ES2232273B1 - NEW THERAPEUTIC APPLICATIONS OF GLUCOPROTEIN CD14S. - Google Patents
NEW THERAPEUTIC APPLICATIONS OF GLUCOPROTEIN CD14S.Info
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- ES2232273B1 ES2232273B1 ES200300665A ES200300665A ES2232273B1 ES 2232273 B1 ES2232273 B1 ES 2232273B1 ES 200300665 A ES200300665 A ES 200300665A ES 200300665 A ES200300665 A ES 200300665A ES 2232273 B1 ES2232273 B1 ES 2232273B1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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Abstract
Nuevas aplicaciones terapéuticas de la glucoproteína CD14s. El CD14s tiene aplicación para la prevención o tratamiento de enfermedades que cursan con un estado inflamatorio crónico o mantenido, que incluyen diabetes mellitus de tipo 2, obesidad, síndrome metabólico, enfermedad arteriosclerótica, hipertensión arterial, hiperandrogenismo ovárico funcional, o cualquier otro proceso asociado a resistencia a la insulina.New therapeutic applications of the CD14s glycoprotein. The CD14s has application for the prevention or treatment of diseases that have a chronic or maintained inflammatory state, including type 2 diabetes mellitus, obesity, metabolic syndrome, arteriosclerotic disease, arterial hypertension, functional ovarian hyperandrogenism, or any other process associated with insulin resistance
Description
Nuevas aplicaciones terapéuticas de la glucoproteína CD14s.New therapeutic applications of the CD14s glycoprotein.
La presente invención se encuadra dentro del sector médico-farmacéutico y más concretamente, del relacionado con las enfermedades que cursan con un estado inflamatorio crónico o mantenido.The present invention fits within the medical-pharmaceutical sector and more specifically, of related to diseases that occur with a state chronic or maintained inflammatory.
Más específicamente, la presente invención propone el uso de la glucoproteína CD14s en el tratamiento preventivo o terapéutico de dichas enfermedades inflamatorias crónicas.More specifically, the present invention proposes the use of CD14s glycoprotein in the treatment preventive or therapeutic of said inflammatory diseases Chronicles.
El CD14s es una glucoproteína soluble de mamífero que está presente de forma constitutiva en la superficie de monocitos y macrófagos y, en menor grado, de neutrófilos (Goyert, 1988). Esta molécula tiene una alta afinidad por el lipopolisacárido (LPS) y otras sustancias de origen bacteriano que son potentes inductores de la respuesta inflamatoria del organismo (Wright, 1990; Sweet, 1996). Además, en la actualidad se ha conseguido preparar CD14s recombinante humano por técnicas de ingeniería genética convencionales.CD14s is a soluble mammalian glycoprotein which is constitutively present on the surface of monocytes and macrophages and, to a lesser extent, neutrophils (Goyert, 1988). This molecule has a high affinity for lipopolysaccharide (LPS) and other substances of bacterial origin that they are potent inducers of the body's inflammatory response (Wright, 1990; Sweet, 1996). In addition, currently it has managed to prepare human recombinant CD14s by techniques of Conventional genetic engineering
El organismo responde al LPS bacteriano liberando un gran número de moléculas inflamatorias al plasma (factor alfa de necrosis tumoral, interleuquina 1 e interleuquina 6, entre otras; Malizevski, 1991) causantes de la disfunción cardiovascular (shock endotóxico) y letalidad en caso de una entrada masiva de LPS en la circulación (sepsis; Haziot 1995).The organism responds to bacterial LPS by releasing a large number of plasma inflammatory molecules (alpha factor of tumor necrosis, interleukin 1 and interleukin 6, between others; Malizevski, 1991) Causes of cardiovascular dysfunction (endotoxic shock) and lethality in case of a massive entry of LPS in the circulation (sepsis; Haziot 1995).
