109 results on '"Nicolas, Wiernsperger"'
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2. The desert gerbil Psammomys obesus as a model for metformin-sensitive nutritional type 2 diabetes to protect hepatocellular metabolic damage: Impact of mitochondrial redox state.
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Inès Gouaref, Dominique Detaille, Nicolas Wiernsperger, Naim Akhtar Khan, Xavier Leverve, and Elhadj-Ahmed Koceir
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Medicine ,Science - Abstract
INTRODUCTION:While metformin (MET) is the most widely prescribed antidiabetic drug worldwide, its beneficial effects in Psammomys obesus (P. obesus), a rodent model that mimics most of the metabolic features of human diabetes, have not been explored thoroughly. Here, we sought to investigate whether MET might improve insulin sensitivity, glucose homeostasis, lipid profile as well as cellular redox and energy balance in P. obesus maintained on a high energy diet (HED). MATERIALS AND METHODS:P. obesus gerbils were randomly assigned to receive either a natural diet (ND) consisting of halophytic plants (control group) or a HED (diabetic group) for a period of 24 weeks. MET (50 mg/kg per os) was administered in both animal groups after 12 weeks of feeding, i.e., the time required for the manifestation of insulin resistance in P. obesus fed a HED. Parallel in vitro experiments were conducted on isolated hepatocytes that were shortly incubated (30 min) with MET and energetic substrates (lactate + pyruvate or alanine, in the presence of octanoate). RESULTS:In vivo, MET lowered glycemia, glycosylated haemoglobin, circulating insulin and fatty acid levels in diabetic P. obesus. It also largely reversed HED-induced hepatic lipid alterations. In vitro, MET increased glycolysis but decreased both gluconeogenesis and ketogenesis in the presence of glucogenic precursors and medium-chain fatty acid. Importantly, these changes were associated with an increase in cytosolic and mitochondrial redox states along with a decline in respiration capacity. CONCLUSIONS:MET prevents the progression of insulin resistance in diabetes-prone P. obesus, possibly through a tight control of gluconeogenesis and fatty acid β-oxidation depending upon mitochondrial function. While the latter is increasingly becoming a therapeutic issue in diabetes, the gut microbiota is another promising target that would need to be considered as well.
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- 2017
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3. A comment on metformin and COVID-19 with regard to 'Metformin use is associated with a decrease in the risk of hospitalization and mortality in COVID-19 patients with diabetes: A population-based study in Lombardy'
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Abdallah, Al-Salameh, Nicolas, Wiernsperger, Bertrand, Cariou, and Jean-Daniel, Lalau
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Hospitalization ,Diabetes Mellitus, Type 2 ,SARS-CoV-2 ,COVID-19 ,Humans ,Hypoglycemic Agents ,Metformin ,Retrospective Studies - Published
- 2022
4. Fructose and cardiometabolic disorders: the controversy will, and must, continue
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Nicolas Wiernsperger, Alain Geloen, and Jean-Robert Rapin
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Fructose ,Triglycerides ,Metabolic syndrome ,Uric acid ,Hypertension ,Diet ,Medicine (General) ,R5-920 - Abstract
The present review updates the current knowledge on the question of whether high fructose consumption is harmful or not and details new findings which further pushes this old debate. Due to large differences in its metabolic handling when compared to glucose, fructose was indeed suggested to be beneficial for the diet of diabetic patients. However its growing industrial use as a sweetener, especially in soft drinks, has focused attention on its potential harmfulness, possibly leading to dyslipidemia, obesity, insulin resistance/metabolic syndrome and even diabetes. Many new data have been generated over the last years, confirming the lipogenic effect of fructose as well as risks of vascular dysfunction and hypertension. Fructose exerts various direct effects in the liver, affecting both hepatocytes and Kupffer cells and resulting in non-alcoholic steatotic hepatitis, a well known precursor of the metabolic syndrome. Hepatic metabolic abnormalities underlie indirect peripheral metabolic and vascular disturbances, for which uric acid is possibly the culprit. Nevertheless major caveats exist (species, gender, source of fructose, study protocols) which are detailed in this review and presently prevent any firm conclusion. New studies taking into account these confounding factors should be undertaken in order to ascertain whether or not high fructose diet is harmful.
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- 2010
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5. Possible links between intestinal permeablity and food processing: a potential therapeutic niche for glutamine
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Jean Robert Rapin and Nicolas Wiernsperger
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Intestinal permeability ,Glycation ,Allergy ,Metabolic syndrome ,Glutamine ,Curcumin ,Medicine (General) ,R5-920 - Abstract
Increased intestinal permeability is a likely cause of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Intestinal permeability is found in many severe clinical situations and in common disorders such as irritable bowel syndrome. In these conditions, substances that are normally unable to cross the epithelial barrier gain access to the systemic circulation. To illustrate the potential harmfulness of leaky gut, we present an argument based on examples linked to protein or lipid glycation induced by modern food processing. Increased intestinal permeability should be largely improved by dietary addition of compounds, such as glutamine or curcumin, which both have the mechanistic potential to inhibit the inflammation and oxidative stress linked to tight junction opening. This brief review aims to increase physician awareness of this common, albeit largely unrecognized, pathology, which may be easily prevented or improved by means of simple nutritional changes.
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- 2010
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6. Short-term treatment with metformin improves the cardiovascular risk profile in first-degree relatives of subjects with type 2 diabetes mellitus who have a metabolic syndrome and normal glucose tolerance without changes in C-reactive protein or fibrinogen
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Luis Mauro Alvim de Lima, Nicolas Wiernsperger, Luiz Guilherme Kraemer-Aguiar, and Eliete Bouskela
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Metformin ,Fibrinogen ,C-reactive protein ,Normoglycemia ,Metabolic syndrome ,Medicine (General) ,R5-920 - Abstract
OBJECTIVE: To study if metformin, when administered to first-degree relatives of type 2 diabetes mellitus subjects who have metabolic syndrome and normal glucose tolerance, could improve the cardiovascular risk profile and reduce the levels of both C-reactive protein and fibrinogen. INTRODUCTION: Metabolic syndrome is associated with higher cardiovascular morbidity and mortality. Metformin has vasculo-protective effects even in normoglycemic subjects, and C-reactive protein and fibrinogen are considered markers of endothelial injury and inflammation. METHODS: Thirty-one non-diabetic first-degree relatives of type 2 diabetes mellitus subjects with metabolic syndrome were randomized (1:1) and double-blinded for placement in the placebo and metformin groups (850mg bid/±90days); 16 subjects were administered metformin (mean age 40.0 [33.5-50] years; 13 females) and 15 subjects were in the placebo group (mean age 37.0 [32-42] years; 9 females). Blood samples were collected at baseline and at the end of treatment for biochemical analyses, including an assessment of C-reactive protein and fibrinogen levels. RESULTS: Metformin improved the lipid profile and decreased fasting plasma glucose, systolic blood pressure, weight and body mass index without changing body composition. For those in the placebo we identified no changes in fibrinogen (282.2 [220.4-323.7] mg/L vs. 286.7 [249.6-295.1] mg/L; NS) or in C-reactive protein levels (0.68 [0.3-1.2] vs. 0.64 [0.3-1.0] mg/L; NS). The same was also observed for the levels of fibrinogen (303.9 [217.6-347.6] mg/L vs. 290.9 [251.5-301.9] mg/L; NS) and C-reactive proteins (0.78 [0.3-1.1] vs. 0.80 [0.4-0.9] mg/L; NS) in the metformin group. CONCLUSIONS: Metformin treatment in first-degree relatives of type 2 diabetes mellitus sufferers who have metabolic syndrome and normal glucose tolerance improved the cardiovascular risk profile without changing the levels of C-reactive protein and fibrinogen.
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- 2009
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7. Microcirculation in obesity: an unexplored domain
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Nicolas Wiernsperger, Pierre Nivoit, and Eliete Bouskela
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doença cardiovascular ,diabetes mellitus ,peso ao nascer ,síndrome metabólica ,leptina ,cardiovascular disease ,birth weight ,metabolic syndrome ,leptin ,Science - Abstract
Obesity is traditionally linked to diabetes and cardiovascular diseases. Very recent experimental, clinical and epidemiological, sometimes provocative, data challenge this automaticity by showing that not the amount but the distribution of fat is the important determinant. Moderate abdominal fat accumulation may thus be more harmful than even consequent overweight. In view of the worldwide burden of obesity, factors leading to it in children and young adults must urgently be identified. Since obesity is a very complex cardiometabolic situation, this will require to focus investigations on uncomplicated obese subjects and adequate animal models. The recent discovery of intergenerational transmissions of obesity risk factors and also the key role played by gestational and perinatal events (epigenetic factors) give rise to completely new concepts and research avenues. Considering the potential close relationship between microcirculation and tissue metabolism, demonstrations of structural and/or functional abnormalities in microvascular physiology very early in life of subjects at risk for obesity might provide a solid basis for further investigations of such links. Microcirculation(arterioles, capillaries and venules) is conceivably a key compartment determining over one or several decades the translation of genetic and epigenetic factors into fat accumulation. Available animal models should serve to answer this cardinal question.A obesidade é tradicionalmente associada ao diabetes e adoenças cardiovasculares. Dados muito recentes, algumasvezes provocativos, experimentais, clínicos e epidemiológicos questionam essa associação automática mostrando que não é a quantidade, mas a distribuição de gordura que é o determinante importante. O acúmulo moderado de gordura abdominal pode ser mais danoso que o conseqüente sobrepeso. Tendo em vista o aumento mundial da obesidade, fatores que levam a isso em crianças e adultos jovens devem ser urgentemente identificados. Como a obesidade é uma situação cardiometabólica muito complexa, essa identificação deve ser feita em obesos não-complicados e em modelos animais adequados. A recente descoberta da transmissão inter-geração de fatores de risco da obesidade e também do papel fundamental da gestação e de eventos perinatais (fatores epi-genéticos) dão origem a conceitos e linhas de pesquisa completamente novos. Considerando a estreita relação potencial entre a microcirculação e o metabolismo tecidual, demonstrações de anormalidades estruturais e/ou funcionais na fisiologia microvascular muito cedo na vida de pessoas com risco para obesidade podem fornecer uma base sólida para investigações futuras dessas ligações. A microcirculação (arteríolas, capilares e vênulas) é conceitualmente um compartimento chave na determinação em uma ou várias décadas dos fatores genéticos e epi-genéticos em acúmulo de gordura. Os modelos experimentais disponíveis devem servir para responder essa questão extremamente relevante.
