RESUMEN
Since the outbreak of Covid-19, several observational studies on diabetes and Covid-19 have reported a favourable association between metformin and Covid-19-related outcomes in patients with type 2 diabetes mellitus (T2DM). This is not surprising since metformin affects many of the pathophysiological mechanisms implicated in SARS-CoV-2 immune response, systemic spread and sequelae. A comparison of the multifactorial pathophysiological mechanisms of Covid-19 progression with metformin's well-known pleiotropic properties suggests that the treatment of patients with this drug might be particularly beneficial. Indeed, metformin could alleviate the cytokine storm, diminish virus entry into cells, protect against microvascular damage as well as prevent secondary fibrosis. Although our in-depth analysis covers many potential metformin mechanisms of action, we want to highlight more particularly its unique microcirculatory protective effects since worsening of Covid-19 disease clearly appears as largely due to severe defects in the structure and functioning of microvessels. Overall, these observations confirm that metformin is a unique, pleiotropic drug that targets many of Covid-19's pathophysiology processes in a diabetes-independent manner.
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COVID-19 , Diabetes Mellitus Tipo 2 , Metformina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Metformina/uso terapéutico , Microcirculación , SARS-CoV-2Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 2 , Metformina , COVID-19/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hospitalización , Humanos , Hipoglucemiantes/efectos adversos , Metformina/uso terapéutico , Estudios Retrospectivos , SARS-CoV-2RESUMEN
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 < 0.0001) and on day 28 (16.0 vs 28.6%, P < 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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COVID-19/mortalidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , COVID-19/terapia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Respiración Artificial/mortalidadRESUMEN
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.
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Acidosis Láctica/inducido químicamente , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Acidosis Láctica/epidemiología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Factores de RiesgoRESUMEN
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 ß-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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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hígado/efectos de los fármacos , Metformina/uso terapéutico , Mitocondrias Hepáticas/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Gerbillinae , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Mitocondrias Hepáticas/metabolismo , Oxidación-Reducción/efectos de los fármacosRESUMEN
Due to limited knowledge and chemical class effect assimilation the biguanide metformin has long been considered as a useful but risky treatment for type 2 diabetes treatment. The worldwide long-term experience of clinical use of this compound and the growing knowledge about its mechanisms of action have, however, reversed this reputation to the point that nowadays it is not only considered as relatively harmless but even increasingly as a cellular protector. The present mini-review simply aims at giving a brief overview of the evidences accumulated overt recent periods and to provide the reader with information as to mechanistic hypotheses, knowing that there remains a lot to be done to better understand the pleiotropic behavior of this drug and its possible future new therapeutic applications. Data are shown at a glance for the kidney but also for other various organs and cell types corroborating this new notion for an old drug and paradox.
RESUMEN
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.
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Enfermedad del Hígado Graso no Alcohólico/terapia , Humanos , Enfermedad del Hígado Graso no Alcohólico/etiologíaRESUMEN
Despite skeletal muscle being considered by many as the source of insulin resistance, physiology tells us that the liver is a central and cardinal regulator of glucose homeostasis. This is sometimes underestimated because, in contrast with muscle, investigations of liver function are technically very difficult. Nevertheless, recent experimental and clinical research has demonstrated clearly that, due in part to its anatomic position, the liver is exquisitely sensitive to insulin and other hormonal and neural factors, either by direct intrahepatic mechanisms or indirectly by organ cross-talk with muscle or adipose tissue. Because the liver receives absorbed nutrients, these have a direct impact on liver function, whether via a caloric excess or via the nature of food components (eg, fructose, many lipids, and trans fatty acids). An emerging observation with a possibly great future is the increase in intestinal permeability observed as a consequence of high fat intake or bacterial modifications in microbiota, whereby substances normally not crossing the gut gain access to the liver, where inflammation, oxidative stress, and lipid accumulation leads to fatty liver, a situation observed very early in the development of diabetes. The visceral adipose tissue located nearby is another main source of inflammatory substances and oxidative stress, and also acts on hepatocytes and Kupffer cells, resulting in stimulation of macrophages. Liberation of these substances, in particular triglycerides and inflammation factors, into the circulation leads to ectopic fat deposition and vascular damage. Therefore, the liver is directly involved in the development of the prediabetic cardiometabolic syndrome. Treatments are mainly metformin, and possibly statins and vitamin D. A very promising avenue is treatment of the leaky gut, which appears increasingly to be an important causal factor in hepatic insulin resistance and steatosis.