La respuesta inflamatoria está, asimismo,
íntimamente ligada a la regulación del metabolismo energético y,
consecuentemente, es un conocido modulador de la sensibilidad a la
insulina, tanto en situaciones de respuesta inflamatoria aguda como
de inflamación crónica (Fernández-Real, 1999;
Pickup, 1998). En efecto, la resistencia a la insulina es inducida
y modulada por un estado de inflamación de bajo grado mantenida
caracterizado por el aumento de la expresión de citoquinas
proinflamatorias (principalmente el factor alfa de necrosis
tumoral) y de reactantes de fase aguda (proteína C reactiva,
sustancia A amiloide, glicoproteína \alpha1 ácida, ácido siálico
y el corti-
sol).The inflammatory response is also closely linked to the regulation of energy metabolism and, consequently, is a known modulator of insulin sensitivity, both in situations of acute inflammatory response and chronic inflammation (Fernández-Real, 1999; Pickup, 1998). Indeed, insulin resistance is induced and modulated by a state of low-grade inflammation maintained characterized by increased expression of proinflammatory cytokines (mainly the tumor necrosis alpha factor) and acute phase reactants (C-reactive protein , substance A amyloid, acidic α1 glycoprotein, sialic acid and corti-
Sun).
La respuesta inflamatoria es causante, asimismo, de disfunción endotelial. Se ha comentado previamente la inducción de shock endotóxico en caso de sepsis. Asimismo, la enfermedad endotelial crónica, conocida como arteriosclerosis, parece ser también secundaria a un estado de inflamación de bajo grado mantenida (Fernández-Real, 1999; Pickup, 1998).The inflammatory response is also causing of endothelial dysfunction. Induction has been previously commented of endotoxic shock in case of sepsis. Also the disease Chronic endothelial, known as arteriosclerosis, appears to be also secondary to a state of low grade inflammation maintained (Fernández-Real, 1999; Pickup, 1998).
Los mecanismos que regulan la respuesta del organismo al LPS, por tanto, son cruciales en la defensa del organismo ante un proceso inflamatorio agudo, como en el caso de una sepsis bacteriana, y pueden regular, asimismo, la sensibilidad a la insulina y el daño vascular crónico en sujetos insulinoresistentes que presentan una activación mantenida de factores proinflamatorios. La neutralización del LPS es posible, in vivo, gracias a la acción del factor soluble del receptor CD14 (CD14s; Schutt, 1992).The mechanisms that regulate the body's response to LPS, therefore, are crucial in the body's defense against an acute inflammatory process, such as in the case of bacterial sepsis, and can also regulate insulin sensitivity and damage. Chronic vascular disease in insulin-resistant subjects who have sustained activation of pro-inflammatory factors. The neutralization of LPS is possible, in vivo , thanks to the action of the soluble factor of the CD14 receptor (CD14s; Schutt, 1992).
El CD14s se encuentra en altas concentraciones (2 a 4 \mug/ml) en plasma procedente tanto de la secreción celular (leucocitos, hepatocitos y adipocitos) como de la proteolisis enzimática del receptor celular (CD14 celular) anclado a la membrana por un residuo de fosfatidilinositol glucosilado (Tobias, 1994). Es conocido también que las lipoproteínas plasmáticas inducen la liberación del LPS de la superficie del monocito y que el CD14s se encuentra involucrado en este proceso, actuando como una transportador del LPS desde la superficie celular a las partículas de lipoproteínas ricas en triglicéridos (Wurfel, 1995; Kitchens, 1999). Este proceso atenúa, por tanto, la respuesta inflamatoria al lipopolisacárido (Harris, 1990).The CD14s are found in high concentrations (2 at 4 µg / ml) in plasma from both cell secretion (leukocytes, hepatocytes and adipocytes) as of proteolysis Enzymatic cell receptor (cell CD14) membrane anchored by a glycosylated phosphatidylinositol residue (Tobias, 1994). Is also known that plasma lipoproteins induce release of the LPS from the monocyte surface and that the CD14s are is involved in this process, acting as a LPS transporter from cell surface to particles of triglyceride-rich lipoproteins (Wurfel, 1995; Kitchens, 1999). This process attenuates, therefore, the inflammatory response to lipopolysaccharide (Harris, 1990).
