation nerveuse de l'homéostasie énergétique. Il existe dans cette structure des neurones spécialisés (gluco-sensibles) qui détectent notamment l'hyperglycémie puis déclenchent des réponses adaptées comme le maintien de la glycémie, en stimulant la sécrétion d'insuline ou encore le rassasiement. Les astrocytes sont suspectés de participer à la détection neuronale du glucose. Dans l'ensemble du cerveau, il existe un couplage métabolique entre astrocytes et neurones. Le lactate, issu de la métabolisation du glucose par les astrocytes, est transporté par les neurones par des transporteurs aux monocarboxylates (MCTs). De plus, il a récemment été montré que les jonctions gap (GJ), à l'origine de la formation de réseaux au sein des astrocytes sont indispensables au passage du glucose de la circulation sanguine vers les neurones en activité. Ces GJ astrocytaires sont formées majoritairement de connexines 43 et 30 (Cxs).Mon travail de thèse s'est orienté suivant deux axes, qui ont visé à étudier le rôle des astrocytes dans la détection hypothalamique du glucose et du lactate. Dans un premier temps, nous avons montré que le lactate, comme le glucose, est détecté au niveau central et induit une sécrétion d'insuline. Dans un modèle de rat hyperglycémique pendant 48h (qui présente aussi une hyperlactatémie), nous avons montré que la détection du glucose et du lactate est altérée. Ces modifications ne sont pas dues à une variation de l'expression protéique des MCTs astrocytaires ou neuronale de l'hypothalamus.Dans un deuxième temps, nous nous sommes intéressés au rôle des Cxs astrocytaires. La Cx43 est très exprimée autour des micro-vaisseaux sanguins de l'hypothalamus médio-basal (MBH), un site présentant de nombreux neurones gluco-sensibles. L'expression de la Cx30 est plus diffuse dans cette structure. Nous montrons également que l'expression protéique des Cxs astrocytaires varie très rapidement suite à des modifications du statut métabolique (jeûne, réalimentation, hyperglycémie). Afin d'évaluer l'implication de la Cx43 astrocytaire (majoritaire) dans la détection hypothalamique du glucose, nous avons inhibé son expression dans le MBH, in vivo, en injectant des siRNA permettant d'inhiber la synthèse de cette protéine. L'inhibition de la Cx43 (30% à 72h) induit une diminution de la prise alimentaire sans modification du poids, de la glycémie et de l'insulinémie comparée aux témoins. Suite à l'injection carotidienne de glucose (censée mimer une hyperglycémie), la sécrétion d'insuline est fortement inhibée chez les animaux siCx43. De même, l'effet satiétogène du glucose semble inhibé chez ces animaux lors de la réalimentation après un jeûne.Ces résultats montrent pour la première fois, de façon intégrée, l'importance des connexines, et probablement des réseaux astrocytaires, lors de la détection hypothalamique du glucose. Ces nouvelles données renforcent l'importance du rôle métabolique des astrocytes lors de fonctions neuronales précises
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Devère, Mélodie. "Découverte et caractérisation de nouveaux réseaux neuronaux peptidergiques gouvernant l'homéostasie énergétique et glucidique." Electronic Thesis or Diss., Normandie, 2024. http://www.theses.fr/2024NORMR031.
