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Biotechnology --- bioengineering --- vaccins --- fermentatie --- biobrandstoffen --- glucose-isomerase --- biotechnologie

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Pancreatic islets play an essential role in glucose homeostasis due to the fact that they secrete the only hypoglycaemic hormone, insulin, and hyperglycaemic hormone, glucagon. In β-cells, glucose stimulates insulin secretion by closing ATP sensitive K+ channels (K+-ATP channels) located on the plasma membrane. Closure of K+-ATP channels leads to membrane depolarization followed by activation of voltage-gated Ca2+ channels. The subsequent increase of [Ca2+]c triggers insulin secretion. On the other hand in α-cells, glucose inhibits glucagon secretion by an unknown mechanism.
The aim of this work is to understand the way glucose influence isolated α-cells. Study of α-cells is difficult because this cell type is not easily identifiable and is present in small quantity in islets. To get round this problem, we used a new genetically modified mouse model (expressing EYFP specifically under the control of insulin or glucagon promoter) allowing fast identification of α or β-cells. We put in evidence existence of K+-ATP channels in α-cells. We showed that contrary to β-cells, variations in glucose concentration does not affect neither K+-ATP channels activity nor [Ca2+]c of α-cells. We also noted that inhibition of glucose metabolism, thus diminution of ATP synthesis stimulates K+-ATP channels activity, α-cells are equipped with voltage-gated channels which identify is matter of controversy. Our study reveals that Ca2+ influx occurring under low glucose conditions depends on opening of voltage-gated L type Ca2+ channels. [Ca2+]c decreases when mitochondrial metabolism is inhibited or when K+-ATP channels are closed. NAD(P)H production during glycolysis reflects ATP synthesis by mitochondria. We have found that neither glucose nor pyruvate and α-ketoisocaproate (KIC) influence α-cells NAD(P)H fluorescence, whereas β-cells respond to both glucose and KIC. Altogether, these results suggest that, as in β-cells, K+-ATP channels activity modulate α-cells [Ca2+]c. In addition, glucose does not affect NAD(P)-H fluorescenceα, K+-ATP channels activity and [Ca2+]c. Therefore, it is proposed that regulation of glucagon secretion occurs through paracrine effects of glucose Etant donné qu’ils sécrètent la seule hormone hypoglycémiante, l’insuline, et une hormone hyperglycémiante, le glucagon, les îlots pancréatiques jouent un rôle essentiel dans l’homéostasie glucidique. Dans la cellule β, le glucose stimule la sécrétion d’insuline en fermant les canaux K+ sensibles à l’ATP (les canaux K+-ATP) situés au niveau de la membrane plasmique. La fermeture de ces canaux entraîne une dépolarisation membranaire activant les canaux Ca2+ voltage-dépendants. L’influx de Ca2+ qui en résulte, augmente la [Ca2+]c et déclenche la sécrétion d’insuline. D’autre part dans la cellule α, le glucose inhibe la sécrétion de glucagon par un mécanisme inconnu. La compréhension du mode d’action du glucose sur les cellules α isolées est l’objectif premier de ce mémoire. L’étude de la cellule α n’est pas évidente car ce type cellulaire est difficilement identifiable et n’est présent qu’en faible quantité au sein des îlots. Pour contourner ce problème, nous avons donc utilisé un nouveau modèle de souris génétiquement modifiées (exprimant l’EYFP spécifiquement sous le contrôle du promoteur de l’insuline ou du glucagon) permettant l’identification rapide des cellules α ou des cellules β. Sur base de nos connaissances de la cellule β, nous avons mis en évidence l’existence des canaux K+-ATP dans les cellules α. Nous avons montré que, à l’inverse des cellules β, les variations de la concentration en glucose n’affectent pas ni l’activité des canaux K+-ATP, ni la [ca2+]c des cellules α. Nous avons également constaté qu’un inhibition du métabolisme du glucose, et donc une diminution de la synthèse d’ATP, stimule l’activité des canaux K+-ATP. La cellule α est équipée de canaux voltage-dépendants dont l’identité est controversée. Notre étude a révélé que l’influx de Ca2+ présent spontanément à une faible concentration en glucose passe par les canaux Ca2+ voltage dépendant de type L. La [Ca2+]c diminue lorsque le métabolisme du glucose est inhibé, ou lorsque les canaux K+-ATP sont ouverts, et elle augmente lorsque les canaux K+-ATP sont fermés. Ces données suggèrent que ces canaux K+ modulent l’influx de Ca2+. La production de NAD(P)H lors de la glycolyse reflète la synthèse d’ATP par les mitochondries. Il s’est avéré que ni le glucose et ni le pyruvate et l’ α-cétoisocaproate, deux substances dont le métabolisme alimente le cycle de Krebs, n’influencent aucunement la fluorescence du NAD(P)H des cellules α, tandis que les cellules β répondent au glucose et au KIC. Globalement, nos résultats suggèrent que dans les cellules α les canaux K+-ATP modulent la [Ca2+]c comme dans les cellules β. De plus, le glucose et son métabolisme n’affectent pas la séquence d’évènements aboutissant à la sécrétion du glucagon. Enfin, l’absence d’effet du glucose sur des cellules α isolées suggère que le glucose agit sur les cellules à glucagon via des facteurs paracrines