En resumen, el CD14s es una molécula glucoproteica que circula en plasma a altas concentraciones derivada de la secreción directa celular o de la proteolisis no enzimática del receptor de membrana para el LPS: el CD14. La función principal del CD14s parece ser la de neutralizar el LPS circulante o presente en la superficie celular mediante su transporte a lipoproteínas circulantes ricas en triglicéridos. El CD14s regula de esta manera la respuesta inflamatoria del organismo al LPS en situaciones agudas (sepsis) y es posible que module la respuesta inflamatoria mantenida asociada a la insulinoresistencia y arteriosclerosis.In summary, CD14s is a molecule Glycoprotein circulating in plasma at high concentrations derived from direct cell secretion or non-proteolysis Enzymatic membrane receptor for LPS: CD14. The CD14s main function seems to be to neutralize the LPS circulating or present on the cell surface through its transport to circulating lipoproteins rich in triglycerides. He CD14s thus regulates the inflammatory response of the organism to the LPS in acute situations (sepsis) and it is possible to modulate the maintained inflammatory response associated with insulin resistance and arteriosclerosis.
En los párrafos precedentes se ha hecho referencia abreviada a determinadas citas bibliográficas que seguidamente se dan completas para su mejor localización:In the preceding paragraphs it has been done abbreviated reference to certain bibliographic citations that then they are given complete for their best location:
- Fernández-Real JM and Ricart W 1999 Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine/phenotype to thriftiness. Diabetologia 42:1367-1374.- Fernández-Real JM and Ricart W 1999 Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine / phenotype to thriftiness. Diabetology 42: 1367-1374.
- Goyert SM, Ferrero E, Rettig WJ, Yenamandra AK, Obata F, Le Beau MM 1988 The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science 239: 497-500.- Goyert SM, Ferrero E, Rettig WJ, Yenamandra AK, Obata F, Le Beau MM 1988 The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science 239: 497-500.
- Harris HW, Grunfeld C, Feingold KR, Rapp JH 1990 Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice. J Clin Invest 86: 696-702.- Harris HW, Grunfeld C, Feingold KR, Rapp JH 1990 Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice. J Clin Invest 86: 696-702.
- Haziot A, Rong GW, Lin X-Y, Silver J and Goyert SM 1995 Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol 154:6529-6532.- Haziot A, Rong GW, Lin XY, Silver J and Goyert SM 1995 Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol 154: 6529-6532.
- Kitchens RL, Wolfbauer G, Albers JJ, Munford RS 1999 Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface. J Biol Chem 274: 34116-34122.- Kitchens RL, Wolfbauer G, Albers JJ, Munford RS 1999 Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface. J Biol Chem 274: 34116-34122.
- Malizevski, Wright 1991 CD14 and Immune Response to Lipopolysaccharide, Science, 252:1321-1322.- Malizevski , Wright 1991 CD14 and Immune Response to Lipopolysaccharide, Science , 252: 1321-1322.
- Pickup JC and Crook MA 1998 Is type II diabetes mellitus a disease of the innate immune system. Diabetologia 41:1241-1248.- Pickup JC and Crook MA 1998 Is type II diabetes mellitus a disease of the innate immune system. Diabetology 41: 1241-1248.
- Schutt C, Schilling T, Grunwald U, Schonfeld W, Kruger C 1992 Endotoxin-neutralizing capacity of soluble CD14. Res Immunol 143:71-8.- Schutt C, Schilling T, Grunwald U, Schonfeld W, Kruger C 1992 Endotoxin-neutralizing capacity of soluble CD14. Res Immunol 143: 71-8.
- Sweet JM, Hume DA 1996 Endotoxin signal transduction in macrophages. J Leukoc Biol 60: 8-26.- Sweet JM, Hume DA 1996 Endotoxin signal transduction in macrophages. J Leukoc Biol 60: 8-26.
- Tobias PS, Ulevitch RJ 1994 CD14 is a pattern recognition receptor. Immunity 1: 509-516.- Tobias PS, Ulevitch RJ 1994 CD14 is a pattern recognition receiver. Immunity 1: 509-516.
- Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC 1990 CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249: 1431-1433.- Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC 1990 CD14, a receiver for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249: 1431-1433.
- Wurfel MM, Hailman E, Wright SD 1995 Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med 181: 1743-1754.- Wurfel MM, Hailman E, Wright SD 1995 Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med 181: 1743-1754.