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La progression alarmante des épidémies d’obésité et de diabète à l’échelle mondiale fait du traitement de ces maladies un enjeu majeur de santé publique. Afin de développer de nouvelles approches thérapeutiques pour lutter contre la « Diabésité », il est crucial de comprendre l’étiologie de ces affections. Des recherches récentes mettent en lumière le rôle clé des réseaux neuronaux hypothalamiques dans la régulation de l’homéostasie énergétique et glucidique par le cerveau. Dans ce contexte, cette thèse visait à déterminer le rôle de deux systèmes neuropeptidergiques, le système 26RFa/GPR103 et le système orexinergique au sein des réseaux neuronaux gouvernant le métabolisme énergétique et glucidique. Au cours de ma thèse, nous avons montré que l’injection centrale de 26RFa exerce un effet antihyperglycémiant associé à une augmentation de la sécrétion d’insuline. De plus, l’action centrale de l’insuline étant abolie chez les souris déficientes en 26RFa ou lors de la co-administration de l’antagoniste du récepteur au 26RFa, nous avons établi que les neurones à 26RFa sont les relais de l’action centrale de l’insuline stimulant ainsi sa propre sécrétion par le pancréas.Nous avons donc entrepris une étude neuroanatomique qui a révélé l’existence d’une sous-population de neurones de l’aire hypothalamique latérale exprimant à la fois le 26RFa et les orexines. Nos données montrent que les orexines exercent une action centrale antihyperglycémiante similaire à celle du 26RFa. De plus, la caractérisation glycémique et énergétique des souris déficientes en orexines montre un phénotype hypophagique et pro-hyperglycémiant. De façon surprenante, nous avons observé que l’activation chémogénétique (DREADD) des neurones à 26RFa et orexines de l’aire hypothalamique latérale induit un effet prohyperglycémiant. De plus, cette activation réduit l’expression d’ARNm du 26RFa et des orexines, tandis que leur inhibition augmente l’expression des deux neuropeptides, de façon similaire à celle induite par une hyperglycémie. Ainsi, pour assurer l’homéostasie glucidique, une hyperglycémie inhiberait les neurones à 26RFa et orexines, augmentant ainsi l’expression de ces deux neuropeptides connus pour leur effet antihyperglycémiant. Enfin, ces travaux suggèrent que le 26RFa est nécessaire à la réponse orexinergique lors d’une élévation de la glycémie, soulignant l'existence d'une interaction génique entre les orexines et le 26RFa. L’ensemble des données obtenues souligne l’importance des neurones à 26RFa et orexines de l’aire hypothalamique latérale dans la régulation de l’homéostasie énergétique et glucidique. L’étude de la modulation de ces systèmes neuropeptidergiques en condition de « diabésité » offre un espoir d’améliorer les approches thérapeutiques existantes<br>The alarming rise in obesity and diabetes epidemics worldwide has made the treatment of these diseases a major public health issue. To develop new therapeutic approaches to combat "diabesity", it is crucial to understand the etiology of these pathologies. Recent research highlight the key role of hypothalamic neural networks in the brain regulation of energy and glucose homeostasis. In this context, this thesis aimed to determine the role of two neuropeptidergic systems, the 26RFa/GPR103 system and the orexinergic system, within the neural networks governing energy and glucose metabolism.During my thesis, we demonstrated that central injection of 26RFa exerts an antihyperglycemic effect associated with an increased insulin secretion. Furthermore, the central action of insulin is abolished in 26RFa-deficient mice or when co-administering a 26RFa receptor antagonist, establishing that 26RFa neurons relay the central action of insulin to regulate glucose homeostasis, thereby stimulating its own secretion by the pancreas.We conducted a neuroanatomical study revealing the existence of a subpopulation of neurons in the lateral hypothalamic area expressing both 26RFa and orexins. Our data show that orexins exert a central antihyperglycemic action similar to that of 26RFa. Additionally, the glycemic and energy characterization of orexin-deficient mice reveals a hypophagic and pro-hyperglycemic phenotype of the mice.Surprisingly, we observed that chemogenetic activation (DREADD) of 26RFa and orexin neurons in the lateral hypothalamic area induces a pro-hyperglycemic effect. Moreover, this activation reduces the mRNA expression of 26RFa and orexins, while their inhibition increases the expression of both neuropeptides, similar to the effect induced by an hyperglycemia. These observations suggest that, to ensure glucose homeostasis, hyperglycemia would inhibit 26RFa and orexin neurons, leading to the increased expression of the two neuropeptides known for their antihyperglycemic effect.Finally, our data promote the evidence that 26RFa is necessary for the orexinergic response to elevated blood glucose, highlighting the occurrence of a genetic interaction between orexins and 26RFa. Collectively, the data of this thesis emphasize the importance of 26RFa and orexin neurons of the lateral hypothalamic area in the regulation of energy and glucose homeostasis. Studying the modulation of these neuropeptidergic systems in the context of "diabesity" offers hope for improving the existing therapeutic approaches
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Cham, Chee Wee. "Glucose homeostasis in rat liver transplantation." Thesis, University of Newcastle Upon Tyne, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309095.
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Ste, Marie Linda. "Role of norepinephrine in glucose homeostasis /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/9258.
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BonDurant, Lucas Donald. "Regulation of glucose homeostasis by FGF21." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6060.
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Fibroblast Growth Factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 is dynamically regulated by nutrient sensing and consequently functions as a critical regulator of nutrient homeostasis. In addition, recent studies with new genetic and molecular tools have provided critical insight into the actions of this exciting endocrine factor. Dissection of these FGF21-regulated pathways has tremendous potential for new targeted therapies to treat metabolic disease. The goals of this thesis are 1) to identify FGF21’s physiological role as a carbohydrate-regulated signal of macronutrient-specific satiety and 2) to determine the mechanism and tissues responsible for mediating the pharmacological effects of FGF21.