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- 2007
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8. Substitution of drinking water by fructose solution induces hyperinsulinemia and hyperglycemia in hamsters Substituição da água por solução de frutose induz hiperinsulinemia e hiperglicemia em hamster
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Carlos Magno M. R. Barros, Rosane Q. Lessa, Mauricio P. Grechi, Tanial L. M. Mouço, Maria das Graças C. Souza, Nicolas Wiernsperger, and Eliete Bouskela
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Insulinemia ,Glicemia ,Solução de frutose ,Modelo experimental ,Hamster ,Hyperglycemia ,Fructose solution ,Experimental animal model ,Medicine (General) ,R5-920 - Abstract
PURPOSE: To test the possibility of obtaining a practical and stable model of hyperinsulinemia and hyperglycemia in hamsters, substituting the drinking water by 10% or 20% fructose solutions for a period of 2, 4, or 6 months. METHODS: Male hamsters were divided into 3 main groups, further divided in 3 subgroups: Two months: Group Ia control (n = 51) received filtered water, Group Ib (n = 49) received 10% fructose solution instead of water, Group Ic (n=8) received 20% fructose solution instead of water. Four months: Group IIa control (n=8), Group IIb 10% fructose (n = 7), Group IIc 20% fructose (FIIc, n = 7). Six months: Group IIIa control (n = 6), Group IIIb 10% Fructose (n = 6), Group IIIc 20% Fructose (n = 5). All groups were fed with the same laboratory diet. The animals were weighed every 2 weeks during the study period. On the final day of each experiment (61st, 121st, and 181st day after the beginning of the study, respectively), the animals were weighed and anesthetized for blood collection to determine plasma glucose and insulin after at least a 12-h fast. Ten animals of group Ia and 10 of group Ib were evaluated to determine changes in macromolecular permeability induced by ischemia/reperfusion as measured in the cheek pouch microcirculation. RESULTS: Compared to controls, the animals that drank the 10% or 20% fructose solution had significantly greater weight gain (P < .001), fasting plasma glucose (P < .001) Reperfusion, after 30 min ischemia, resulted in an immediate but reversible increase in postcapillary leakage (L) of 89.0 ± 2.0 L/cm² (group Ia - controls), and 116.5 ± 4.8 L/cm² (group Ib 10% fructose), P < .001.These results suggest that chronic administration of either 10% or 20% fructose solutions could be used to experimentally induce a stable hamster model of hyperinsulinemia and hyperglycemia. CONCLUSION: The model might facilitate the study of basic mechanisms of hyperglycemia and hyperinsulinemia affecting the microvasculature as demonstrated by the findings regarding ischemia/reperfusion after only 2 months of treatment.OBJETIVO: Testar a possibilidade de obtenção de um modelo prático e estável de hiperinsulinemia e hiperglicemia em hamsters substituindo a água de beber por soluções de frutose a 10% ou 20% por um período de dois, quatro ou seis meses. MÉTODOS: Hamsters machos foram divididos em 3 grupos e cada grupo subdividido em 3 subgrupos. Dois meses: Grupo Ia-controle (n=51), recebeu água filtrada, Grupo Ib-(n=49), recebeu solução de frutose a 10% ao invés de água e Grupo Ic-( n=8), recebeu solução de frutose a 20% ao invés de água. Quatro meses: Grupo IIa - controle (n=8), Grupo IIb - 10% frutose (n=7) e Grupo IIc - 20% frutose (n=7). Seis meses: Grupo IIIa - controle (n=6), Grupo IIIb - 10% frutose (n=6) e Grupo IIIc - 20% frutose (n=5). Todos os animais foram alimentados com a mesma dieta padrão de laboratório. Os animais foram pesados a cada 2 semanas durante o período do estudo. No dia do final do experimento (61º, 121º e 181º dia, respectivamente, após o início do estudo), os animais foram pesados e anestesiados para coleta de sangue para determinação da glicose e da insulina sérica, após jejum de pelo menos 12 h. Em 10 animais do grupo Ia e em 10 do grupo Ib avaliamos, na microcirculação da bolsa da bochecha, a variação da permeabilidade a macromoléculas induzida por isquemia/reperfusão. RESULTADOS: Comparados ao grupo controle, os animais que beberam soluções de frutose a 10 ou 20% tiveram um aumento significativo de massa corporal (p
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- 2007
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9. Obstructive sleep apnea and insulin resistance: a role for microcirculation? Apnéia obstrutiva do sono e resistência à insulina: qual o papel da microcirculação?
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Nicolas Wiernsperger, Pierre Nivoit, and Eliete Bouskela
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Apnéia obstrutiva do sono ,Resistência à insulina ,Hypoxia ,Síndrome metabólica ,Microcirculação ,Obstructive sleep apnea ,Insulin resistance ,Metabolic syndrome ,Microcirculation ,Medicine (General) ,R5-920 - Abstract
Obstructive sleep apnea is an increasingly recognized medical problem. The recent attention to its frequency in the general population and its important role in metabolic, vascular, and behavioral aspects have sharply increased the number and nature of investigations, thereby revealing new aspects that open new approaches in research. Whereas obstructive sleep apnea is a well-known phenomenon accompanying obesity and diabetes, new findings strongly suggest that this close relationship may also operate in the opposite direction. Indeed obstructive sleep apnea may be a primary feature inducing or aggravating a series of vascular and metabolic disturbances closely resembling the metabolic syndrome. This review will discuss established and potential mechanisms responsible for these changes. Obstructive sleep apnea indeed appears to gather all the elements necessary to induce insulin resistance, hypertension, and possibly heart failure. After careful analysis of these modifications and considering how they are intertwined, we propose that microcirculation could represent the common denominator mediating the progression of this pathology, as it is eventually the case in the metabolic syndrome and diabetes domain. This plausible hypothesis is discussed in detail and should be verified by appropriate preclinical and clinical protocols, which are now achievable by using noninvasive techniques in humans.A apnéia obstrutiva do sono é um problema médico cujo reconhecimento tem aumentado. As últimas pesquisas mostrando sua freqüência na população em geral e seu importante papel metabólico, vascular e comportamental aumentou o número e a natureza das investigações revelando, assim, novos aspectos que abrem caminhos para estudos. Embora a apnéia obstrutiva do sono seja um fenômeno bem conhecido acompanhando diabetes e obesidade, novas descobertas sugerem que esta relação causal pode também ser verdadeira no sentido inverso. Na realidade, a apnéia obstrutiva do sono pode ser o marco inicial ou primário que induz ou agrava uma série de distúrbios vasculares e metabólicos que se aproximam da síndrome metabólica. Esta revisão discutirá mecanismos estabelecidos e potenciais responsáveis por estas mudanças. A apnéia obstrutiva do sono parece realmente juntar todos os elementos necessários para induzir resistência à insulina, hipertensão e possivelmente insuficiência cardíaca. Após análise cuidadosa destas modificações, considerando que as mesmas são interligadas, propomos que a microcirculação, como ocorre nos casos de síndrome metabólica e diabetes, poderia representar o denominador comum que mediaria a progressão desta patologia. Esta hipótese é discutida em detalhe e deve ser verificada em estudos pré-clínicos e clínicos apropriados que são atualmente possíveis usando técnicas não-invasivas em humanos.
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- 2006
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10. La metformine est associée à une moindre mortalité chez les patients diabétiques hospitalisés pour la COVID-19
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Bertrand Cariou, Samy Hadjad, Rachel Desailloud, Matthieu Pichelin, Matthieu Wargny, investigateurs de Coronado, Pierre Gourdy, Nicolas Wiernsperger, Jean-Daniel Lalau, Thomas Goronflot, and Abdallah Al-Salameh
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0301 basic medicine ,Inflammation ,COVID-19 et maladies métaboliques ,Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,CORONADO ,COVID-19 ,030209 endocrinology & metabolism ,Mortalité ,Metformin ,Metformine ,Death ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Intensive care ,Internal Medicine ,France ,Mini Dossier ,Cardiology and Cardiovascular Medicine ,Réanimation - Abstract
Resume Les effets anti-inflammatoires et modulateurs de l’immunite de la metformine legitimaient la recherche d’un meilleur pronostic chez les diabetiques hospitalises pour la maladie a coronavirus 2019 (COVID-19) traites par metformine, comparativement a ceux qui ne le sont pas. Une telle recherche a pu etre menee a partir de la cohorte nationale CORONADO, qui a inclus les patients diabetiques de type 2 hospitalises pour la COVID-19, entre le 10 mars et le 10 avril 2020 et avec une methodologie robuste : un critere de jugement principal combinant a J7 l’intubation tracheale et le deces ; une courbe de survie Kaplan–Meier ; et, surtout, une analyse de regression logistique ponderee par un score de propension. Ce sont, au total, pres de 2500 patients qui ont ete etudies, dont pres des deux-tiers traites par metformine. Ces derniers avaient globalement moins de comorbidites, liees au diabete ou non, mais, en revanche, des signes de la COVID-19 plus francs. Parmi les resultats, le fait plus marquant a ete une mortalite nettement moindre dans le groupe traite par metformine que dans le groupe non traite par metformine, et ce, des J7 (8,2 % versus 16,1 %, respectivement). Ce differentiel persistait a J28 (16,0 % versus 28,6 %, respectivement). L’hypothese d’un benefice lie a la metformine doit maintenant etre confirmee par une etude d’intervention, dont dans la population generale.
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- 2021
11. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19
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Anne Dutour, Matthieu Wargny, Michael Joubert, D. Gouet, Thierry Duriez, Rachel Desailloud, Gaëtan Prévost, Pierre Gourdy, Bertrand Cariou, Matthieu Pichelin, Christelle Raffaitin-Cardin, Thomas Goronflot, Frédérique Olivier, Ingrid Julier, Céline Gonfroy, Ingrid Allix, Laurent Meyer, Etienne Larger, Coralie Amadou, Lucien Marchand, Dominique Seret-Bégué, Pierre-Jean Saulnier, Charles Thivolet, Abdallah Al-Salameh, Camille Vatier, Olivier Bourron, Ronan Roussel, Samy Hadjadj, Jean-François Gautier, Nicolas Wiernsperger, Pascale Quiniou, Jean-Daniel Lalau, Michel Marre, CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de l'Environnement Industriel et des Risques, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Association REMEDES [Ville-sur-Jarnioux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre Hospitalier de Cholet (CHC), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Nord [CHU - APHM], Centre Hospitalier René Dubos [Pontoise], Centre Hospitalier de La Rochelle (CHR), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Alès-Cévennes (CHAC), Hôpital Cochin [AP-HP], Centre Hospitalier Saint Joseph (CH St Joseph), Hôpital Ambroise Paré [AP-HP], Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, Centre hospitalier de Cahors, Département d'Endocrinologie, Diabète et Maladies Métaboliques [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Libourne, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Gonesse (CHU Gonesse), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and CarMeN, laboratoire
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Male ,medicine.medical_specialty ,endocrine system diseases ,Propensity score ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Lower risk ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Mechanical ventilation ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Clinical endpoint ,Humans ,Hypoglycemic Agents ,Survival analysis ,Aged ,Aged, 80 and over ,business.industry ,Mortality rate ,General Medicine ,Middle Aged ,medicine.disease ,Respiration, Artificial ,Metformin ,3. Good health ,[SDV] Life Sciences [q-bio] ,Hospitalization ,Death ,Diabetes Mellitus, Type 2 ,Propensity score matching ,Original Article ,Female ,business ,Covid-19 ,medicine.drug - Abstract
International audience; AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P \textless 0.0001) and on day 28 (16.0 vs 28.6%, P \textless 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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- 2020
12. New concepts in microvascular function and metabolic diseases: importance of cephalic phase of insulin response
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Eliete Bouskela, Nicolas Wiernsperger, Wellington Santana da Silva, Luiz Guilherme Kraemer-Aguiar, and Caroline Buss
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Type 1 diabetes ,Adrenal disorder ,business.industry ,Insulin ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Cephalic phase ,030204 cardiovascular system & hematology ,medicine.disease ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Diabetes mellitus ,medicine ,Glucose homeostasis ,Hormone metabolism ,business - Published
- 2018
13. Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm
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Mette Marie Hougaard Christensen, Alessandro Protti, Nicolas Wiernsperger, Marc E. De Broe, Farshad Kajbaf, and Jean Daniel Lalau
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medicine.medical_specialty ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,digestive, oral, and skin physiology ,nutritional and metabolic diseases ,Physiology ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,medicine.disease ,Metformin ,Clinical Practice ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Lactic acidosis ,Internal Medicine ,medicine ,Hyperlactatemia ,Intensive care medicine ,business ,Adverse effect ,medicine.drug - Abstract
Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin-treated patients. Accordingly, we propose a check-list as a guide to clinical practice.
- Published
- 2017
14. Treatment Strategies for Fatty Liver Diseases
- Author
-
Nicolas Wiernsperger
- Subjects
Pharmacology ,education.field_of_study ,business.industry ,Fatty liver ,Population ,General Medicine ,medicine.disease ,Bioinformatics ,Therapeutic index ,Non-alcoholic Fatty Liver Disease ,medicine ,Humans ,Treatment strategy ,Epigenetics ,Prediabetes ,Steatosis ,Metabolic syndrome ,education ,business - Abstract
Hepatic steatosis, a hallmark of non-alcoholic fatty liver diseases (NAFLD), is an early marker as well as a cause of the cardiometabolic syndrome, prediabetes and NIDDM. Its high prevalence in the general population and its many causes and complex mechanisms make it a pathology which must be treated and requires careful diagnosis also in terms of underlying causes, which may strongly vary among subjects. The recent awareness of the commonness of NAFLD has prompted intensive research which unraveled many different mechanisms causing hepatic steatosis, from diet to intestinal diseases and liver receptors. Epigenetic factors must be added to this list. A variety of causes and mechanisms open many different potential therapeutic approaches. This review aims at summarizing the effects of a selected series of old and new treatments for which there exist at least a reasonable amount of data. Many show efficacy in animals but human data are less convincing largely because of poor amount of data and generally they lack histological confirmation. Many drugs either induce undesirable side-effects or have tight therapeutic dose windows. The recent recognition of a key role of intestinal microbiota in NAFLD and metabolic syndrome may represent a major therapeutic breakthrough by the modulation of bacteria in the gut. Performing randomized long-term clinical studies including liver biopsies appears as prerequisite to determine which treatment is the most valuable, however not ignoring that the therapeutic choice may require individualization among subjects as a function of the origins of NAFLD.