Apoyándose en los conocimientos expuestos anteriormente y en las enseñanzas de algunas patentes de la técnica anterior en que se preconiza el empleo del CD14s como antiinflamatorio (por ejemplo, Patente US No. 5.804.189 y otras), los presentes inventores han encaminado sus esfuerzos investigadores en demostrar la eficacia del uso del CD14s en procesos relacionados con un estado inflamatorio crónico. Para ello han llevado a cabo experimentos que les han permitido concluir exitosamente su invención en los términos previstos, la cual se expone con todo detalle en los siguientes apartados de la siguiente memoria descriptiva.Based on the exposed knowledge previously and in the teachings of some patents of the technique previous in which the use of CD14s is recommended as anti-inflammatory (for example, US Patent No. 5,804,189 and others), the present inventors have directed their research efforts in demonstrating the effectiveness of the use of CD14s in related processes with a chronic inflammatory state. For this they have carried out experiments that have allowed them to successfully conclude their invention in the terms provided, which is set forth with all detail in the following sections of the following report descriptive
La presente invención tal y como se indica en su enunciado se refiere a nuevas aplicaciones terapéuticas de la glucoproteína CD14s.The present invention as indicated in its statement refers to new therapeutic applications of the CD14s glycoprotein.
La presente invención está basada en la hipótesis de que el LPS produce insulinoresistencia en humanos al activar la cadena inflamatoria, lo que unido al hecho de que (1) es bien conocida la asociación clínica y experimental entre inflamación y resistencia a insulina y que (2) el CD14s bloquea la actividad del LPS, dicho CD14s podría utilizarse con éxito en todos aquellos procesos que cursen con insulinoresistencia.The present invention is based on the hypothesis that LPS produces insulin resistance in humans by activating the inflammatory chain, which together with the fact that (1) is fine known clinical and experimental association between inflammation and insulin resistance and that (2) the CD14s blocks the activity of the LPS, said CD14s could be used successfully in all those processes that occur with insulin resistance.
Los estudios efectuados por los inventores demuestran que existe una correlación negativa entre las concentraciones séricas del CD14s y parámetros de resistencia a la insulina, obesidad e hipertensión en varones sanos. Dichos estudios indican también que los sujetos obesos presentan concentraciones séricas disminuidas de CD14s y que, en sujetos diabéticos de tipo 2, las concentraciones circulantes de CD14s se asocian inversamente con el grado de disfunción vascular. Finalmente, estudios de experimentación animal muestran que la administración de CD14s recombinante humano a ratones diabéticos (ob/ob) disminuye la glucemia basal sin producir cambios en el peso corporal, el peso del músculo sóleo, el peso del tejido adiposo epipidimal ni la ingesta de alimento.The studies carried out by the inventors demonstrate that there is a negative correlation between serum concentrations of CD14s and resistance parameters to Insulin, obesity and hypertension in healthy men. Such studies also indicate that obese subjects have concentrations serum levels of CD14s and that, in diabetic subjects of type 2, circulating concentrations of CD14s are inversely associated with the degree of vascular dysfunction. Finally, studies of Animal experimentation show that the administration of CD14s Recombinant human to diabetic mice (ob / ob) decreases the Basal glycemia without producing changes in body weight, weight of the soleus muscle, epipidymal adipose tissue weight or food intake
En resumen, los hallazgos de los presentes inventores ponen de manifiesto que la concentración sérica de CD14s está disminuida en sujetos obesos, es directamente proporcional a la sensibilidad a la insulina en sujetos sanos e inversamente proporcional al grado de disfunción vascular en pacientes diabéticos de tipo 2, sugiriendo que es una proteína protectora del desarrollo de insulinoresistencia y de las alteraciones vasculares asociadas a ésta. Esta conclusión está apoyada por los efectos hipoglucemiantes (sin modificar el peso ni la ingesta) que se ha observado tras la administración de CD14s recombinante humano a ratones diabéticos.In summary, the findings of those present inventors show that the serum concentration of CD14s is decreased in obese subjects, is directly proportional to Insulin sensitivity in healthy subjects and inversely proportional to the degree of vascular dysfunction in patients Type 2 diabetics, suggesting that it is a protective protein of the development of insulin resistance and vascular disorders associated to it. This conclusion is supported by the effects hypoglycemic agents (without changing weight or intake) that has been observed after administration of human recombinant CD14s to diabetic mice
Por lo tanto, de acuerdo con la presente invención, el CD14s, puede ser administrado a animales o humanos para la prevención o tratamiento de enfermedades que cursen con un estado inflamatorio crónico o mantenido. La finalidad de la administración de CD14s es tanto preventiva (evitar el desarrollo de estas enfermedades) como terapéutica (tratar estas enfermedades una vez que se han instaurado).Therefore, in accordance with this invention, the CD14s, can be administered to animals or humans for the prevention or treatment of diseases that occur with a chronic or maintained inflammatory state. The purpose of the CD14s administration is both preventive (avoid development of these diseases) as therapeutic (treat these diseases once they have been established).