To address the first goal, we used different FGF21 genetic knockout mouse models to determine if loss of FGF21 would affect macronutrient preference. We found that loss of FGF21 led to an increase in simple sugar intake whereas this had no effect on other macronutrients such as lipid or protein. To further characterize the relationship between carbohydrates and FGF21, in vitro and in vivo techniques revealed that FGF21 transcription in the liver increased in response to carbohydrate intake and this was dependent on the presence of a transcription factor activated by carbohydrates, ChREBP. We next addressed whether or not increased FGF21 levels would affect preference for simple sugars. We found that in response to increased circulating levels of FGF21, either through genetic overexpression or pharmacological administration, FGF21 would lead to a significant decrease in caloric and non-caloric sweeteners. Finally, we were able to determine that FGF21 was signaling to the hypothalamus to mediate this suppression of simple sugar intake through region specific knockout of the co-receptor beta-klotho.
To address the pharmacological actions of FGF21, we generated an adipose-specific KLB KO mouse using mice that express Cre-recombinase under the adiponectin promoter. These mice lack the co-receptor for FGF21 in adipose tissue and are a more reliable adipose knockout model than previous studies that have used aP2-Cre mice. We were able to determine that the acute glucose lowering effects of FGF21 are mediated through direct signaling to adipose tissue and that FGF21 enhances insulin sensitivity by increasing glucose uptake in brown adipose tissue. However, FGF21 mediates its chronic effects, including lowering body weight and triglycerides, by signaling to some other non-adipose tissue. Overall our work has shown that FGF21 can significantly regulate glucose metabolism through multiple mechanisms.
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Ng, Natasha Hui Jin. "The role of glucose-6-phosphatase catalytic domain in glucose homeostasis." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:1e5fc469-d474-45e8-9a6b-6b56d1cd3b77.
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Over the past decade, there has been unprecedented increase in the number of genetic loci associating with type 2 diabetes (T2D) risk and related glycemic traits, thanks to advances in sequencing technologies and access to large sample sizes. Identification of associated genetic variants across the frequency spectrum can provide valuable insight into disease pathophysiology. However, the translation into biological insights has been slow often due to uncertainties over the underlying effector transcripts. G6PC2/ABCB11 is one locus characterised by common non-coding variants that are strongly associated with fasting plasma glucose (FG) levels in healthy adults. The work presented in this thesis aims to understand how protein-coding variants in glycemic trait loci such as G6PC2 contribute to the variability of glycemic traits and in addition gain further insight into the physiological role of G6PC2. To evaluate the role of coding variants in glycemic trait variation, an exome array genotyping study of non-diabetic European individuals (n=33,407) reported multiple coding variants in G6PC2 that were independently associated with FG. I designed and conducted in vitro assays to functionally assess these variants and showed that they result in loss of function (LOF) due to reduced protein stability. This established G6PC2 as the effector transcript influencing FG and highlighted a critical role for G6PC2 (encoding the islet-specific glucose-6-phosphatase catalytic subunit) in glucose homeostasis. To investigate the role of low frequency (MAF=1-5%) and rare (MAF<1%) coding variants in influencing glycemic traits, recent large-scale exome array meta-analyses and whole exome sequencing were carried out as part of MAGIC (n=144,060) and the T2D-GENES/GoT2D consortia (n=12,940) respectively. G6PC1, a gene homolog of G6PC2 that primarily acts through the liver, was uncovered as a novel glycemic locus. My functional follow-up studies demonstrated that rare coding variants in G6PC1 exhibited LOF to influence both FG and FI levels. As rare variation in G6PC2 not previously identified could also affect G6PC2 function and modulate glycemic traits, I also functionally characterised a suite of rare non-synonymous G6PC2 variants. Most of the variants tested exhibited markedly reduced protein levels and/or loss of glycosylation. Several variants were also found to impact on enzymatic activity through inactivating or activating mechanisms to influence FG levels. Finally, to gain better understanding of the function of G6PC2 I performed gene knockdown studies in the EndoC-βH1 human beta cell model followed by insulin secretion analyses. G6PC2 knockdown resulted in increased insulin secretion at sub-threshold glucose stimulation levels, consistent with studies in knockout mouse models. In addition, expression of LOF G6PC2 variants were found to upregulate ER stress responses. These results warrant further studies of the precise roles that G6PC2, an ER-resident protein, plays in regulating insulin secretory function and ER homeostasis in the beta cell. Overall, my work described multiple rare coding variants in both G6PC1 and G6PC2 that alter protein function to regulate glucose metabolism through diverse mechanisms in different tissues. Improved understanding of these effector transcripts will open up opportunities for the exploration of new therapeutic targets for glucose regulation and T2D.