- Published
- 2015
15. Novel findings in the cephalic phase of digestion: A role for microcirculation?
- Author
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Caroline Buss, Priscila A. Maranhão, Luiz Guilherme Kraemer-Aguiar, Carolina Marinho, Eliete Bouskela, Nicolas Wiernsperger, and Maria das Graças Coelho de Souza
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Capillary recruitment ,medicine.medical_treatment ,Experimental and Cognitive Psychology ,Vasomotion ,Biology ,Administration, Cutaneous ,Microcirculation ,Behavioral Neuroscience ,Basal (phylogenetics) ,Skin Physiological Phenomena ,Internal medicine ,medicine ,Humans ,Insulin ,Pancreatic polypeptide ,Skin ,Cephalic phase ,Iontophoresis ,Red blood cell ,medicine.anatomical_structure ,Endocrinology ,Cephalic phase of digestion ,Digestion ,Cues ,Blood Flow Velocity ,Photic Stimulation - Abstract
The cephalic phase of digestion (CPD) has been extensively investigated in terms of digestion and metabolism. Nevertheless, microcirculatory changes required to prepare peripheral tissues in order to dispose nutrients have never been assessed. In this study, microvascular function has been evaluated to determine its behavior and potential association to hormonal secretions during CPD. Thirty-nine healthy male subjects, 23.4 ± 0.5 years (mean ± SD) and BMI of 23.3 ± 2.3 kg/m(2), were randomized into receiving cognitive-sensorial stimuli to elicit CPD (CPD group, n=20) or not (control group, n=19), after a 12-h overnight fast. Main outcomes were differences in resting and peak functional capillary density (FCD, cap/mm(2)); resting red blood cell velocity (RBCV), peak RBCV (RBCV(max)) and time taken to reach it (TRBCV(max)); peak flow and vasomotion, before and after CPD and their associations with insulin and/or pancreatic polypeptide (PP). In the CPD group, basal FCD (24.9 ± 7.6 to 28.3 ± 8.1, p=0.005), peak FCD (27.8 ± 6.3 to 32.6 ± 7.1, p=0.002), RBCV (0.306 ± 0.031 to 0.330 ± 0.027 mm/s, p=0.005), RBCV(max) (0.336 ± 0.029 to 0.398 ± 0.292 mm/s, p=0.005) and peak flow (23.5 ± 14.3 to 26.9 ± 15.8 PU, p
- Published
- 2012
16. Fructose and cardiometabolic disorders: the controversy will, and must, continue
- Author
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Jean-Robert Rapin, Nicolas Wiernsperger, and Alain Géloën
- Subjects
medicine.medical_specialty ,Review ,Fructose ,Biology ,Bioinformatics ,chemistry.chemical_compound ,Insulin resistance ,Risk Factors ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Vascular Diseases ,Triglycerides ,Hypertriglyceridemia ,lcsh:R5-920 ,General Medicine ,medicine.disease ,Obesity ,Metabolic syndrome ,Diet ,Endocrinology ,chemistry ,Liver ,Sweetening Agents ,Hypertension ,Uric acid ,lcsh:Medicine (General) ,Dyslipidemia - Abstract
The present review updates the current knowledge on the question of whether high fructose consumption is harmful or not and details new findings which further pushes this old debate. Due to large differences in its metabolic handling when compared to glucose, fructose was indeed suggested to be beneficial for the diet of diabetic patients. However its growing industrial use as a sweetener, especially in soft drinks, has focused attention on its potential harmfulness, possibly leading to dyslipidemia, obesity, insulin resistance/metabolic syndrome and even diabetes. Many new data have been generated over the last years, confirming the lipogenic effect of fructose as well as risks of vascular dysfunction and hypertension. Fructose exerts various direct effects in the liver, affecting both hepatocytes and Kupffer cells and resulting in non-alcoholic steatotic hepatitis, a well known precursor of the metabolic syndrome. Hepatic metabolic abnormalities underlie indirect peripheral metabolic and vascular disturbances, for which uric acid is possibly the culprit. Nevertheless major caveats exist (species, gender, source of fructose, study protocols) which are detailed in this review and presently prevent any firm conclusion. New studies taking into account these confounding factors should be undertaken in order to ascertain whether or not high fructose diet is harmful.
- Published
- 2010
17. Short-term treatment with metformin improves the cardiovascular risk profile in first-degree relatives of subjects with type 2 diabetes mellitus who have a metabolic syndrome and normal glucose tolerance without changes in C-reactive protein or fibrinogen
- Author
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Eliete Bouskela, Luis Mauro Alvim de Lima, Luiz Guilherme Kraemer-Aguiar, and Nicolas Wiernsperger
- Subjects
Adult ,Male ,medicine.medical_specialty ,Clinical Sciences ,Normoglycemia ,Fibrinogen ,Statistics, Nonparametric ,C-reactive protein ,Double-Blind Method ,Risk Factors ,Internal medicine ,Humans ,Hypoglycemic Agents ,Medicine ,First-degree relatives ,lcsh:R5-920 ,medicine.diagnostic_test ,biology ,business.industry ,Type 2 Diabetes Mellitus ,General Medicine ,Middle Aged ,medicine.disease ,Metabolic syndrome ,Metformin ,Pedigree ,Endocrinology ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,biology.protein ,Female ,business ,Lipid profile ,lcsh:Medicine (General) ,Body mass index ,Biomarkers ,medicine.drug - Abstract
OBJECTIVE: To study if metformin, when administered to first-degree relatives of type 2 diabetes mellitus subjects who have metabolic syndrome and normal glucose tolerance, could improve the cardiovascular risk profile and reduce the levels of both C-reactive protein and fibrinogen. INTRODUCTION: Metabolic syndrome is associated with higher cardiovascular morbidity and mortality. Metformin has vasculo-protective effects even in normoglycemic subjects, and C-reactive protein and fibrinogen are considered markers of endothelial injury and inflammation. METHODS: Thirty-one non-diabetic first-degree relatives of type 2 diabetes mellitus subjects with metabolic syndrome were randomized (1:1) and double-blinded for placement in the placebo and metformin groups (850mg bid/±90days); 16 subjects were administered metformin (mean age 40.0 [33.5-50] years; 13 females) and 15 subjects were in the placebo group (mean age 37.0 [32-42] years; 9 females). Blood samples were collected at baseline and at the end of treatment for biochemical analyses, including an assessment of C-reactive protein and fibrinogen levels. RESULTS: Metformin improved the lipid profile and decreased fasting plasma glucose, systolic blood pressure, weight and body mass index without changing body composition. For those in the placebo we identified no changes in fibrinogen (282.2 [220.4-323.7] mg/L vs. 286.7 [249.6-295.1] mg/L; NS) or in C-reactive protein levels (0.68 [0.3-1.2] vs. 0.64 [0.3-1.0] mg/L; NS). The same was also observed for the levels of fibrinogen (303.9 [217.6-347.6] mg/L vs. 290.9 [251.5-301.9] mg/L; NS) and C-reactive proteins (0.78 [0.3-1.1] vs. 0.80 [0.4-0.9] mg/L; NS) in the metformin group. CONCLUSIONS: Metformin treatment in first-degree relatives of type 2 diabetes mellitus sufferers who have metabolic syndrome and normal glucose tolerance improved the cardiovascular risk profile without changing the levels of C-reactive protein and fibrinogen.
- Published
- 2009
18. Metabolic disturbances linked to obesity: the role of impaired tissue perfusion
- Author
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Eliete Bouskela, Daniel Alexandre Bottino, Nicolas Wiernsperger, Luiz Guilherme Kramer-Aguiar, and Nivaldo Ribeiro Villela
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Inflammation ,Microcirculation ,Insulin resistance ,Internal medicine ,Renin–angiotensin system ,Animals ,Humans ,Medicine ,Obesity ,Endothelial dysfunction ,business.industry ,General Medicine ,medicine.disease ,Rats ,Oxidative Stress ,Endocrinology ,Adipose Tissue ,Cardiovascular Diseases ,Regional Blood Flow ,Hypertension ,Vascular Resistance ,Endothelium, Vascular ,Insulin Resistance ,Metabolic syndrome ,medicine.symptom ,business ,Perfusion - Abstract
Associated with elevated risk of cardiovascular events and cancer, obesity is a worldwide problem affecting developed and developing countries. Microcirculatory vessels, represented by arterioles, capillaries and venules (mean internal diameter < 100 µm), are the place where blood/tissue nutrition and exchange effectively take place. Microvascular dysfunction is an early event in obesity probably secondary to endothelial dysfunction and capillaries rarefaction. New research techniques allow the investigation of the microcirculation in different vascular beds in humans. Studies suggest a link between endothelial dysfunction and visceral obesity. Oxidative stress, inflammation and rennin-angiotensin system are among factors considered to be involved on microvascular dysfunction in obesity. Microcirculatory impairment present in obesity suggests that it could be an important causal factor in obesity-related disorders such as insulin resistance and hypertension.
- Published
- 2009
19. Sleep Apnea Is Induced by a High-fat Diet and Reversed and Prevented by Metformin in Non-obese Rats*
- Author
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Michel Petitjean, Stéphane Delanaud, Alain Géloën, Jean-Pierre Libert, Gérard Dewasmes, Nicolas Wiernsperger, and Wiâm Ramadan
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Central apnea ,Drug Evaluation, Preclinical ,Medicine (miscellaneous) ,Rats, Sprague-Dawley ,Sleep Apnea Syndromes ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Hypoglycemic Agents ,Plethysmograph ,Sleep Stages ,Nutrition and Dietetics ,business.industry ,Body Weight ,Sleep apnea ,Apnea ,medicine.disease ,Dietary Fats ,Obesity ,Metformin ,Rats ,Diet, Atherogenic ,medicine.symptom ,Sleep ,business ,medicine.drug - Abstract
Objective: We assessed the relationship between a high-fat (HF) diet and central apnea during rapid eye movement and non-rapid eye movement sleep stages by recording ventilatory parameters in 28 non-obese rats in which insulin resistance had been induced by an HF diet. We also studied whether metformin (an anti-hyperglycemic drug frequently used to treat insulin resistance) could reverse sleep apnea or prevent its occurrence in this experimental paradigm. Research Methods and Procedures: Rats were fed with a standard diet (10 rats), an HF diet (8 rats), or an HF diet concomitantly with metformin treatment (10 rats). Each animal was instrumented for electroencephalographic and electromyographic recording. After 3 weeks, ventilatory parameters during sleep were recorded with a body plethysmograph. All rats were treated with metformin for 1 week, after which time the ventilatory measurements were measured again. Results: Our results showed that the three groups of animals did not differ in terms of body growth over the entire experimental period. The HF diet did not modify sleep structure or minute ventilation in the different sleep stages. A great increase (+266 ± 48%) in central apnea frequency was observed in insulin-resistant rats. This was explained by an increase in both post-sigh (+195 ± 35%) and spontaneous apnea (+437 ± 65%) in the different sleep stages. These increases were suppressed by metformin treatment. Discussion: Insulin resistance induced by the HF diet could be the promoter of sleep apnea in non-obese rats. Metformin is an efficient curative and preventive treatment for sleep apnea, suggesting that insulin resistance modifies the ventilatory drive independently of obesity.