El CD14s a utilizar en la presente invención puede ser CD14 soluble de mamífero, particularmente el CD14s recombinante humano o cualquier proteína o sustancia que contenga la SEQ ID Nº: 1.The CD14s to be used in the present invention it can be soluble mammalian CD14, particularly CD14s human recombinant or any protein or substance that contains SEQ ID NO: 1.
Entre las enfermedades que cursan con un estado inflamatorio crónico o mantenido se incluyen la diabetes mellitus de tipo 2, la obesidad, el síndrome metabólico (conjunto de manifestaciones caracterizadas por uno o varios de los siguientes síntomas: resistencia a insulina, dislipemia, obesidad, hipertensión arterial, alteraciones de la coagulación e hiperuricemia), la enfermedad arteriosclerótica, la hipertensión arterial, el hiperandrogenismo ovárico funcional, y cualquier otro estado que asocie resistencia a la insulina.Among the diseases that occur with a state Chronic or maintained inflammatory diabetes mellitus are included Type 2, obesity, metabolic syndrome (set of manifestations characterized by one or more of the following Symptoms: insulin resistance, dyslipidemia, obesity, arterial hypertension, coagulation disorders e hyperuricemia), arteriosclerotic disease, hypertension arterial, functional ovarian hyperandrogenism, and any other state that associates insulin resistance.
La presente invención se ilustra adicionalmente mediante los siguientes ejemplos, que no deben considerarse limitativos de su alcance.The present invention is further illustrated. by the following examples, which should not be considered limiting its scope.
El objetivo de este ensayo es estudiar el efecto de la administración sistémica de CD14s recombinante humano (CD14rh) sobre parámetros de insulinoresistencia en animales de experimentación obesos (ratones C57BL/6J ob/ob).The objective of this essay is to study the effect of the systemic administration of human recombinant CD14s (CD14rh) on insulin resistance parameters in animals of Obese experimentation (C57BL / 6J ob / ob mice).
Se utilizaron ratones C57BL/6J ob/ob (The Jackson Lab.) machos de 10 semanas de edad. Estos animales presentaban obesidad con hiperfagia, hiperinsulinemia, resistencia a la insulina e hiperglucemia moderada.C57BL / 6J ob / ob mice (The Jackson were used Lab.) 10-week-old males. These animals presented obesity with hyperphagia, hyperinsulinemia, insulin resistance and moderate hyperglycemia.
Para la infusión continua del reactivo, se implantaron bombas Alzet (bomba 1002, 100 \mul) en la parte dorsal de 20 ratones: 10 con el CD14rh y 10 con suero salino. De modo que fueron 10 ratones tratados (1-3-5-7-9-11-13-15- 17-19) y 10 ratones control (2-4-6-8-10-12-14-16-18-20). Se ensayó una dosis de 1 \mug/g/día administrada de forma subcutánea durante 12 días.For continuous reagent infusion, it is Alzet pumps (pump 1002, 100 µl) were implanted in the dorsal part of 20 mice: 10 with CD14rh and 10 with saline. So that were 10 mice treated (1-3-5-7-9-11-13-15- 17-19) and 10 control mice (2-4-6-8-10-12-14-16-18-20). A dose of 1 µg / g / day was administered administered in a manner subcutaneous for 12 days.
Transcurridos 12 días y después de 16 horas en ayuno, se realizó un ensayo de tolerancia intraperitoneal a la glucosa (GTT). Para ello se inyectaron 2 g/kg de glucosa (Glucosomon, 50%) intraperitonealmente. Se obtuvieron muestras de sangre de la cola de los ratones (\sim20 \mul) a los 0, 15, 30, 60, 120 y 180 min de la administración de la glucosa. Los niveles de la glucosa en sangre se determinaron utilizando un glucómetro convencional (Menarini) y los niveles de insulina se determinaron por ELISA (Mercodia Ultrasensitive Mouse Insulin ELISA).After 12 days and after 16 hours in fasting, an intraperitoneal tolerance test to the glucose (GTT). To do this, 2 g / kg of glucose were injected (Glucosomon, 50%) intraperitoneally. Samples of tail blood of mice (? 20) at 0, 15, 30, 60, 120 and 180 min of glucose administration. The levels of blood glucose were determined using a glucometer Conventional (Menarini) and insulin levels were determined by ELISA (Mercodia Ultrasensitive Mouse Insulin ELISA).