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Johnstone, Helen C. "Glucose homeostasis in fasting children with endocrinopathies." Thesis, University of Newcastle upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424085.
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Sabatini, Paul Vincent. "The role of NPAS4 in glucose homeostasis." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58381.
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Type 2 diabetes is characterized by hyperglycemia associated with reduced insulin secretion from pancreatic beta cells and impaired insulin sensitivity at peripheral target tissues. There is a growing body of evidence that supports the importance of bHLH-PAS domain transcription factors in promoting beta cell function. With the recent identification of neuronal PAS domain protein 4 (NPAS4) within the central nervous system, studies were undertaken to determine whether NPAS4 is expressed in beta cells, how its expression is regulated in response to changing environmental signals and uncover the functional significance of NPAS4 in the maintenance of glucose homeostasis. Together, experiments within this thesis demonstrate that NPAS4 is expressed within the pancreatic beta cell and is rapidly upregulated in response to membrane depolarization and calcium influx. Further, this induction was impaired in a mouse model of beta cell dysfunction and within islets from individuals with T2D. Overexpression studies performed in vitro identified NPAS4 as a novel negative regulator of insulin expression and GLP-1 potentiated insulin secretion. Furthermore, NPAS4 protected beta cells from maladaptive cellular pathways that promote cell dysfunction and death; including endoplasmic reticulum stress and activation of HIF1α. Finally, the characterization of three different Npas4 mouse knockout models suggests that continued NPAS4 expression in the beta cell is required to maintain differentiation status and cellular function. An independent role for NPAS4 in the maintenance of glucose homeostasis was also discovered in other Pdx1-Cre expressing cells, likely within the hypothalamus. Together, the data suggest beta cells induce NPAS4 expression during periods of cellular activity and acts as a protective factor to protect cells in order to promote the maintenance of euglycemia.<br>Medicine, Faculty of<br>Graduate
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Sundbom, Maj. "Novel pharmaceutical approaches to regulate glucose homeostasis." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-743-6/.
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Mészáros, Gergő. "CaMK1D controls β-cell mass and glucose homeostasis". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ035.
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Le diabètes mellites de type 2 (T2DM) est caractérisé par une hyperglycémie provenant d’une dérégulation de la sécrétion d’insuline combinée avec une altération de l’action de l’insuline. CaMK1D est un nouveau gène identifié, dont le rôle reste à explorer. Dans l’étude exposée ici, j’ai montré que CaMK1D a un effet majeur sur la régulation du glucose. J’ai observé une réduction exceptionnelle des taux de glucose sanguins à jeun, ce qui entraine une amélioration globale de la tolérance au glucose. Les souris mutantes montrent une augmentation conséquente dans les niveaux sanguins d’insuline. Les souris invalidées pour CaMK1D présentent des ilots pancréatiques de taille plus importante due à une hypertrophie des cellules béta. De plus, les souris mutantes sont protégées contre la stéatose hépatique. Dans l’ensemble, mon travail met en évidence le nouveau rôle clé de CaMK1D chez les cellules béta et apporte plus de compréhension quant à son rôle lors du développement du T2DM<br>Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia resulting from defects in insulin secretion in combination with impaired insulin action. CaMK1D represents one potential candidate gene, the in vivo function remained elusive. In this work, I have found that CaMK1D plays a central role in blood glucose regulation. Pancreas-specific CaMK1D knockout mice display dramatically reduced fasting blood glucose levels leading to an overall improved glucose tolerance. CaMK1D knockout mice show markedly higher ad libitum and fasting insulin levels. Interestingly, pancreas-specific CaMK1D knockout mice display islet hyperplasia caused by beta-cell hypertrophy. Furthermore, conditional knockout mice are protected against high-fat feeding-induced hepatic steatosis. Overall, my work establishes an essential role of CaMK1D in pancreatic beta-cells and provides further understanding about its role in the development of T2DM
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Baggio, Laurie L. "The role of incretin hormones in glucose homeostasis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ59004.pdf.