- Published
- 2007
20. Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome
- Author
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C.M. Laflor, Nicolas Wiernsperger, Eliete Bouskela, Luciana Bahia, L. G. Kraemer de Aguiar, Daniel Alexandre Bottino, and Nivaldo Ribeiro Villela
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Coronary Disease ,Microcirculation ,Endocrinology ,Insulin resistance ,Double-Blind Method ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Medicine ,Skin ,Metabolic Syndrome ,medicine.diagnostic_test ,business.industry ,Microangiopathy ,Middle Aged ,medicine.disease ,Metformin ,Capillaries ,Oxidative Stress ,Blood pressure ,Diabetes Mellitus, Type 2 ,Female ,Metabolic syndrome ,business ,Lipid profile ,Diabetic Angiopathies ,medicine.drug - Abstract
Aims Insulin resistance and a parental history of diabetes mellitus are independently associated with endothelial dysfunction. Oxidative stress has a pivotal role in the pathophysiology of vascular injury. Metformin, in addition to its glucose-lowering properties, has vasculoprotective effects. We investigated whether metformin has beneficial effects on the nutritive skin capillary circulation and deceases oxidative stress in a group at high risk for Type 2 diabetes mellitus (T2DM) and cardiovascular disease. Methods Thirty normoglycaemic subjects with the metabolic syndrome (MS), who had first-degree relatives with T2DM, participated. The mean age was 39.1 ± 8.4 years and body mass index (BMI) 35.7 ± 4.8 kg/m2 (mean ±sd). Subjects were randomized 1 : 1 to receive placebo (n = 14) or metformin (n = 16; 1700 mg/day) in a double-blind study. At baseline and post treatment, blood and urine samples were collected for biochemical and 8-epi-prostaglandin F2α (8-epi-PGF2α) analysis, respectively. Microcirculation was assessed by nailfold videocapillaroscopy, analysing afferent (AF), efferent (EF) and apical (AP) diameters of capillary loops, functional capillary density (FCD), red blood cell velocity at rest (RBCV), after 1 min arterial occlusion (RBCVmax) and time (TRBCVmax) taken to reach it. Results Groups did not differ significantly in anthropometric, clinical, laboratory or microvascular measurements at baseline. In the metformin group, weight, BMI, systolic blood pressure and fasting plasma glucose fell, and lipid profile and microcirculatory parameters FCD, AF, EF, AP, RBCVmax and TRBCVmax improved (all P
- Published
- 2007
21. List of Contributors
- Author
-
John M. Abbamonte, Ahmad Afaghi, Olubukola Ajala, Renata Moneda Alberto dos Santos, Siddhartha S. Angadi, Gol-Naz Arjomand, Kristin J. August, Sachin L. Badole, Christophe Beauloye, Luc Bertrand, Guenther Boden, F. Boubred, M. Jason Brooke, José Abrão Cardeal da Costa, Zijian Chen, Allan Stubbe Christensen, Christian Loepfe, Francesco Corrado, Giuseppe D’Antona, Amy A. Devitt, Patrick English, M. Florentin, Glenn A. Gaesser, Søren Gregersen, Refaat A. Hegazi, Sandrine Horman, Syed Khalid Imam, Ganesh B. Jangam, Catherine Jarrett, Chiemi Kamada, Caitlin S. Kelly, Arash Kordi, Jeremy Krebs, Daniel Y. Li, Fabíola Pansani Maniglia, Maria Lisa Marcon, Claire T. McEvoy, Jeffrey I. Mechanick, Dean J. Mikami, D. Mitanchez, Bradley J. Needleman, Laura Nollino, Sabrena F. Noria, Ezekiel Uba Nwose, Agostino Paccagnella, Athanasia K. Papazafiropoulou, Amber Parry-Strong, Kalyani Y. Patil, Roberta Pirolo, Jahan Porhomayon, Ioannis Protopsaltis, Vinod D. Rangari, Abhishek Rege, James A. Rydlewicz, Leila Sabzmakan, Rashmi Saini, Behzad Salari, Shabnam Samankan, Maria Sambataro, Angelo Santamaria, Kostantinos Sarantos, Brandon J. Sawyer, Farzad Shidfar, Prachi Shukla, U. Simeoni, Michele Tessarin, V. Tsimihodimos, Wesley J. Tucker, Cecile Vennos, Michael A. Via, Lone Viggers, Claudia Vigo, Nicolas Wiernsperger, W.H. Wilson Tang, Jayne V. Woodside, and C. Yzydorczyk
- Published
- 2015
22. Microcirculation
- Author
-
Nicolas Wiernsperger
- Subjects
medicine.medical_specialty ,Glucose uptake ,Insulin ,medicine.medical_treatment ,Inflammation ,Vasomotion ,Vasodilation ,Biology ,medicine.disease ,Microcirculation ,Postprandial ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,medicine.symptom - Abstract
The mechanisms underlying insulin resistance are still incompletely defined, and target cell biochemical abnormalities, while numerous, do not fully explain the reductions in organ glucose uptake in vivo. Since the highlighting of insulin vasodilatory actions, experimental and later clinical research has provided demonstrations of a key role of the smallest vessels in partly determining the muscle uptake of glucose. While insulin alone acts as a dilator at the level of the terminal arterioles feeding the capillary units, the more physiological state of combined elevated glucose and insulin, such as in the postprandial period, is characterized by microflow redistribution due to activation of precapillary vasomotion. It was found that glucose delivery, i.e., microflow, accounts for 30–40% of muscle glucose uptake. This process is hampered by inflammation factors or NO inhibition. The ubiquitous presence of concomitant insulin resistance and microvascular dysfunction in most various diseases suggests a causal, bidirectional, link between both processes. Possible mechanisms leading to derangements in this relation are reviewed.
- Published
- 2015
23. Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance
- Author
-
Luiz Guilherme Kraemer de Aguiar, Luciana R. Bahia, Nivaldo Villela, Camila Laflor, Fernando Sicuro, Nicolas Wiernsperger, Daniel Bottino, and Eliete Bouskela
- Subjects
Adult ,Blood Glucose ,Male ,Metabolic Syndrome ,Nitroprusside ,Advanced and Specialized Nursing ,Vasodilator Agents ,Endocrinology, Diabetes and Metabolism ,Glucose Tolerance Test ,Middle Aged ,Metformin ,Body Mass Index ,Placebos ,Diabetes Mellitus, Type 2 ,Double-Blind Method ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Female ,Endothelium, Vascular - Abstract
OBJECTIVE—Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients. RESEARCH DESIGN AND METHODS—The study included 31 subjects (age 38.3 ± 7.6 years and BMI 36.3 ± 5.2 kg/m2), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothelium-dependent (acetylcholine 7.5, 15, and 30 μg/min) and independent (sodium nitroprusside 2, 4, and 8 μg/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment. RESULTS—The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters. CONCLUSIONS—We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects.
- Published
- 2006
24. 5-Aminoimidazole-4-Carboxamide-1-β-<scp>d</scp>-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation
- Author
-
Bruno Guigas, Louis Hue, Nicolas Wiernsperger, Didier Vertommen, Benoit Viollet, Fabrizio Andreelli, Nellie Taleux, Marc Foretz, and Luc Bertrand
- Subjects
Male ,medicine.medical_specialty ,Oligomycin ,Phosphofructokinase-2 ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Models, Biological ,chemistry.chemical_compound ,Adenosine Triphosphate ,AMP-activated protein kinase ,Internal medicine ,Glucokinase ,Internal Medicine ,medicine ,Animals ,Glycolysis ,Rats, Wistar ,Protein kinase A ,biology ,Kinase ,Adenylate Kinase ,AMPK ,Ribonucleotides ,Aminoimidazole Carboxamide ,Metformin ,Rats ,Kinetics ,Protein Transport ,Glucose ,Endocrinology ,Liver ,chemistry ,biology.protein ,Cattle ,Oligomycins - Abstract
AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver α1 and α2 AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions.
- Published
- 2006
25. Metformin delays the manifestation of diabetes and vascular dysfunction in Goto–Kakizaki rats by reduction of mitochondrial oxidative stress
- Author
-
Peter Rösen and Nicolas Wiernsperger
- Subjects
Blood Glucose ,Male ,Mitochondrial ROS ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Aorta, Thoracic ,Type 2 diabetes ,In Vitro Techniques ,Mitochondrion ,medicine.disease_cause ,Aconitase ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Rats, Wistar ,business.industry ,Insulin ,Rats, Inbred Strains ,medicine.disease ,Metformin ,Mitochondria ,Rats ,Disease Models, Animal ,Oxidative Stress ,Diabetes Mellitus, Type 2 ,business ,Diabetic Angiopathies ,Oxidative stress ,medicine.drug - Abstract
Background and aim This study was undertaken to test the hypothesis that hyperglycaemia induces the generation of reactive oxygen species (ROS) by mitochondria and that the oxidative stress thereby exerted is diminished by treatment with metformin. As a parameter of mitochondrial ROS formation, the activity of mitochondrial aconitase activity was determined using Goto–Kakizaki (GK) rats as model of type 2 diabetes. Methods In parallel with the development of diabetes (glucose, insulin), the generation of oxidative stress was determined in aortic tissue, heart and kidney of GK rats by measurement of lipid peroxides, oxidized proteins (carbonyl activity) and mitochondrial aconitase activity. Vascular activity was determined in aortae by measuring the endothelium-dependent vasodilatation in response to acetylcholine, and vasoconstriction in response to phenylephrine. Results At the age of 12–14 weeks, blood glucose levels rose dramatically from 7.5 up to 16.2 mM, indicating the manifestation of an overt diabetes. In addition, the glucose tolerance was impaired. The increase in blood glucose was not accompanied by changes in plasma insulin. Whereas the lipid peroxides in plasma only showed a tendency to increase, the amount of oxidized proteins (carbonyl moieties) increased from 4.6 to 10.9 µmol/mg protein (2.4 fold). In addition, the lipid peroxides in tissue were increased. Mitochondrial aconitase activity was reduced in the aorta and kidney, but not in the heart of diabetic animals. Treatment with metformin nearly normalized the hyperglycaemia and prevented the rise in carbonyl, tissue lipid peroxides and the fall in aconitase activity. Whereas the endothelium-dependent vasodilatation was not affected by the diabetes, the reaction of aortae in response to phenylephrine was strongly enhanced, changes which were prevented by treatment with metformin. Conclusions These observations provide in vivo evidence that the generation of ROS plays an important role in the onset of diabetes and the development of vascular dysfunction in GK rats with type 2 diabetes. Copyright © 2006 John Wiley & Sons, Ltd.
- Published
- 2006
26. Is non-insulin dependent glucose uptake a therapeutic alternative? Part 1: physiology, mechanisms and role of non insulin-dependent glucose uptake in type 2 diabetes
- Author
-
Nicolas Wiernsperger
- Subjects
Blood Glucose ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Glucose Transport Proteins, Facilitative ,Type 2 diabetes ,Biology ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Insulin ,Glycogen ,Glucokinase ,Cell Membrane ,Glucose transporter ,Biological Transport ,General Medicine ,medicine.disease ,Diabetes Mellitus, Type 2 ,Basal (medicine) ,chemistry - Abstract
Summary Several decades of research for treating type 2 diabetes have yielded new drugs but the actual experience with the available oral antidiabetic compounds clearly shows that therapeutic needs are not matched. This highlights the urgent need for exploring other pathways. All cell types have the capacity to take up glucose independently of insulin, whereby basal but also hyperglycaemia-promoted glucose supply is ensured. Although poorly explored, insulin-independent glucose uptake might nevertheless represent a therapeutic target, as an alternative to the clear limits of actual drug treatments. This review not only critically examines some major pathways not requiring insulin (although they may be influenced by the hormone) but importantly, this analysis extends to the clinical applicability of these potential therapeutic principles by also considering their predictable tolerability for long-term therapy. In particular vascular safety (the ultimate problem linked with diabetes) will be envisaged because of the ubiquitous distribution of glucose transporters and some linked mechanisms. Several mechanisms can be identified which do not require insulin for their functioning. The first part of this review deals with the description, the regulation and the limits of some mechanisms representing potential pharmacological targets capable of having a highly significant impact on glucose uptake. These selected topics are: a) unmasking and/or activation of glucose transporters in cell plasma membranes, b) insulin mimetics acting at postreceptor level, c) activation of AMPK, d) increasing nitric oxide and e) increasing glucose-6P and glycogen stores.
- Published
- 2005
27. Signaling Pathways Involved in Human Vascular Smooth Muscle Cell Proliferation and Matrix Metalloproteinase-2 Expression Induced by Leptin
- Author
-
Nicolas Wiernsperger, Jean-Claude Mamputu, Ling Li, and Geneviève Renier
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,NADPH oxidase ,Vascular smooth muscle ,biology ,Endocrinology, Diabetes and Metabolism ,Leptin ,digestive, oral, and skin physiology ,Adipokine ,Metformin ,Endocrinology ,Internal medicine ,Internal Medicine ,biology.protein ,medicine ,Signal transduction ,Protein kinase C ,medicine.drug - Abstract
Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal–regulated kinase (ERK)1/2, and nuclear factor-κB (NF-κB) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-κB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-κB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.