RESUMEN
We tested the hypothesis that metformin produces arterial dilatation indirectly, by directly exposing the endothelial surface, of an occluded test segment of the pig iliac artery in vivo, to test blood containing metformin or excess insulin, with and without the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride. Such exposure to metformin 1 µg/mL caused the artery to dilate at constant pressure, and this was abolished when NG-nitro-L-arginine methyl ester hydrochloride was coadministered with metformin. The onset of dilatation occurred approximately 4 minutes after the commencement of endothelial exposure to metformin; this contrasts with the approximate 10 minutes required for a similar response to luminal hyperinsulinemia. After the release of flow occlusion, the subsequent flow-mediated dilatation was slightly but significantly enhanced compared with control for metformin; the effect of insulin on flow-mediated dilatation was not statistically significant. The hypothesis was disproved, as we have shown that insulin and metformin, like insulin, directly stimulate NO production by endothelium of a conduit artery; this function may be of value in delaying the atherothrombotic process. The time taken for the commencement of NO production is shorter for metformin than for insulin; the clinical relevance of this finding is unclear.
Asunto(s)
Insulina/farmacología , Metformina/farmacología , Óxido Nítrico/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Hipoglucemiantes/farmacología , Arteria Ilíaca/efectos de los fármacos , Arteria Ilíaca/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Porcinos , Factores de TiempoRESUMEN
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<0.01) increased while TRBCV(max) decreased (4.9 ± 1.5 to 3.5 ± 1.2s, p=0.01). No significant changes could be detected in the control group. Groups have not presented differences for insulin, but PP significantly increased in the CPD group and was positively associated to basal FCD increase (rho=0.527, p=0.03). In conclusion, neurally-mediated anticipatory responses of digestion elicited functional capillary recruitment associated to PP in healthy men, suggesting a precocious role for microcirculation in the physiology of digestion and nutrient homeostasis.
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Digestión/fisiología , Microcirculación/fisiología , Administración Cutánea , Adolescente , Adulto , Velocidad del Flujo Sanguíneo/fisiología , Señales (Psicología) , Humanos , Insulina/administración & dosificación , Insulina/sangre , Iontoforesis/métodos , Masculino , Polipéptido Pancreático/sangre , Estimulación Luminosa/métodos , Piel/irrigación sanguínea , Fenómenos Fisiológicos de la PielRESUMEN
Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed.
RESUMEN
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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Dieta/efectos adversos , Suplementos Dietéticos/efectos adversos , Manipulación de Alimentos , Hipersensibilidad a los Alimentos/etiología , Motilidad Gastrointestinal/fisiología , Absorción Intestinal/fisiología , Curcumina/uso terapéutico , Glutamina/uso terapéutico , Productos Finales de Glicación Avanzada/efectos adversos , Productos Finales de Glicación Avanzada/farmacocinética , Humanos , Inflamación/metabolismo , Síndrome Metabólico/etiología , PermeabilidadRESUMEN
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.
Asunto(s)
Dieta , Fructosa/efectos adversos , Síndrome Metabólico/inducido químicamente , Edulcorantes/efectos adversos , Enfermedades Vasculares/inducido químicamente , Fructosa/metabolismo , Humanos , Hipertrigliceridemia/inducido químicamente , Hígado/metabolismo , Factores de Riesgo , Edulcorantes/metabolismo , Ácido Úrico/metabolismoRESUMEN
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.
Asunto(s)
Humanos , Dieta/efectos adversos , Suplementos Dietéticos/efectos adversos , Manipulación de Alimentos , Hipersensibilidad a los Alimentos/etiología , Motilidad Gastrointestinal/fisiología , Absorción Intestinal/fisiología , Curcumina/uso terapéutico , Glutamina/uso terapéutico , /efectos adversos , /farmacocinética , Inflamación/metabolismo , Síndrome Metabólico/etiología , PermeabilidadRESUMEN
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.