Se obtuvieron los siguientes resultados:The following results were obtained:
- \bullet?
- El tratamiento con CD14rh no produjo diferencias significativas entre los ratones tratados y los ratones control en la evolución del peso corporal, la ingesta de alimento y el peso del músculo sóleo y el tejido adiposo epididimal.Treatment with CD14rh does not produced significant differences between the treated mice and the control mice in the evolution of body weight, the intake of food and weight of the soleus muscle and adipose tissue epididymal
- \bullet?
- El tratamiento con CD14rh disminuyó los niveles basales de glucosa sérica en los ratones tratados respecto a los controles. Las concentraciones séricas de insulina disminuyeron concomitantemente al descenso de glucosa sérica en ratones tratados con CD14rh, aunque sin alcanzar significación estadística.The treatment with CD14rh decreased baseline serum glucose levels in mice treated regarding controls. Serum concentrations of insulin decreased concomitantly with glucose decrease serum in mice treated with CD14rh, but not reached statistical significance.
Estos resultados permiten concluir que el CD14rh tiene un efecto hipoglucemiante en ratones obesos ob/ob, probablemente relacionado con una mejoría en la sensibilidad a la insulina.These results allow us to conclude that the CD14rh It has a hypoglycemic effect on ob / ob obese mice, probably related to an improvement in sensitivity to insulin.
El objetivo del presente ejemplo fue estudiar las concentraciones séricas de CD14s en relación al grado de obesidad y parámetros inflamatorios en sujetos sanos, en base a la hipótesis de que el CD14 soluble (CD14s), que circula a altas concentraciones de manera constitutiva en el plasma, juega un papel importante en la neutralización del lipopolisacárido (LPS). El RNAm del CD14 se ha hallado en el tejido adiposo además de en las células del sistema inmune.The objective of this example was to study the serum concentrations of CD14s in relation to the degree of obesity and inflammatory parameters in healthy subjects, based on the hypothesis that the soluble CD14 (CD14s), which circulates at high concentrations constitutively in the plasma, it plays an important role in neutralization of lipopolysaccharide (LPS). The mRNA of CD14 is found in adipose tissue in addition to system cells immune.
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Se midieron las concentraciones de CD14s (EASIA, inmunoensayo de sensibilidad ampliada por enzima en fase sólida) en relación a medidas antropométricas y parámetros inflamatorios (fracciones solubles del receptor del factor de necrosis tumoral alfa 1 y 2, TNFR1s y TNFR2s, EASIA) en sujetos sanos.The concentrations of CD14s (EASIA, solid phase enzyme enhanced sensitivity immunoassay) in relation to anthropometric measurements and inflammatory parameters (soluble fractions of the tumor necrosis factor receptor alpha 1 and 2, TNFR1s and TNFR2s, EASIA) in healthy subjects.
Las concentraciones séricas de CD14s no se correlacionaron significativamente con el índice de masa corporal (IMC) en el análisis global de sujetos (r = 0,06, p = 0,30, n = 229). No obstante, en pacientes delgados (IMC<25, n = 100), el CD14s se asoció significativamente con el IMC (r = 0,36, p <0,0001). Estos hallazgos no fueron observados en pacientes obesos (r = 0,03, p = 0,67). Resultados especulares se observaron entre las concentraciones de CD14s y las del TNFR2: en sujetos obesos, pero no en sujetos delgados, se apreció una asociación inversa entre ambos parámetros (r = -0,26, p <0,01, y r = 0,01, p = 0,87, respectivamente). Los sujetos con IMC mayor de 30 kg/m^{2} presentaron concentraciones disminuidas de CD14s (4,41 \pm 1,5 frente a 4,83 \pm 1,2; p = 0,01).The serum concentrations of CD14s are not correlated significantly with body mass index (BMI) in the global analysis of subjects (r = 0.06, p = 0.30, n = 229). However, in thin patients (BMI <25, n = 100), the CD14s were significantly associated with BMI (r = 0.36, p <0.0001). These findings were not observed in patients. obese (r = 0.03, p = 0.67). Specular results were observed. between the concentrations of CD14s and those of TNFR2: in subjects obese, but not in thin subjects, an association was appreciated inverse between both parameters (r = -0.26, p <0.01, and r = 0.01, p = 0.87, respectively). Subjects with BMI greater than 30 kg / m2 had decreased concentrations of CD14s (4.41 ± 1.5 versus 4.83 ± 1.2; p = 0.01).