- Published
- 2005
28. Glomerular proliferation during early stages of diabetic nephropathy is associated with local increase of sphingosine-1-phosphate levels
- Author
-
Michel Lagarde, Nicolas Wiernsperger, Karen Geoffroy, Lysiane Troncy, and Samer El Bawab
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Sphingosine-1-phosphate ,Kidney Glomerulus ,Biophysics ,Sphingosine kinase ,Ceramidase ,Biology ,urologic and male genital diseases ,Biochemistry ,Streptozocin ,Amidohydrolases ,Diabetic nephropathy ,chemistry.chemical_compound ,Mesangial cells ,Sphingosine ,Structural Biology ,Neutral Ceramidase ,Internal medicine ,Diabetes mellitus ,Ceramidases ,Genetics ,medicine ,Animals ,Diabetic Nephropathies ,Rats, Wistar ,Molecular Biology ,Cell Proliferation ,Streptozotocin ,urogenital system ,Cell Biology ,Glomerular proliferation ,medicine.disease ,Sphingolipid ,Rats ,Phosphotransferases (Alcohol Group Acceptor) ,Endocrinology ,chemistry ,Lysophospholipids ,medicine.drug - Abstract
In this study, the effects of short-term diabetes (4 days) on rat renal glomerular cells proliferation and the potential involvement of sphingolipids in this process were investigated. Immunohistochemical analysis showed that streptozotocin (STZ)-induced diabetes promoted increased intra-glomerular hyperplasia, particularly marked for mesangial cells. This was associated with a concomitant increase in neutral ceramidase and sphingosine-kinase activities and the accumulation of the pro-proliferative sphingolipid sphingosine-1-phosphate, in glomeruli isolated from kidney cortex of STZ-treated rats. These results suggest a possible involvement of sphingolipid metabolites in the glomerular proliferative response during the early stages of diabetic nephropathy.
- Published
- 2005
29. a-Series Gangliosides Mediate the Effects of Advanced Glycation End Products on Pericyte and Mesangial Cell Proliferation
- Author
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Daniel Ruggiero, Michel Lagarde, Elodie Masson, Lysiane Troncy, Samer El Bawab, and Nicolas Wiernsperger
- Subjects
0303 health sciences ,medicine.medical_specialty ,Kidney ,Mesangial cell ,Cell growth ,Renal glomerulus ,Endocrinology, Diabetes and Metabolism ,Renal cortex ,Biology ,medicine.disease ,Diabetic nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Glycation ,030220 oncology & carcinogenesis ,Internal medicine ,Internal Medicine ,medicine ,Pericyte ,030304 developmental biology - Abstract
Advanced glycation end products (AGEs) are involved in the development of microvascular complications, including alterations of retinal pericyte and renal mesangial cell growth occurring during diabetic retinopathy and diabetic nephropathy, respectively. Because gangliosides are implicated in the regulation of cell proliferation, we hypothesized that AGEs could exert cellular effects in part by modulating ganglioside levels. Results of the present study indicate that AGEs caused an inhibition of both bovine retinal pericyte (BRP) and rat renal mesangial cell (RMC) proliferation, associated with an increase of a-series gangliosides consecutive to GM3 synthase activity increase and GD3 synthase activity inhibition. Similar modifications were also found in the renal cortex of diabetic db/db mice compared with controls. Treatment of BRP and RMC with exogenous a-series gangliosides decreased proliferation and blockade of a-series gangliosides with specific antibodies partially protecting the two cell types from the AGE-induced proliferation decrease. Further, inhibition of GM3 synthase using specific SiRNA partially reversed the AGE effects on mesangial cell proliferation. These results suggest that a-series gangliosides are mediators of the adverse AGE effects on BRP and RMC proliferation. They also raise the hypothesis of common mechanisms involved in the development of diabetic retinopathy and diabetic nephropathy.
- Published
- 2005
30. Involvement of gangliosides in glucosamine-induced proliferation decrease of retinal pericytes
- Author
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Michel Lagarde, Elodie Masson, Nicolas Wiernsperger, Samer El Bawab, and Merck & Co. Inc
- Subjects
Biochemistry ,chemistry.chemical_compound ,brp ,0302 clinical medicine ,hp ,Glucosamine ,gfat ,0303 health sciences ,bsa ,music.instrument ,hptlc ,ppmp ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,dl-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol ,gangliosides ,3. Good health ,diabetic retinopathy ,medicine.anatomical_structure ,lipids (amino acids, peptides, and proteins) ,Pericyte ,high-performance thin-layer chromatography ,pbs ,medicine.medical_specialty ,Meperidine ,dulbecco’s modified eagle’s medium ,hank’s balanced salt solution ,Context (language use) ,G(M1) Ganglioside ,Biology ,Retina ,pericytes ,03 medical and health sciences ,Lactosylceramide ,glucosamine-6-phosphate by glutamine:f-6-p amidotransferase ,bovine serum albumin ,Internal medicine ,medicine ,Animals ,music ,Cell Proliferation ,030304 developmental biology ,hbss ,Ganglioside ,bovine retinal pericyte ,Cell growth ,Retinal ,hexosamine pathway ,Endocrinology ,chemistry ,Cattle ,dmem ,030217 neurology & neurosurgery - Abstract
The hexosamine pathway (HP) is a biochemical hypothesis recently proposed explaining cellular alterations occurring during diabetic microvascular complications. Diabetic retinopathy is a common microvascular complication of diabetes, and it is known that cell proliferation is severely affected during the development of the disease. Particularly, early stages are characterized by death of the retinal microvascular cells, pericytes. Gangliosides have often been described to regulate cell growth; however, very few studies focused on the potential role of gangliosides in diabetic microvascular alterations. The aim of this article was to investigate the effect of the HP activation on pericyte proliferation and determine the potential implication of gangliosides in this process. Results indicate first that HP activation, mimicked by glucosamine treatment, decreased pericyte proliferation. Second, glucosamine treatment induced a modification of gangliosides pattern, particularly GM1 and GD3 were significantly increased. Next, results showed that exogenous addition of a-series gangliosides (GM3, GM2, GM1, GD1a) and b-series ganglioside (GD3) caused a decrease of pericyte proliferation, whereas nonsialylated precursors glucosylceramide and lactosylceramide were without effect. Furthermore, when ganglioside biosynthesis was blocked using PPMP, a glucosylceramide synthase inhibitor, the effects of glucosamine on pericyte proliferation were partially reversed. Our results suggest that in retinal pericytes, gangliosides and particularly GM1 and GD3 that are increased in response to glucosamine, are involved in the antiproliferative effect of glucosamine. These observations also underlie the potential involvement of gangliosides in a pathological context, such as diabetic microvascular complications.
- Published
- 2004
31. Involvement of caspase-10 in advanced glycation end-product-induced apoptosis of bovine retinal pericytes in culture
- Author
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Nicolas Wiernsperger, Michel Lagarde, Ulriche Denis, Marc Lecomte, and Daniel Ruggiero
- Subjects
Glycation End Products, Advanced ,Ceramide ,Apoptosis ,Retina ,Amino Acid Chloromethyl Ketones ,Caspase-10 ,chemistry.chemical_compound ,Diabetic retinopathy ,Annexin ,Glycation ,medicine ,Animals ,Caspase 10 ,Molecular Biology ,Caspase ,Pericyte ,Diacylglycerol kinase ,Advanced glycation end-product ,Caspase 8 ,biology ,Cell biology ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Caspases ,biology.protein ,Molecular Medicine ,Cattle ,Oligopeptides - Abstract
Apoptosis appears to be the death mechanism of pericyte loss observed in diabetic retinopathy. We have previously shown that advanced glycation end-products (AGE-MGX) induce apoptosis of retinal pericytes in culture associated with diacylglycerol (DAG)/ceramide production. In the present study, we investigated possible caspase involvement in this process. Bovine retinal pericytes (BRP) were cultured with AGE-MGX and apoptosis examined after annexin V staining. Effects of peptidic inhibitors of caspases were determined on DAG/ceramide production and apoptosis. Pan-caspase inhibitor z-VAD-fmk (50 microM) was able to inhibit both DAG/ceramide production and apoptosis, whereas caspase-3-like inhibitor z-DEVD-fmk (50 microM) or caspase-9 inhibitor z-LEHD-fmk (50 microM) was only active on apoptosis. This differential effect strongly suggests involvement of initiator caspase(s) upstream and effector caspase(s) downstream DAG/ceramide production in AGE-mediated apoptosis. Pericyte treatment with caspase-8 inhibitor z-IETD-fmk (50 microM) did not protect cells against AGE-induced apoptosis and we failed to detect caspase-8 in pericytes by immunoblotting assay. Interestingly, one inhibitor of caspase-10 and related caspases z-AEVD-fmk (50 microM) inhibited both AGE-MGX-induced apoptosis and DAG/ceramide formation in pericytes. Cleavage of caspase-10 precursor into its active subunits was demonstrated by immunoblotting assay in pericytes incubated with AGE-MGX. These results strongly suggest that caspase-10, but not caspase-8, might be involved in the early phase of AGE-induced pericyte apoptosis, in contrast to caspase-9 and -3-like enzymes involved after DAG/ceramide production. This finding may provide new therapeutic perspectives for early treatment in diabetic retinopathy.
- Published
- 2004
32. Bimodal Effect of Advanced Glycation End Products on Mesangial Cell Proliferation Is Mediated by Neutral Ceramidase Regulation and Endogenous Sphingolipids
- Author
-
Michel Lagarde, Karen Geoffroy, Nicolas Wiernsperger, and Samer El Bawab
- Subjects
Glycation End Products, Advanced ,Male ,Diacylglycerol Kinase ,Ceramide ,medicine.medical_specialty ,Time Factors ,Blotting, Western ,Biology ,Glucosylceramides ,Models, Biological ,Biochemistry ,Amidohydrolases ,Diabetes Mellitus, Experimental ,Diabetic nephropathy ,chemistry.chemical_compound ,Sphingosine ,Glycation ,Neutral Ceramidase ,Internal medicine ,Ceramidases ,medicine ,Animals ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Chromatography, High Pressure Liquid ,Sphingolipids ,Dose-Response Relationship, Drug ,Mesangial cell ,Cell Biology ,medicine.disease ,Sphingolipid ,Glomerular Mesangium ,Rats ,Phosphotransferases (Alcohol Group Acceptor) ,Endocrinology ,Gene Expression Regulation ,chemistry ,Ceramidase activity ,Lysophospholipids ,Cell Division ,Thymidine - Abstract
Advanced glycation end-products (AGE) are generated by chronic hyperglycaemia and may cause diabetic microvascular complications such as diabetic nephropathy. Many factors influence the development of diabetic nephropathy; however, dysregulation of mesangial cell (MC) proliferation appears to play an early and crucial role. In this study, we investigated the effects of AGE on rat MC proliferation and the involvement of sphingolipids in the AGE response. Results show a bimodal effect of AGE on MC proliferation. Thus, low AGE concentrations (
- Published
- 2004
33. Noninvasive Orthogonal Polarization Spectral Imaging as Applied to Microvascular Studies in Mice
- Author
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Michel Lagarde, Nicolas Wiernsperger, C. Renaudin, P. Nivoit, and A. M. Chevrier
- Subjects
Nitroprusside ,Diabetic microangiopathy ,Pathology ,medicine.medical_specialty ,Vasodilator Agents ,Stimulation ,Vasodilation ,Microcirculation ,Mice ,In vivo ,medicine ,Animals ,Insulin ,Muscle, Skeletal ,Microscopy, Video ,Chemistry ,Orthogonal polarization spectral imaging ,General Medicine ,Acetylcholine ,Mice, Inbred C57BL ,Arterioles ,Microscopy, Polarization ,Sodium nitroprusside ,Research Article ,Biomedical engineering ,medicine.drug - Abstract
In vivo observations of the mouse microcirculation can hardly be performed due to technical difficulties, limiting the knowledge that could be obtained from gene manipulated mice models. The aim of the present study was to check the applicability of a novel optical system, the orthogonal polarization spectral technology, to study the mouse microcirculation. In anaesthetized mice, the spinotrapezius muscle microcirculation was observed in situ. The diameter of precapillary arterioles was measured before and after a pharmacological or hormonal stimulation. High-contrast images of the muscle microcirculation were obtained and significant vasodilatation of arterioles was observed after topical applications of acetylcholine, sodium nitroprusside, and insulin. As compared to conventional techniques, orthogonal polarization spectral imaging makes it possible to assess and study microvascular beds in mice, which were inaccessible until now, allowing the use of gene manipulated mice to investigate, for example, the mechanisms involved in the development of diabetic microangiopathy.