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Steiler, Tatiana L. "Kinase cascades in the regulation of glucose homeostasis /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-201-2/.
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Larson, Kara L. "Regulation of Glucose Homeostasis by the PHLPP1 Phosphatase." UKnowledge, 2014. http://uknowledge.uky.edu/biochem_etds/17.
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Type 2 diabetes mellitus is a metabolic disease that affects one in ten people in the United States. It is caused by a combination of genetics and lifestyle factors. Disease progression begins with insulin resistance in peripheral tissues followed by pancreatic beta-cell failure. The mechanisms behind disease progression are not completely understood. PH domain leucine rich repeat protein phosphatase 1 (PHLPP1) is a known regulator of Akt and other members of the AGC kinase family. Akt has been established to play a role in numerous metabolic signaling pathways, including insulin action. It is hypothesized that as a regulator of Akt, PHLPP1 would have an important function in glucose homeostasis. Glucose tolerance tests performed on 8-week old Phlpp1-/- mice revealed no significant difference in glucose tolerance compared to wild type, however these mice did exhibit increased fasting blood glucose levels. Glucose tolerance tests were repeated at 20 weeks on the same mice and, interestingly, they displayed impaired glucose tolerance compared to wild type. Insulin tolerance tests showed that 8-week old mice have increased insulin sensitivity, however, the 20-week old mice were insulin-resistant compared to control animals. The 20-week old knockout mice also had significantly higher fasting blood glucose levels compared to 8-week old mice. To determine if the increased fasting blood glucose levels are due to increased hepatic glucose output, pyruvate tolerance tests were performed on both the 8 & 20 week old mice. Old mice displayed significantly increased hepatic glucose production compared to wild type. EchoMRI done on 24-week old mice showed significantly increased fat mass and decreased lean mass in the Phlpp1-/- mice compared to wild type littermates. Western blot analysis of liver samples from 32 week old Phlpp1-/- mice indicates loss of Akt signaling accompanied by a decrease in IRS2 protein levels, a common indicator of insulin resistance. These data suggest that Phlpp1-/- mice mimic the development of type 2 diabetes in humans, and provide a unique animal model to study the progression of type 2 diabetes and diabetes-associated complications.
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Chen, Mimi Zhu. "The effect of bariatric surgery on glucose homeostasis." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665171.
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Bariatric surgery is very effective at inducing weight loss and diabetes resolution in morbidly obese patients. Whether WL or increased incretin response is the crucial factor in normalising diabetes is still debatable. This thesis work prospectively investigated how bariatric surgery affected insulin action and beta-cell function in patients with morbid obesity and type 2 diabetes. Understanding these can help us to optimise diabetes treatments in patients with morbid obesity. I first discussed how obesity affects insulin sensitivity and beta-cell function, evidences that bariatric surgery is superior to conventional medical therapy at inducing weight loss and euglycaemia, and its associated mechanisms. I concluded that more robust data are needed to understand the effects of LAGB and RYGB surgery on glucose homeostasis, as this will have clinical implications for patients undergoing bariatric surgery (Chapter 1). I then described and justified the methods used for investigating insulin sensitivity and insulin secretion in the two studies (GLIPO and ISP) that make up this thesis (Chapter 2). I demonstrated that at 1 week post-op, improvements in glycaemia, insulin sensitivity and weight were the same in all patients, despite unilateral increase in incretin responses in the RYGB group. At 18 months I found that RYGB (n=32) had induced greater weight loss than LAGB (n=17). This resulted in better glycaemic control, further insulin sensitivity enhancement and marked improvements in insulin secretion and pancreatic secretory reserve in this group (Chapter 3&4). Finally, I demonstrated that marked weight loss after RYGB normalised insulin signalling (PI3K-Akt), but not glucose uptake in muscle. This suggested that major defects in the insulin signalling pathway still exist and may explain why not all patients can achieve diabetes remission after RYGB (Chapter 5). In conclusion, the degree of weight loss, not enhanced incretin response, is the major determinant of glycaemic improvement after bariatric surgery. This improvement is first brought about by improvements in insulin sensitivity followed by improvements in insulin secretion.
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Flechner, Lawrence Martin. "Role of the CREB pathway in glucose homeostasis /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3129937.
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Shipley, Timothy I. "The Role of VMN Glucose-Sensitive Neurones in the Control of Glucose Homeostasis." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511846.