La disminución de las concentraciones de CD14s en sujetos obesos puede indicar un aumento de la actividad inflamatoria, dado su papel crucial en la neutralización del LPS.The decrease in CD14s concentrations in obese subjects may indicate an increase in activity inflammatory, given its crucial role in the neutralization of LPS
El objetivo de este ejemplo fue estudiar el CD14s plasmático y el polimorfismo C-159T en relación a parámetros de resistencia a la insulina en sujetos sanos y pacientes con diabetes mellitus de tipo 2, en base a la hipótesis de que el CD14s, que circula a altas concentraciones de manera constitutiva en el plasma, juega un papel importante en la neutralización del lipopolisacárido (LPS). Un polimorfismo del gen del CD14 (una transición C-T en posición -159), parece jugar un papel importante en la regulación de las concentraciones circulantes del CD14s.The objective of this example was to study the CD14s plasma and C-159T polymorphism in relation to Insulin resistance parameters in healthy subjects and patients with type 2 diabetes mellitus, based on the hypothesis that the CD14s, which circulates at high concentrations constitutively in the plasma plays an important role in the neutralization of lipopolysaccharide (LPS). A polymorphism of the CD14 gene (a C-T transition in position -159), seems to play a important role in the regulation of concentrations circulating CD14s.
Se midieron las concentraciones séricas de CD14s (mediante EASIA) y el polimorfismo del gen del CD14 en 123 sujetos sanos y en 32 pacientes con diabetes de tipo 2. En un subgrupo de 32 pacientes, se realizó, además, un ensayo de tolerancia oral a la glucosa (TTOG) y un ensayo de tolerancia endovenosa a la glucosa con muestreos repetidos.Serum concentrations of CD14s were measured (using EASIA) and the polymorphism of the CD14 gene in 123 subjects healthy and in 32 patients with type 2 diabetes. In a subgroup of 32 patients, an oral tolerance test was also performed glucose (TTOG) and an endovenous glucose tolerance test with repeated sampling.
En la siguiente tabla se recogen los datos correspondientes a las variables antropométricas y analíticas de los sujetos controles.The following table shows the data corresponding to the anthropometric and analytical variables of the control subjects.
En varones, las concentraciones séricas de CD14s, ajustadas para la concentración de triglicéridos, se correlacionaron significativamente con la insulinemia basal (r = -0,25, p = 0,C29), el índice basal de resistencia a la insulina (FIRI, r = -0,28, p = 0,014) y el ácido úrico circulante (r = -0,30, p = 0,006). En varones no fumadores (n = 44), el CD14s se correlacionó significativamente con el perímetro abdominal (r = -0,30, p = 0,03), el FIRI (r = -0,30, p = 0,03), la presión arterial sistólica (r = -0,32, p = 0,029) y la presión arterial diastólica (r = -0,34, p = 0,022). Se realizó, asimismo, un análisis de regresión lineal múltiple para predecir el FIRI. En este análisis, el IMC (p <0,00001), las concentraciones basales de triglicéridos (p = 0,003) y el CD14s (p = 0,04), pero no la edad, sexo, perímetro abdominal ni calidad de fumador, contribuyeron de manera independiente al 26% de la varianza del FIRI.In men, serum concentrations of CD14s, adjusted for triglyceride concentration, it correlated significantly with baseline insulinemia (r = -0.25, p = 0, C29), the baseline insulin resistance index (FIRI, r = -0.28, p = 0.014) and circulating uric acid (r = -0.30, p = 0.006). In non-smoking men (n = 44), the CD14s are correlated significantly with the abdominal perimeter (r = -0.30, p = 0.03), the FIRI (r = -0.30, p = 0.03), the pressure systolic blood pressure (r = -0.32, p = 0.029) and blood pressure diastolic (r = -0.34, p = 0.022). There was also a Multiple linear regression analysis to predict the FIRI. In this analysis, BMI (p <0.00001), baseline concentrations of triglycerides (p = 0.003) and CD14s (p = 0.04), but not age, sex, abdominal perimeter or smoking quality, contributed 26% independent of the FIRI variance.