- Published
- 2004
34. Effect of glycated LDL on microvascular tone in mice: a comparative study with LDL modified in vitro or isolated from diabetic patients
- Author
-
Michel Lagarde, C. Renaudin, P. Nivoit, Nicolas Wiernsperger, and P. Moulin
- Subjects
Glycation End Products, Advanced ,medicine.medical_specialty ,Glycosylation ,Endocrinology, Diabetes and Metabolism ,Muscle, Smooth, Vascular ,Microcirculation ,Mice ,Species Specificity ,Arteriole ,In vivo ,Glycation ,medicine.artery ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Animals ,Humans ,business.industry ,Skeletal muscle ,medicine.disease ,In vitro ,Lipoproteins, LDL ,Arterioles ,Endocrinology ,medicine.anatomical_structure ,Muscle Tonus ,Circulatory system ,lipids (amino acids, peptides, and proteins) ,business - Abstract
In vitro studies have suggested that glycation of LDL might be implicated in diabetic microangiopathy. We therefore investigated the in vivo effects of LDL glycated in vitro on the mouse skeletal muscle arteriolar tone. Since glycation naturally occurs during diabetes, we also tested the effects of LDL isolated from diabetic patients.In anaesthetized mice, the spinotrapezius muscle microcirculation was observed, in situ, using the orthogonal polarization spectral imaging technology. The diameter of terminal (20 microm) and small arterioles (20-40 microm) was measured before and after a bolus intravenous injection of glycated LDL followed by a continuous perfusion (115 micro g/kg/min).A slight decrease of terminal and small arterioles diameter (10%) was observed with native LDL and LDL isolated from healthy subjects. In contrast, mildly glycated LDL induced a clear vasoconstriction of arterioles (15%), which was further increased when highly glycated LDL was perfused (22%). LDL isolated from diabetic patients mimicked the vasoconstriction obtained with in vitro mildly glycated LDL, which underwent similar glycation as those isolated from diabetic patients.Our results show in vivo that acute perfusion of both types of glycated LDL (artificially or naturally modified), cause major microvascular modification by enhancing arteriolar tone in skeletal muscle. These findings highlight a new role of glycated LDL at the level of microvessels. We suggest that glycation of LDL could contribute to the impaired vascular reactivity observed in diabetes.
- Published
- 2003
35. Effects of chronic treatment with glibenclamide and/or metformin on the resistance to ischaemia of isolated hearts from Zucker Diabetic Fatty rats (ZDF/GMI-fa/fa)
- Author
-
Nicole Lavanchy, Jean Verdetti, Georges Christe, Francine Cand, and Nicolas Wiernsperger
- Subjects
medicine.medical_specialty ,Glycogen ,business.industry ,Endocrinology, Diabetes and Metabolism ,Ischemia ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,medicine.disease ,Metformin ,Glibenclamide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Rate pressure product ,chemistry ,Diabetes mellitus ,Internal medicine ,Heart rate ,Internal Medicine ,medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
The study was carried out to determine whether metformin (M) had any deleterious effect on the tolerance to ischaemia of the isolated diabetic rat when administered chronically in combination with glibenclamide (G). The male Zucker Diabetic Fatty (ZDF) rat served as a model of type 2 diabetes that resembles the human syndrome. Three groups of rats were treated for one month with M (100 mg/kg) or G (2 mg/kg) or G + M in their daily food. One group was untreated (C). Aortically perfused hearts were subjected to a 25-minute global low-flow ischaemia and a 30-minute reperfusion. Heart rate (HR), left ventricular developed pressure (LVDP), rate pressure product (RPP) and coronary flow (CF) were monitored. When compared to C hearts, the hearts from G + M rats showed improvements in HR, LVDP and RPP at the end of reperfusion. Hearts from G and M rats exhibited no difference. Myocardial glycogen stores at the end of reperfusion were higher in hearts from G + M rats than in the three other groups. The study did not reveal any deleterious effect of the chronic G + M therapy on the functional recovery of the isolated diabetic heart submitted to ischaemia and reperfusion: indeed, an increase in residual contractile capacity was found. Br J Diabetes Vasc Dis 2003;3:375‐80
- Published
- 2003
36. Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation
- Author
-
Nicolas Wiernsperger, Jean-Claude Mamputu, and Geneviève Renier
- Subjects
Monocyte adhesion ,endocrine system diseases ,business.industry ,Cell adhesion molecule ,Endocrinology, Diabetes and Metabolism ,United Kingdom Prospective Diabetes Study ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,Metformin ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Immunology ,Internal Medicine ,medicine ,Cardiology and Cardiovascular Medicine ,business ,Foam cell ,medicine.drug - Abstract
The United Kingdom Prospective Diabetes Study (UKPDS) found that metformin reduces macrovascular complications in type 2 diabetic patients. To investigate the mechanisms involved we examined the effect of metformin on monocyte adhesion to human endothelial cells (ECs) induced by advanced glycation end-products (AGE), and on monocyte differentiation into macrophages and foam cell formation. Treatment of human ECs with AGEs (100 µg/ml) for up to 12 hours significantly increased human monocyte adhesion. Pre-treatment of the cells with metformin (0.1—2.5 µg/ml) inhibited AGE-induced monocyte adhesion and expression of endothelial cell adhesion molecules. In culture, human monocytes spontaneously differentiated into macrophages, as indicated by phenotypic changes, and increased expression of lectin-like oxidised low-density lipoprotein (LDL) receptor and scavenger receptor type A. Incubation of these cells in the presence of metformin decreased expression of all of these parameters. Metformin also inhibited foam cell formation induced by minimally modified LDL. Overall, these results suggest new mechanisms by which metformin may reduce the risk of vascular complications in patients with type 2 diabetes.
- Published
- 2003
37. Impaired glucose tolerance and metformin: clinical and mechanistic aspects
- Author
-
Nicolas Wiernsperger and Leif Sparre Hermann
- Subjects
medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Impaired glucose tolerance ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,medicine.diagnostic_test ,business.industry ,nutritional and metabolic diseases ,Lipid metabolism ,medicine.disease ,Impaired fasting glucose ,Metformin ,Endocrinology ,Postprandial ,Cardiology and Cardiovascular Medicine ,Lipid profile ,business ,medicine.drug - Abstract
The Diabetes Prevention Program (DPP) showed that metformin reduced the incidence of diabetes in subjects with impaired glucose tolerance (IGT) who were at high risk of progression to type 2 diabetes. Metformin was not as efficient as intensive life style intervention, but had a clinically significant effect in obese individuals and in those with impaired fasting glucose (IFG). This review discusses the clinical implications and the mechanistic aspects of the effect of metformin in IGT and IFG. Acute actions of metformin on postprandial metabolism to improve hepatic glucose handling and improve the lipid profile could contribute to the lower incidence of diabetes. Longer term improvements in haemodynamic parameters and reduced oxidative stress are also implicated. Metformin offers a potential alternative or complement to lifestyle intervention for IGT, and deserves further evaluation in this respect.
- Published
- 2002
38. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function
- Author
-
Pierre Devos, Nicolas Wiernsperger, Dominique Detaille, Bruno Guigas, Xavier Leverve, Hamant, Sarah, Laboratory of Comparative Biochemistry and Physiology, Facultés Universitaires Notre Dame de la Paix (FUNDP), Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lyonnaise Industrielle Pharmaceutique, and LIPHA s.a.
- Subjects
medicine.medical_specialty ,MESH: Mitochondria ,MESH: Drug Delivery Systems ,Xenopus ,Respiratory chain ,Mitochondrion ,MESH: Metformin ,Biochemistry ,MESH: Oocytes ,Xenopus laevis ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,MESH: Xenopus laevis ,MESH: Hypoglycemic Agents ,Internal medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Animals ,Hypoglycemic Agents ,MESH: Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,MESH: Respiration ,Pharmacology ,Differential centrifugation ,Drug Carriers ,0303 health sciences ,biology ,Respiration ,Intracellular Membranes ,Oocyte ,biology.organism_classification ,Metformin ,Mitochondria ,MESH: Drug Carriers ,MESH: Intracellular Membranes ,medicine.anatomical_structure ,Endocrinology ,Mechanism of action ,Cytoplasm ,MESH: Subcellular Fractions ,030220 oncology & carcinogenesis ,Liposomes ,Oocytes ,MESH: Liposomes ,medicine.symptom ,Cell fractionation ,Subcellular Fractions - Abstract
International audience; From recent findings about the indirect effect of metformin (MET) targeted on the respiratory chain complex I, we reconsidered this question and tried to determine the causality of any alteration at this enzymatic level using Xenopus laevis oocytes. Addition of MET (50 microM) reduced by 40% the rotenone-sensitive activity of complex I only in incubating intact oocytes but not in mitochondria isolated by differential centrifugation. The drug prior injected inside these cells had also no measurable effect. In spite of this and the weak binding of MET to the mitochondrial fraction, there was a fairly good correlation between the marked inhibitory action of MET on complex I and its progressive appearance within the oocyte cytoplasm. The intriguing observation that MET as a liposomal form was again able to exert its role when added directly to isolated mitochondria is in accordance with a membrane-mediated uptake and vesicular routing of MET. Furthermore, a temperature-dependent effect was clearly shown. At 4 degrees, oocytes failed to take up efficiently MET and accordingly its subsequent action on respiration was therefore lost. Likewise, MET transport was hindered and inhibition of complex I totally disappeared when a structural analog, asymmetrical dimethylarginine (ADMA), was placed together with MET either at an identical concentration or in excess. These data strongly support the view that MET may recognise some specific membranous sites, likely belonging to effector systems, before penetrating the cell in a bound state via an obscure endocytotic event which still has to be identified.
- Published
- 2002
39. Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet
- Author
-
Gilles Mithieux, Nicolas Wiernsperger, Jean-Claude Bordet, and Ludovic Guignot
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Phosphatase ,Dehydrogenase ,Type 2 diabetes ,Biology ,Pentose phosphate pathway ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Basal (phylogenetics) ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Phosphorylase a ,Glycogen ,Gluconeogenesis ,Phosphate ,medicine.disease ,Dietary Fats ,Metformin ,Rats ,Endocrinology ,Liver ,chemistry ,Glucose-6-Phosphatase ,Lactates ,medicine.drug - Abstract
The aim of this study was to understand by which intrahepatic mechanism metformin (Met) may inhibit basal hepatic glucose production (HGP) in type 2 diabetes. We studied rats that were fed for 6 weeks a high-fat (HF) diet, supplemented (HF-Met) or not (HF) with Met (50 mg · kg−1 · day−1). Basal HGP, assessed by 3-[3H]glucose tracer dilution, was lower by 20% in HF-Met rats compared with HF-rats: 41.6 ± 0.7 vs. 52 ± 1.5 μmol · kg−1 · min−1 (means ± SE, n = 5; P < 0.01). Glucose-6 phosphatase (Glc6Pase) activity, assayed in a liver lobe freeze-clamped in situ, was lower by 25% in HF-Met rats compared with HF-rats (7.9 ± 0.4 vs. 10.3 ± 0.9 μmol · min−1 · g−1 wet liver; P < 0.05). Glucose-6 phosphate and glycogen contents, e.g., 42 ± 5 nmol/g and 3.9 ± 2.4 mg/g, respectively, in HF-rats were dramatically increased by three to five times in HF-Met rats, e.g., 118 ± 12 nmol/g and 19.6 ± 4.6 mg/g (P < 0.05 and P < 0.01, respectively). Glucose-6 phosphate dehydrogenase activity was increased in HF-Met compared with HF rats (1.51 ± 0.1 vs. 1.06 ± 0.08 μmol · min−1 · g−1; P < 0.01). Intrahepatic lactate concentration tended to be lower in the Met-group (−30%; NS), whereas plasma lactate concentration was higher in HF-Met rats (1.59 ± 0.15 mmol/l) than in HF rats (1.06 ± 0.06 mmol/l; P < 0.05). We concluded that Met decreases HGP in insulin-resistant HF-fed rats mainly by an inhibition of hepatic Glc6Pase activity, promoting glycogen sparing. Additional mechanisms might involve the diversion of glucose-6 phosphate into the pentose phosphate pathway and an inhibition of hepatic lactate uptake.