Asunto(s)
Humanos , Dieta , Fructosa/efectos adversos , Síndrome Metabólico/inducido químicamente , Edulcorantes/efectos adversos , Enfermedades Vasculares/inducido químicamente , Fructosa/metabolismo , Hipertrigliceridemia/inducido químicamente , Hígado/metabolismo , Factores de Riesgo , Edulcorantes/metabolismo , Ácido Úrico/metabolismoRESUMEN
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 (850 mg bid/+/-90 days); 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.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/diagnóstico , Hipoglucemiantes/efectos adversos , Síndrome Metabólico/metabolismo , Metformina/efectos adversos , Linaje , Adulto , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Diabetes Mellitus Tipo 2/genética , Método Doble Ciego , Femenino , Fibrinógeno/metabolismo , Humanos , Hipoglucemiantes/farmacología , Masculino , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Metformina/farmacología , Persona de Mediana Edad , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
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 microm), 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 renin-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.
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Resistencia a la Insulina/fisiología , Microcirculación/fisiología , Obesidad/fisiopatología , Tejido Adiposo , Animales , Enfermedades Cardiovasculares/etiología , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/etiología , Obesidad/complicaciones , Obesidad/metabolismo , Estrés Oxidativo/fisiología , Ratas , Flujo Sanguíneo Regional/fisiología , Resistencia Vascular/fisiologíaRESUMEN
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.
Associada ao aumento do risco de eventos cardiovasculares e ao câncer, a obesidade é um problema mundial, que atinge tanto países desenvolvidos quanto em desenvolvimento. A microcirculação é composta por arteríolas, capilares e vênulas (diâmetro interno médio < 100 µm) e é o local onde ocorrem a oferta de nutrientes e as trocas entre o tecido e o sangue. A disfunção microcirculatória é um evento precoce na obesidade e este pode ser secundário à disfunção endotelial ou à redução no número de capilares (rarefação capilar). Novas técnicas em pesquisa permitem a avaliação da microcirculação em diferentes leitos vasculares em humanos. Estudos sugerem uma correlação entre disfunção endotelial e obesidade visceral. Acredita-se que o estresse oxidativo, a inflamação e a atividade aumentada do sistema renina-angiotensina estão entre os fatores envolvidos nessa associação. O comprometimento microcirculatório presente na obesidade sugere que esse pode ser um fator causal importante nas desordens relacionadas com a obesidade, como resistência insulínica e hipertensão.
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Animales , Humanos , Ratas , Resistencia a la Insulina/fisiología , Microcirculación/fisiología , Obesidad/fisiopatología , Tejido Adiposo , Enfermedades Cardiovasculares/etiología , Endotelio Vascular/fisiopatología , Hipertensión/etiología , Obesidad/complicaciones , Obesidad/metabolismo , Estrés Oxidativo/fisiología , Flujo Sanguíneo Regional/fisiología , Resistencia Vascular/fisiologíaRESUMEN
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.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/prevención & control , /diagnóstico , Hipoglucemiantes/efectos adversos , Síndrome Metabólico/metabolismo , Metformina/efectos adversos , Linaje , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Método Doble Ciego , /genética , Fibrinógeno/metabolismo , Hipoglucemiantes/farmacología , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Metformina/farmacología , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
Free radical production is increased during diabetes. Serum albumin is a major antioxidant agent, and structural modification of albumin induced by glucose or free radicals impairs its antioxidant properties. Therefore the aim of the present study was to compare the antioxidant capacities and structural changes in albumin in patients with T2DM (Type 2 diabetes mellitus) treated with MET (metformin) or SU (sulfonylureas) and in healthy control subjects. Structural changes in albumin were studied by fluorescence quenching in the presence of acrylamide. Albumin thiols and fructosamines, reflecting oxidized and glycation-induced changes in serum albumin respectively, were assessed. Structural changes in albumin were demonstrated by a significant decrease in fluorescence quenching in patients with T2DM, with patients treated with MET exhibiting a significant difference in the conformation of albumin compared with patients treated with SU. Oxidation, resulting in a significant decrease in thiol groups and plasma total antioxidant capacity, and glycation, associated with a significant increase in fructosamines, were both found when comparing healthy control subjects with patients with T2DM. When patients treated with MET were compared with those treated with SU, oxidative stress and glycation were found to be significantly lower in MET-treated patients. In conclusion, patients with T2DM have a decrease in the antioxidant properties of serum albumin which may aggravate oxidative stress and, thus, contribute to vascular and metabolic morbidities. Moreover, a significant protection of albumin was found in patients with T2DM treated with MET.