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Osundiji, Mayowa Azeez. "Hypothalamic glucose sensing plays a critical role in the control of glucose homeostasis." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612423.
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Smith, Kirsty Louise. "Metabolic hormones and energy homeostasis." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411789.
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Neary, Nicola Marguerite. "Gut hormones and energy homeostasis." Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/7152.
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Pears, John Stuart. "Glucose-6-phosphatase : its structure, function and regulation in relation to blood glucose homeostasis." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/20100.
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Hepatic glucose-6-phosphatase (G6Pase) catalyses the final step in blood glucose production by the liver. It is a multicomponent system: the catalytic subunit is on the luminal surface of the endoplasmic reticulum membrane; there are transport proteins for glucose-6-phosphate, inorganic phosphate and glucose across the ER membrane; and there is a calcium-binding stabilising protein associated to the catalytic subunit. In fasted and diabetic humans (and rat models) kinetic analysis has shown that the capacity of the glucose-6-phosphate transport protein is the rate-limiting step in G6Pase activity, making this protein vital in controlling hepatic glucose output. However, deficiency of any part of this system will lead to hypoglycaemia and other possible metabolic upsets (type 1 glycogen storage diseases). The structure and known regulation of the G6Pase system are reviewed in the introduction to this thesis. The aims of the work presented here are to investigate the human glucose-6-phosphatase system by studying adult patients newly diagnosed with abnormalities of the G6Pase system, and tissues not previously proven to contain G6Pase in healthy adults thereby improving understanding of the enzyme, its regulation and physiological role and to look for a tissue more accesible than liver in which to study human G6Pase activity. A unique series of eight adult patients each with an abnormality of hepatic G6Pase (two with previously unrecorded defects) is presented and the features of these cases are discussed with reference to the existing literature on type 1 glycogen storage diseases. The cases demonstrate how difficult it can be to prove hypoglycaemia in adults; the diversity of presenting symptoms and signs; the use of a screening test (blood glucose response to a 1mg intramuscular dose of glucagon) for such patients; and the benefits of developing reliable assays for the protein components of the G6Pase system. This series of patients also give further clues to the physiological role of glucose-6-phosphatase in extra-hepatic tissues and the regulation of the hepatic G6Pase system. The diagnosis and subsequent follow-up of the above patients would have been eased by being able to study a more accessible tissue than liver. Intestinal mucosa and neutrophils have been described as abnormal in G6Pase deficiencies. Therefore G6Pase activity was sought in these tissues from normal adult humans.
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Krishnan, Binu. "Hypothalamic and autonomic responses to change in glucose homeostasis." Thesis, Exeter and Plymouth Peninsula Medical School, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544012.
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Abrahamsson, Niclas. "On the Impact of Bariatric Surgery on Glucose Homeostasis." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-276381.
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Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2. In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery. In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS). In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms. In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response. In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.
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Kindel, Tammy Lyn. "The Effects of Duodenal-jejunal Bypass on Glucose Homeostasis." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1280778030.
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Stevens, Joseph R. "The Effects of Low Dose Endotoxin on Glucose Homeostasis." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/64849.
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Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, also known as metabolic endotoxemia. In healthy rodents (non-obese and insulin sensitive), there is evidence that blood endotoxin levels fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. High-fat feeding in these animals altered these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not understood. The goal of this study was to determine the effects of short-term and long-term increases in endotoxin of a low magnitude on insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis in cell culture that short-term low-dose endotoxin treatments would enhance insulin-signaling and glycogen synthesis while long-term treatments would have inhibitory effects. Under our second hypothesis, we examined whether short-term low-dose treatments of endotoxin would contribute to improvements in glucose tolerance in a mouse model. In contrast to our first hypothesis, short-term endotoxin treatments did not improve insulin signaling or glycogen synthesis although long-term treatments did contribute to decreases in glycogen synthesis. Interestingly, short-term endotoxin treatments resulted in significant improvements in glucose clearance in the mouse model; this is believed to be partly attributed to LPS inhibiting gluconeogenesis. Future studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels.<br>Ph. D.
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Hawke, Zoe Belinda. "Ventromedial hypothalamic neurones in energy homeostasis." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495608.
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The processes that control energy homeostasis are extremely complex and involve /nteractions between peripheral organs, the hypothalamus and the brainstem, as well as inputs from sensory and reward centres of the brain. Researchers have come a long way in recent years in elucidating the networks that control energy balance, but recent transgenic models have shown that over-emphasis may have been put on the arcuate nucleus Research is now shifting to extra-arcuate sites'including the ventromedial nucleus (VMN) which, unlike characterised in terms of its cellular phenotypes.