- Published
- 2002
40. Glycosphingolipid Changes Induced by Advanced Glycation End-Products
- Author
-
Michel Lagarde, Marc Lecomte, Audrey Natalizio, Daniel Ruggiero, and Nicolas Wiernsperger
- Subjects
Glycation End Products, Advanced ,medicine.medical_specialty ,Cell ,Biophysics ,Apoptosis ,Models, Biological ,digestive system ,Biochemistry ,Glycosphingolipids ,chemistry.chemical_compound ,Glycation ,Gangliosides ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Cells, Cultured ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Diabetic Retinopathy ,Ganglioside ,Microcirculation ,Fatty Acids ,Fatty acid ,Retinal ,Cell Biology ,Diabetic retinopathy ,Glycosphingolipid ,medicine.disease ,carbohydrates (lipids) ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Metabolic effects ,Cattle ,lipids (amino acids, peptides, and proteins) ,Endothelium, Vascular ,Cell Division - Abstract
The effects of advanced glycation end-products (AGEs) on retinal microvascular cell glycosphingolipids were investigated as a potential pathogenic mechanism of diabetic retinopathy. The results obtained showed that, in microvascular retinal endothelial cells and pericytes, AGEs increased the amount of all glycosphingolipids studied (from 25 to 115% depending on the glycosphingolipid species), except for a specific ganglioside, GD3, which decreased by 35% only in pericytes. Glycosphingolipid profiles and GM3 fatty acid analysis did not show any qualitative differences after incubation with AGEs, suggesting that AGEs only induced quantitative changes in cell glycosphingolipids. These results show a new metabolic effect of AGEs, which could be involved in the microvascular alterations observed in diabetic retinopathy.
- Published
- 2001
41. The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis
- Author
-
Doss W. Neal, Melody Knauf, Alan D. Cherrington, Nicolas Wiernsperger, Chang An Chu, and Nicole Muscato
- Subjects
Glycerol ,Male ,medicine.medical_specialty ,Time Factors ,Glycogenolysis ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Fatty Acids, Nonesterified ,Biology ,Carbohydrate metabolism ,Acetoacetates ,Plasma ,Dogs ,Endocrinology ,Internal medicine ,medicine ,Animals ,Hypoglycemic Agents ,Glucose homeostasis ,Lactic Acid ,Alanine ,3-Hydroxybutyric Acid ,Fissipedia ,Gluconeogenesis ,Arteries ,Metabolism ,medicine.disease ,biology.organism_classification ,Metformin ,Kinetics ,Glucose ,Liver ,Female ,Glycogen ,medicine.drug - Abstract
Although metformin has been used worldwide to treat type 2 diabetes for several decades, its mechanism of action on glucose homeostasis remains controversial. To further assess the effect of metformin on glucose metabolism, 10 42-hour-fasted conscious dogs were studied in the absence ([Con] n = 5) and presence ([Met] n = 5) of a portal infusion of metformin (0.15 mg x kg(-1) x min(-1)) over 300 minutes. Hepatic glucose production was measured by both arteriovenous-difference and tracer methods. All dogs were maintained on a pancreatic clamp and in a euglycemic state to ensure that any changes in glucose metabolism would result directly from the effects of metformin. The arterial metformin level was 21 +/- 3 microg/mL during the test period. Net hepatic glucose output (NHGO) decreased in Met dogs from 1.9 +/- 0.2 to 0.7 +/- 0.1 mg x kg(-1) x min(-1) (P < .05). NHGO remained unchanged in Con dogs (1.7 +/- 0.3 to 1.5 +/- 0.3 mg x kg(-1)min(-1)). Tracer-determined glucose production paralleled NHGO. The net hepatic glycogenolytic rate decreased from 1.0 +/- 0.2 to -0.3 +/- 0.2 mg x kg(-1) x min(-1) (P < .05) in Met dogs, but remained unchanged in Con dogs (0.8 +/- 0.2 to 0.8 +/- 0.3 mg x kg(-1) x min(-1)). No significant change in gluconeogenic flux was found in eitherthe Metgroup (1.2 +/- 0.3 to 1.3 +/- 0.3 mg x kg(-1) x min(-1)) or the Con group (1.3 +/- 0.4 to 1.0 +/- 0.3 mg x kg(-1) x min(-1)). No significant changes were observed in glucose utilization or glucose clearance in either group. In conclusion, in the normal fasted dog, (1) the primary acute effect of metformin on glucose metabolism was an inhibition of hepatic glucose production and not a stimulation of glucose utilization; and (2) the inhibition of glucose production was attributable to a decrease in hepatic glycogenolysis and not to an alteration in gluconeogenic flux.
- Published
- 2000
42. Metformin: Intrinsic Vasculoprotective Properties
- Author
-
Nicolas Wiernsperger
- Subjects
Glycosylation ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,United Kingdom Prospective Diabetes Study ,medicine.medical_treatment ,Neovascularization, Physiologic ,Type 2 diabetes ,Bioinformatics ,Endocrinology ,Insulin resistance ,Diabetes mellitus ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Glycemic ,Neovascularization, Pathologic ,Biguanide ,business.industry ,Insulin ,Hemodynamics ,Cardiovascular Agents ,medicine.disease ,Metformin ,Medical Laboratory Technology ,Diabetes Mellitus, Type 2 ,business ,Oxidation-Reduction ,medicine.drug - Abstract
THE BIGUANIDE METFORMIN (dimethylbiguanide) (MET) is a leading drug in the therapy of noninsulin-dependent diabetes mellitus (NIDDM). Over several decades, intensive investigations in experimental and clinical pharmacology have progressively unraveled its modes of action to reduce hyperglycemia and combat insulin resistance.1–3 It has been far less recognized that this drug has multiple biological effects, among which vascular properties have now been discovered. Indeed, for a long time, biguanides were known to have fibrinolytic properties, and subsequently, reports on the vascular effects of MET were few, until a specific symposium was devoted to this subject in 1988 (International Workshop on Vascular Disease and Diabetes Mellitus. A New Approach, Diabete et Metabolisme 14.4bis, 1988). There, a series of exciting presentations underscored the potential interest of these partly unique properties, but it had to await the recent final analysis of the United Kingdom Prospective Diabetes Study (UKPDS) to confirm in-patients the promises set by the pharmacological rationale. Indeed the UKPDS has demonstrated that patients with diabetes receiving MET either as a single therapy or in combination with other treatments experienced an additional 40% reduction in their risk for developing vascular complications when compared with those treated with sulfonylureas or insulin alone.4 Because the glycemic control was similar among these treatment regimen, it is clear that MET obviously exerted a vasculoprotective action largely independent of its wellknown antihyperglycemic action. It is the aim of the present review to provide for the first time a complete overview of the pleiotropic vascular effects of MET, based on data obtained at relevant drug concentrations and limited (with very few exception) to full scientific articles (indeed, dozens of additional abstracts are available). This review updates the supportive arguments that allow the consideration of the potential of this molecule especially for preventing diabetic vascular complications. Importantly, the individual properties are, whenever possible, also described in nondiabetic situations in order to demonstrate intrinsic effects independent of any links with the reduction in glycemia. Indeed, reductions in glycemia and possibly insulinemia are expected to afford some protection against diabetic complications5–6 although this concept is still questioned.7–9 A distinction must also be made here between large and small vessel disease, because it appears that improvements in glycemic control per se have little effects on macrovascular events: indeed, as for strictly controlled type I diabetes in the Diabetes Control and Complications Trial (DCCT), a good achievement of glycemic control versus moderate control was not accompanied by further significant reductions in cardiovascular disease (CVD).10 In fact, in type 2 diabetes, many oral antidiabetic agents are reported to improve vascular defects but these are mostly subsequent to reduction in insulin resistance, in circulating lipids, or hyperglycemia. Data also exist for more recent agents such as glimepiride and some thiazolidinediones but most are in vitro findings that still await confirmation in vivo. However, even in
- Published
- 2000
43. Cellular and molecular mechanisms involved in insulin’s potentiation of glycogen synthase activity by metformin
- Author
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Nicolas Wiernsperger, Pierre Devos, and Dominique Detaille
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Biguanides ,Biology ,Biochemistry ,Xenopus laevis ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Protein kinase A ,Glycogen synthase ,Pharmacology ,Glycogen ,Metformin ,Receptor, Insulin ,Enzyme Activation ,Insulin receptor ,Glycogen Synthase ,Endocrinology ,Mechanism of action ,chemistry ,Enzyme inhibitor ,Oocytes ,biology.protein ,medicine.symptom ,Tyrosine kinase ,Signal Transduction ,Subcellular Fractions - Abstract
By taking advantage of the Xenopus oocyte model, we recently confirmed the in vitro enhancing effect of metformin (MET) on glycogen synthase (GS) activity when induced by insulin (INS). We now investigated some mechanistic aspects of its modulatory role upon the hormonal regulation of this rate-limiting enzyme. The action of 20 mM MET (;3.3 mg/mL) was measurable at early steps in the intracellular metabolic pathway: the amount of adenosine 39,59-cyclic monophosphate (cAMP) was markedly decreased in the presence of the biguanide plus 50 nM INS (to about 60% of control vs 25% with INS alone). The injection of tyrphostin B46, a potent inhibitor of insulin receptor (IR)-associated tyrosine kinase activity, led to a drastic reduction in MET-stimulated GS activity in the presence of INS. MET failed to increase the activity of type 2 protein phosphatases whether INS was present or not. However, a specific inhibitor of type 1 phosphatases, when microinjected, blocked both the hormonal effect on GS and its potentiation by MET. The salient feature of this study was that there was almost no accumulation of radiolabeled MET in oocytes: less than 0.1% was found in the cytosol of cells which had been exposed to MET at a therapeutic dose (10 mM) for up to 16 hr. Moreover, a lack of detectable intracellular MET after a 60-min incubation nevertheless correlated with its sustained action on INS-regulated GS activity. From these results, it could be inferred that the major site of MET action may reside within some membrane components of a signaling complex most likely linked to the IR, but in any case located upstream of the branching of reactions which tightly control GS activity. BIOCHEM PHARMACOL 58;9: 1475-1486, 1999. © 1999 Elsevier Science Inc.
- Published
- 1999
44. Metformin modulates insulin receptor signaling in normal and cholesterol-treated human hepatoma cells (HepG2)
- Author
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Nicolas Wiernsperger, Barbara Mania-Farnell, Gérard Crémel, Pierre Hubert, and Emmanuelle J. Meuillet
- Subjects
medicine.medical_specialty ,Time Factors ,medicine.drug_class ,medicine.medical_treatment ,Drug Resistance ,Biology ,chemistry.chemical_compound ,Internal medicine ,Insulin receptor substrate ,Tumor Cells, Cultured ,medicine ,Humans ,Hypoglycemic Agents ,Insulin ,Phosphorylation ,Pharmacology ,Biguanide ,Cholesterol ,Lipids ,Metformin ,Receptor, Insulin ,Insulin receptor ,Endocrinology ,chemistry ,Glycogenesis ,Lipogenesis ,biology.protein ,Signal Transduction ,medicine.drug - Abstract
The effects of the biguanide anti-hyperglycemic agent, metformin ( N , N ′-dimethyl-biguanide), on insulin signaling was studied in a human hepatoma cell line (HepG2). Cells were cultured in the absence (control cells) or in the presence of 100 μM of a cholesterol derivative, hemisuccinate of cholesterol. Cholesterol hemisuccinate-treatment alters cholesterol and lipid content of HepG2 and modulates membrane fluidity. Cholesterol hemisuccinate-treatment induces a decrease in insulin responsiveness and creates an "insulin-resistant" state in these cells. Exposure to 100 μM of metformin resulted in a significant enhancement of insulin-stimulated lipogenesis in control and cholesterol hemisuccinate-treated cells. In control cells, metformin altered glycogenesis in a biphasic manner. In cholesterol hemisuccinate-treated cells, metformin inhibited basal glycogenesis but restored insulin-stimulated glycogenesis. Hence, to understand the mechanism of metformin action, we analyzed early steps in the insulin signaling pathway, including insulin receptor autophosphorylation, mitogen-activated-protein kinase and phosphatidylinositol 3-kinase activities, in both control and cholesterol hemisuccinate-treated cells. Overall, the results suggest that metformin may interact with the insulin receptor and/or a component involved in the early steps of insulin signal transduction.