Los sujetos sanos homocigotos C/C mostraron una distribución similar de edad, sexo, IMC, masa grasa, índice cintura-cadera, presión arterial, glucemia e insulinemia basales, en relación a los sujetos portadores de un alelo T. No obstante, los sujetos C/C presentaron mayores concentraciones integradas de glucosa durante la TTOG (ABC glucosa; p = 0,02) y menor índice de sensibilidad a la insulina (p = 0,036) que los sujetos portadores de un alelo T.Healthy homozygous C / C subjects showed a similar distribution of age, sex, BMI, fat mass, index waist-hip, blood pressure, blood glucose e Basal insulinemia, in relation to subjects carrying a T allele. However, the C / C subjects presented higher integrated glucose concentrations during TTOG (ABC glucose; p = 0.02) and lower insulin sensitivity index (p = 0.036) that the subjects carrying a T allele.
Los sujetos diabéticos homocigotos C/C también presentaron menor índice de sensibilidad a la insulina (p = 0,03) que los portadores de un alelo T y se observaron mayores concentraciones séricas de proteína C reactiva y de ICAM-1s (p = 0,01) en los primeros.Homozygous diabetic subjects C / C also they had lower insulin sensitivity index (p = 0.03) than the carriers of a T allele and were observed greater serum concentrations of C-reactive protein and of ICAM-1s (p = 0.01) in the former.
Se observa pues una asociación entre las concentraciones circulantes de CD14s y una variante alélica de su gen, con parámetros de resistencia a la insulina en sujetos sanos y pacientes con diabetes mellitus de tipo 2. Se observa también un efecto de un polimorfismo genético sobre la sensibilidad a la insulina y la función endotelial (ICAM-1s) en pacientes con diabetes mellitus de tipo 2.An association between the circulating concentrations of CD14s and an allelic variant of their gene, with insulin resistance parameters in healthy subjects and Type 2 diabetes mellitus patients. effect of a genetic polymorphism on the sensitivity to insulin and endothelial function (ICAM-1s) in Type 2 diabetes mellitus patients.
<110> Fernández-Real Lemos, José Manuel<110> Fernández-Real Lemos, Jose Manuel
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| ES200300665A ES2232273B1 (en) | 2003-03-21 | 2003-03-21 | NEW THERAPEUTIC APPLICATIONS OF GLUCOPROTEIN CD14S. |
| PCT/EP2004/050189 WO2004082578A2 (en) | 2003-03-21 | 2004-02-23 | Use of soluble cd14 for treatment of diseases |
| EP04713556A EP1608396B1 (en) | 2003-03-21 | 2004-02-23 | Use of soluble cd14 for treatment of diseases |
| ES04713556T ES2312966T3 (en) | 2003-03-21 | 2004-02-23 | USE OF THE SOLUBLE CD14 FOR THE TREATMENT OF DISEASES. |
| DE602004016128T DE602004016128D1 (en) | 2003-03-21 | 2004-02-23 | USE OF SOLUBLE CD14 FOR THE TREATMENT OF DISEASES |
| US10/550,265 US7655237B2 (en) | 2003-03-21 | 2004-02-23 | Use of soluble CD14 for treatment of type 2 diabetes mellitus |
| AT04713556T ATE406172T1 (en) | 2003-03-21 | 2004-02-23 | USE OF SOLUBLE CD14 TO TREAT DISEASES |
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| Title |
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| FERNÁNDEZ-REAL, J.M. et al. "A polymorphism in the CD14 monocyte receptor gene involved in the inflammatory cascade is associated with insulin sensitivity". Diabetología, 2001, Vol. 44, Supl. 1, página A23. * |
| GRIMBLE, R.F. "Inflammatory status and insulin resistance". Curr. Opin. Clin. Nutr. Metab. Care, 2002, Vol. 5, nº 5, página 551; resumen. * |
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