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Levi, Jasna. "The role of leptin in the regulation of glucose homeostasis." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/26267.
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The fat derived hormone leptin plays a crucial role in the normal maintenance of body weight and energy expenditure, as well as glucose homeostasis. Low doses of exogenous leptin administered to leptin deficient ob/ob mice are able to reverse the hyperinsulinemia and hyperglycemia without altering body composition. As leptin has the ability to directly suppress insulin secretion from ß-cells, we hypothesise that in the absence of leptin signalling, unregulated insulin secretion leads to hyperinsulinemia which in turn leads to increased adipogenesis and insulin resistance, ultimately culminating in the development of type 2 diabetes in this mouse model. To test this hypothesis we induced an acute state of leptin deficiency with a PEGylated mouse leptin antagonist (PEG-MLA) to determine the hierarchy of leptin action. Metabolic analysis by indirect calorimetry showed that PEG-MLA treatment resulted in increased food intake and respiratory quotient without altering body composition or energy expenditure. These changes in energy balance were accompanied with increased fasting, and glucose stimulated insulin levels. PEG-MLA treated mice also displayed decreased whole-body insulin sensitivity, elevated endogenous hepatic glucose production (HPG), and impaired insulin mediated suppressed of HPG as determined by euglycemic-hyperinsulinemic clamps. Overall, these findings demonstrate that leptin signalling is important in regulating insulin secretion, and that changes in insulin sensitivity occur prior to changes in body composition and energy expenditure in a state of acute leptin deficiency.
It has been recently shown that the liver derived, leptin regulated insulin-like growth factor binding protein-2 (IGFBP-2) is responsible for the anti-diabetic effect of leptin in ob/ob mice. We investigated the mechanism by which leptin regulates IGFBP-2 levels. ob/ob mice with attenuated hepatic leptin signalling or a subdiaphragmatic vagotomy were utilized to determine if leptin acts directly on the liver or centrally to increase plasma IGFBP-2. Our results show that while leptin is able to increase plasma IGFBP-2 levels in ob/ob mice in a dose dependent manner, the mechanism does not involve heptic leptin signalling or vegal efferents and remains to be elucidated.
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Kaur, Achint. "The role of sterol 12α- hydroxylase (Cyp8b1) in glucose homeostasis". Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46516.
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Hawdon, Jane Melinda. "Metabolic adaptation and disordered blood glucose homeostasis in the neonate." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240735.
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Markkula, Silja Pauliina. "Hypothalamic hydrogen peroxide signalling in the control of glucose homeostasis." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609384.
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Castro, Acosta Monica Lizzette. "Beneficial effects of blackcurrant and apple polyphenols on glucose homeostasis." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/beneficial-effects-of-blackcurrant-and-apple-polyphenols-on-glucose-homeostasis(228bad46-5f9c-40be-b7d5-018445aaf7f4).html.
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Epidemiological evidence and randomised controlled trials suggests that dietary patterns with high intakes of fruit and vegetables are associated with reduced risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). Frequent elevated excursions in postprandial glucose concentrations are thought to increase risk of T2D, therefore dietary strategies to control chronic postprandial hyperglycaemia would strengthen efforts to reduce the risk for T2D. Fruit polyphenols are dietary constituents that might help to delay glucose absorption following a carbohydrate-containing meal or beverage and epidemiological studies have shown a negative relationship between ingestion of polyphenols and T2D. Polyphenol dietary intakes and urinary excretions were analysed in a free-living population following the UK dietary guidelines and compared with a population following the average UK diet. In the intervention group, increased consumption of fruit and vegetables (> 5 portions/day) and wholegrain cereals led to an increased intake in polyphenols associated with health benefits, such as anthocyanins, isoflavones and lignans (P<0.05). Randomised clinical trials were conducted using highly purified anthocyanin-rich blackcurrant extract (BE) and polyphenol-rich apple extracts (AE) consumed immediately before a high-carbohydrate (starch and sucrose) test meal. BE (600 mg of blackcurrant anthocyanins), AE (1200 mg of apple polyphenols) and BE+AE (600 mg of blackcurrant anthocyanins + 600 mg of apple polyphenol) reduced postprandial glycaemia relative to control by 57, 63 and 73 %, respectively (P<0.005), but lower doses of an apple extract had no effect on postprandial responses to an oral glucose load. Effective doses of the fruit extracts are equivalent to 100 g of fresh blackcurrant and 600 and 300 g of raw apple. In vitro studies testing physiological concentrations of the blackcurrant and apple extracts used in the randomised clinical trials showed that the polyphenols contained in blackcurrant and apple extracts inhibited total and GLUT-mediated glucose uptake in Caco-2/TC7 cells (a well-known model of the small intestine) and inhibited the sodium-dependent glucose transporter SGLT1 expressed in oocytes. Our results suggest blackcurrant and apple polyphenols may reduce postprandial glycaemia in vivo at least partly by inhibiting glucose uptake in the small intestine. Altogether the findings presented show that advice to consume more fruits and vegetables can effectively increase intakes of specific polyphenols that have been associated with reduced risk of cardio-metabolic diseases, and provides evidence for mechanisms where fruit polyphenols might regulate glucose homeostasis.