Islets of Langerhans --- Cytosol --- Glucose --- Pancreas --- Mice --- Mitochondrial K(ATP) channel

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Human medicine --- Glucose Metabolism Disorders --- Evidence-Based Practice --- Clinical Medicine --- Endocrine System Diseases --- Diseases --- Metabolic Diseases --- Medicine --- Health Occupations --- Nutritional and Metabolic Diseases --- Disciplines and Occupations --- Evidence-Based Medicine --- Diabetes Mellitus --- Diabetes Insipidus --- Glucose Intolerance --- Medicine, Evidence-Based --- Evidence Based Medicine --- Medicine, Evidence Based --- Decision Support Techniques --- Evidence-Based Dentistry --- Evidence-Based Nursing --- Nutritional Physiological Phenomena --- Health Professions --- Health Occupation --- Health Profession --- Profession, Health --- Professions, Health --- Occupations --- Medical Specialities --- Medical Specialties --- Medical Specialty --- Specialities, Medical --- Specialties, Medical --- Specialty, Medical --- Medical Speciality --- Speciality, Medical --- Health Workforce --- Diseases, Metabolic --- Thesaurismosis --- Disease, Metabolic --- Metabolic Disease --- Thesaurismoses --- Diseases of Endocrine System --- Endocrine Diseases --- Disease, Endocrine --- Disease, Endocrine System --- Diseases, Endocrine --- Diseases, Endocrine System --- Endocrine Disease --- Endocrine System Disease --- System Disease, Endocrine --- System Diseases, Endocrine --- Endocrinology --- Medicine, Clinical --- Evidence Based Health Care Management --- Evidence Based Healthcare Management --- Evidence Based Management, Health Care --- Evidence Based Management, Healthcare --- Evidence-Based Healthcare --- Evidence-Based Health Care --- Evidence Based Health Care --- Evidence Based Healthcare --- Evidence Based Practice --- Evidence-Based Health Cares --- Evidence-Based Healthcares --- Health Care, Evidence-Based --- Health Cares, Evidence-Based --- Healthcare, Evidence-Based --- Healthcares, Evidence-Based --- Glucose Metabolic Disorder --- Glucose Metabolic Disorders --- Glucose Metabolism Disorder --- Disorder, Glucose Metabolic --- Disorder, Glucose Metabolism --- Disorders, Glucose Metabolic --- Disorders, Glucose Metabolism --- Metabolic Disorder, Glucose --- Metabolic Disorders, Glucose --- Metabolism Disorder, Glucose --- Metabolism Disorders, Glucose --- Evidence Gaps

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Human medicine --- Glucose Metabolism Disorders --- Evidence-Based Practice --- Clinical Medicine --- Endocrine System Diseases --- Diseases --- Metabolic Diseases --- Medicine --- Health Occupations --- Nutritional and Metabolic Diseases --- Disciplines and Occupations --- Evidence-Based Medicine --- Diabetes Mellitus

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Insulin --- Diabetes Mellitus --- therapeutic use --- drug therapy --- Diabetes --- Treatment --- Diabetes Mellitus. --- Diabetes. --- Insulin. --- therapeutic use. --- Brittle diabetes --- Diabetes mellitus --- IDDM (Disease) --- Insulin-dependent diabetes --- Ketosis prone diabetes --- Type 1 diabetes --- Hormones --- Hypoglycemic agents --- Pancreas --- Proinsulin --- Carbohydrate intolerance --- Endocrine glands --- Diabetic acidosis --- Glycosylated hemoglobin --- Diabetes Insipidus --- Glucose Intolerance --- Secretions --- Diseases --- Clinical Endocrinology