- Published
- 1999
45. Metformin interaction with insulin-regulated glucose uptake, using the Xenopus laevis oocyte model expressing the mammalian transporter GLUT4
- Author
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Pierre Devos, Nicolas Wiernsperger, and Dominique Detaille
- Subjects
medicine.medical_specialty ,Cytochalasin D ,Monosaccharide Transport Proteins ,endocrine system diseases ,Glucose uptake ,medicine.medical_treatment ,Gene Expression ,Muscle Proteins ,Deoxyglucose ,Biology ,Xenopus laevis ,Internal medicine ,medicine ,Animals ,Insulin ,Glucose homeostasis ,Hexose ,Hexose transport ,Nucleic Acid Synthesis Inhibitors ,Pharmacology ,chemistry.chemical_classification ,Glucose Transporter Type 4 ,Dose-Response Relationship, Drug ,Glucose transporter ,Metformin ,Rats ,Glucose ,Endocrinology ,chemistry ,Parathyroid Hormone ,Oocytes ,biology.protein ,3-O-Methylglucose ,GLUT4 ,medicine.drug - Abstract
The primary goal of this work was to better define, in molecular terms, the impact of metformin on hexose carriers. The methodology consisted of determining the zero-trans kinetics of 2-deoxy- d -glucose uptake for the mammalian insulin-sensitive glucose transporter (GLUT4) expressed in Xenopus laevis oocytes. These cells possessed the specialized protein and, when treated with insulin (2 μM) plus metformin (20 μM), showed a markedly enhanced hexose transport activity (2.4-fold increase over basal) as compared to that of cells incubated in the presence of insulin alone (1.8-fold increase over basal). Kinetic analysis of this process revealed that insulin induced a similar response to that observed for the native carrier, i.e., a higher V max . When metformin was added together with insulin, we mainly recorded a significant decrease in apparent K m for the sugar transported, V max being only marginally modified. Parathyroid hormone (PTH), which is known to impair the intrinsic activity of GLUT4, prevented the stimulatory effect of metformin in both kinds of oocytes whereas cytochalasin D, which interferes with the translocation of carriers, was without effect. These results suggest that metformin combined with insulin can maintain glucose homeostasis by increasing the catalytic activity of some hexose carriers or by improving the affinity of GLUT4 for glucose.
- Published
- 1999
46. In vitro and in vivo alterations of enzymatic glycosylation in diabetes
- Author
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Michel Lagarde, Daniel Ruggiero-Lopez, Marc Lecomte, Nadege Rellier, and Nicolas Wiernsperger
- Subjects
Glycation End Products, Advanced ,Male ,Glycosylation ,Fucosyltransferase ,Glycoside Hydrolases ,Sialyltransferase ,Retina ,Streptozocin ,General Biochemistry, Genetics and Molecular Biology ,Fucose ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Glycation ,Animals ,Fucosidase ,Rats, Wistar ,General Pharmacology, Toxicology and Pharmaceutics ,Cells, Cultured ,Galactosyltransferase ,biology ,Glycosyltransferases ,General Medicine ,Rats ,Sialic acid ,Biochemistry ,chemistry ,biology.protein ,Cattle - Abstract
Carbohydrate composition changes of glycoconjugates constituting the glycocalix of microvascular cells could be involved in the alterations of cell-cell interactions observed in diabetic retinopathy. In this field, we have recently reported that advanced glycation end products (AGEs) modify galactose, fucose and sialic acid contents of specific cellular glycoproteins. To better understand the mechanisms involved in glycoprotein modifications in diabetes, we now investigate whether glucose and AGEs could affect the activities of enzymes.involved in galactose, fucose and sialic acid metabolism: glycosyltransferases (synthesis) and glycosidases (catabolism). For this, bovine retinal endothelial cells (BREC) and pericytes (BRP) were cultured in the presence of high glucose concentration or AGEs, and cell glycosidase and glycosyltransferase activities were measured. The same enzymatic activities were studied in the whole retina from streptozotocin-treated rats. The results show that high glucose concentration did not affect glycosidases and glycosyltransferases neither in BRP nor in BREC except for galactosyltransferase activities in BREC. Concerning BRP, only galactosyltransferase activities were altered by AGEs. In contrast, in BREC, AGEs increased β-D galactosidase, α-L fucosidase and neuraminidase activities (+37%, +56%, 36% respectively) whereas galactosyltransferase, fucosyltransferase and sialyltransferase activities were decreased ( − 11%, − 24% and − 23% respectively). In the retina from diabetic rats, β-D galactosidase, α-L fucosidase and neuraminidase activities increased (+70%, +57%, +78% respectively) whereas fucosyl and sialyltransferase decreased ( − 7% and − 15% respectively). The possible consequence of these enzymatic activity changes could be a defect in the carbohydrate content of some glycoproteins that might participate in the endothelial cell dysfunctions in diabetic microangiopathy.
- Published
- 1999
47. An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats
- Author
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S. Halimi, Nicolas Wiernsperger, E. Rossini, P. Faure, Alain Favier, and M. J. Richard
- Subjects
Male ,Lipid Peroxides ,medicine.medical_specialty ,Antioxidant ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Fructose ,Biology ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,Dietary Carbohydrates ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Rats, Wistar ,Pancreatic hormone ,Free Radical Scavengers ,Carbohydrate ,Glucose clamp technique ,medicine.disease ,Metformin ,Rats ,Endocrinology ,chemistry ,Oxidoreductases ,medicine.drug - Abstract
Recently there has been growing interest in the effects of antioxidants on insulin activity. In the present study, we investigated the effect of metformin on free radical activity and insulin sensitivity in high fructose-fed rats, a diet that leads to insulin resistance. The animals were divided into four groups (n = 16 per group; experiment duration = 6 weeks): the control (C) group received a standard diet; the control metformin (CM) group was fed a control diet and received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control (FT) group was fed a diet in which fructose composed 56.8% of the total carbohydrates; and the fructose metformin (FM) group received high-fructose diet and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique was used to determine insulin sensitivity in eight animals per group. Metabolic and oxidative stress parameters were measured in the remaining rats. In the FT rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and lower blood reduced glutathione were observed. Metformin treatment improved both the insulin activity and the antioxidant defense system. In the CM group, metformin had no effect on metabolic parameters, but improved red cell antioxidant enzyme activities and the blood GSH level, which suggests that it has an antioxidant activity independent of its effect on insulin activity.
- Published
- 1999
48. In vivo effect of 8-epi-PGF2α on retinal circulation in diabetic and non-diabetic rats
- Author
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Michel Lagarde, Nicolas Wiernsperger, Marc Lecomte, and E. Michoud
- Subjects
Male ,medicine.medical_specialty ,Isoprostane ,Clinical Biochemistry ,Hemodynamics ,Vasodilation ,Dinoprost ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Prostaglandins H ,Vasoconstrictor Agents ,Rats, Wistar ,Phenylacetates ,Sulfonamides ,Diabetic Retinopathy ,Dose-Response Relationship, Drug ,medicine.diagnostic_test ,business.industry ,Angiography ,Retinal Vessels ,Retinal ,Cell Biology ,Bridged Bicyclo Compounds, Heterocyclic ,Fluorescein angiography ,medicine.disease ,Rats ,Hydrazines ,Endocrinology ,chemistry ,Eicosanoid ,Regional Blood Flow ,Fatty Acids, Unsaturated ,Prostaglandin H2 ,medicine.symptom ,business ,Blood Flow Velocity ,Vasoconstriction - Abstract
Retinal hemodynamic responses to a F2-isoprostane, 8-epi-PGF2alpha, were quantitated in vivo in non-diabetic and diabetic rats using a video fluorescein angiography system. Vascular diameters and retinal mean circulation time were determined before and after 5 microl intra-vitreous injection of 8-epi-PGF2alpha (10(-5) to 10(-3) M), 10(-4) M 8-epi-PGF2alpha, + 10(-3) M SQ29,548 or 10(-3) M LCB2853 (two inhibitors of TXA2 receptor), 10(4) M 9beta-PGF2alpha, or the carrier in non-diabetic animals. Diabetic rats received either 8-epi-PGF2alpha 10(-4) M, or the carrier. Compared to control animals, diabetic rats presented in the basal state a venous vasodilation (P0.01), without modification of retinal mean circulation time or blood flow. After intravitreous injection of 8-epi-PGF2alpha, a significant arterial vasoconstriction was observed in control but not in diabetic animals. This vasoconstriction was concomitant with increased retinal mean circulation time in control but not in diabetic rats, inducing an impaired reduction of blood flow. No vasoconstriction was observed after injection of either the carrier, 9beta-PGF2alpha or the isoprostane associated to the inhibitors of TXA2 receptors. This is the first direct observation that the isoprostane 8-iso-PGF2alpha is a potent vasoconstricting agent in the retina. It occurs at the arterial but not venous level, and is likely mediated through a TXA2-like receptor. Differences observed between control and diabetic animals suggest altered adaptative mechanisms toward vasoconstrictor substances (such as isoprostanes) in diabetic rats.
- Published
- 1998
49. Modification of Enzymatic Antioxidants in Retinal Microvascular Cells by Glucose or Advanced Glycation End Products
- Author
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Clarisse Paget, Nicolas Wiernsperger, Daniel Ruggiero, Michel Lagarde, and Marc Lecomte
- Subjects
Glycation End Products, Advanced ,medicine.medical_specialty ,medicine.disease_cause ,Thiobarbituric Acid Reactive Substances ,Biochemistry ,Antioxidants ,Retina ,Superoxide dismutase ,Glycation ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Cells, Cultured ,chemistry.chemical_classification ,Glutathione Peroxidase ,Dose-Response Relationship, Drug ,biology ,Superoxide Dismutase ,Microcirculation ,Glutathione peroxidase ,Serum Albumin, Bovine ,Catalase ,Enzyme Activation ,Endothelial stem cell ,Glucose ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Hyperglycemia ,biology.protein ,Cattle ,Endothelium, Vascular ,Lipid Peroxidation ,Pericyte ,Mannitol ,Oxidative stress ,medicine.drug - Abstract
Oxidative stress is one possible pathogenic mechanism to explain diabetic microangiopathy. In the present study, we determined the antioxidant enzyme activities in bovine retinal microvessels and cultured retinal microvascular cells: endothelial cells (BREC) and pericytes (BRP). We further investigated the effects of high glucose and advanced glycation end products (AGE) on these enzyme activities in BREC and BRP. Antioxidant enzyme activities in native retinal microvessels and BREC were quite similar but differed markedly from the BRP ones. High glucose decreased Se-GPx activity (about 20%) in BREC compared to mannitol. High concentrations of mannitol or NaCl increased Se-GPx activity (up to 40%) compared to control medium, suggesting that hyperosmolarity could regulate Se-GPx in BREC. No changes in antioxidant enzyme activities were observed when BRP were cultured with glucose or mannitol at high concentrations. AGE-BSA had no effect on enzyme activities in BREC, whereas 20 μM AGE-BSA increased catalase (40%) and superoxide dismutase (60%) activities in BRP. Differences in antioxidant enzyme activities observed between BREC and BRP, cultured with high concentrations of glucose or AGE, might help to explain their different behavior during the pathogenesis of diabetic retinopathy, i.e., early pericyte drop-out and late endothelial cell proliferation.
- Published
- 1998
50. [Untitled]
- Author
-
Bruno Vailhé, Léone Tranqui, Nicolas Wiernsperger, and Marc Lecomte
- Subjects
Cancer Research ,Retina ,Cell type ,biology ,Physiology ,Chemistry ,Angiogenesis ,medicine.medical_treatment ,Clinical Biochemistry ,Cell ,Umbilical vein ,Fibrin ,medicine.anatomical_structure ,In vivo ,Fibrinolysis ,Immunology ,medicine ,Biophysics ,biology.protein - Abstract
This study highlights the importance of several factors involved in the formation of capillary-like structure formation (CLS) using Human Umbilical Vein Endothelial Cells (HUVEC) and Bovine Retinal Endothelial Cells (BREC) cultured on fibrin gels. The fibrin concentration inducing (CLS) was 0.5 mg/ml for HUVEC and 8 mg/ml for BREC. The high fibrin concentration required for the latter cells appeared necessary to counterbalance the extensive fibrinolysis of the gel by the BREC. Fibrin degradation products measured in the culture media showed that fibrin degradation was mandatory but not sufficient for CLS formation. Fibrin degradation acted in concert with the mechanical, concentration dependent properties of the gels to induce CLS. For example, HUVEC did not form CLS on a rigid fibrin of 8 mg/ml in spite of fibrinolysis. As cell reorganisation occurred, the fibrin was disrupted (HUVEC) or pleated (BREC) giving indirect proof of the development of mechanical forces. During CLS formation, an increasing amount of latent TGFβ1 was measured in the medium (1000–1700 pg/ml). The active form of TGFβ1 was not, however, detected and the addition of anti-TGF-β1 antibody to the medium did not influence the formation of the CLS network. Yet, added activated TGF-β1 led to the formation of less organised structures, that were completely abolished by the concomitant addition of the same anti-TGF-β1 antibody. Thus, it is likely that TGF-β1 secreted by the endothelial cells remained in its latent form. In conclusion, a balance between the mechanical properties of fibrin and the fibrinolytic activity of each cell type may regulate CLS formation in our models. We think that the high fibrinolitic activity of the BREC may represent a defense mechanism to protect the retina against thrombosis-induced damage in vivo.
- Published
- 1998
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