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Alkhalidy, Hana Awwad. "Flavonol kaempferol in the regulation of glucose homeostasis in diabetes." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/82485.
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Diabetes mellitus is a major public health concern. Although the accessible novel drugs, techniques, and surgical intervention has improved the survival rate of individuals with diabetes, the prevalence of diabetes is still rising. Type 2 diabetes (T2D) is a result of chronic insulin resistance (IR) and loss of β-cell mass and function. Therefore, the search for naturally occurring, low-cost, and safe compounds that could enhance insulin sensitivity and protect functional β-cell mass can be an effective strategy to prevent this disease. Kaempferol, a flavonol present in various medicinal herbs and edible plants, has been shown to elicit various pharmacological activities in preclinical studies. However, studies investigating the effect of kaempferol on diabetes are limited. In this dissertation, I explored the anti-diabetic potential of dietary intake of kaempferol in diet-induced obese mice and insulin-deficient diabetic mice.
First, kaempferol was supplemented in the diet to determine whether it can prevent IR and hyperglycemia in high fat (HF) diet-induced obese mice or STZ-induced obese diabetic mice. To evaluate its efficacy for treating diabetes, kaempferol was administrated once daily via oral gavage to diet-induced obese and insulin-resistant mice or lean STZ-induced diabetic mice. The results demonstrated that long-term oral administration of kaempferol prevents HFD-induced metabolic disorders in middle-aged obese mice. Oral administration of kaempferol improved glucose intolerance and insulin sensitivity, and this effect was associated with increased Glut4 and AMPKa expression in muscle and adipose tissues. Consistent with our findings from the in iii vitro study in C2C12 muscle cell line, these findings suggest that kaempferol may reduce IR at the molecular level by improving glucose metabolism in peripheral tissues. In the second study, dietary kaempferol supplementation prevented hyperglycemia and glucose intolerance by protecting β-cell against the induced damage in obese STZ-induced diabetic mice. In the third study, the administration of kaempferol by oral gavage significantly ameliorated hyperglycemia and glucose intolerance and reduced the incidence of diabetes from 100 % to 77.8% in lean STZinduced diabetic mice. This kaempferol effect was associated with reduced hepatic glucose production, the primary contributor to hyperglycemia, and increased glucose oxidation in the muscle of diabetic mice. Kaempferol treatment restored hexokinase activity in the liver and skeletal muscle and reduced pyruvate carboxylase (PC) activity and glycogenolysis in the liver.
Unlike its effect on T2D mice, kaempferol effect in lean STZ-induced diabetic mice was not associated with changes in plasma insulin levels. In the last study, we found that administration of kaempferol by oral gavage significantly improved blood glucose control by suppressing hepatic glucose production and improving glucose intolerance in obese insulin-resistant mice. Similar to its effect in old obese mice, kaempferol enhanced whole-body insulin sensitivity. Kaempferol increased Akt and hexokinase activity and decreased PC activity in the liver. However, kaempferol did not exert any changes in glucose metabolism or insulin sensitivity when administered to healthy lean mice. Overall, findings from these studies provide new insight into the role of kaempferol in the regulation of glucose homeostasis and suggest that kaempferol may be a naturally occurring anti-diabetic compound by improving insulin sensitivity, improving glucose regulation and metabolism, and preserving functional β-cell mass.<br>Ph. D.
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Kent, Aysha S. "The role of ghrelin in energy homeostasis." Thesis, Imperial College London, 2006. http://hdl.handle.net/10044/1/11443.
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