Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues.

Lys(9) for Glu(9) substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39)

The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLIP-l's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His(7) and Ala(8), can greatly improve resistance to this enzyme. Little research has assessed what effect Glu(9)-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu(9) of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue, (Lys(9))GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1 (9-36)amide. We investigated the in vivo antagonistic actions of (Lys(9))GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor. (C) 2004 Elsevier Inc. All rights reserved.

DPP IV resistance and insulin releasing activity of a novel di-substituted analogue of glucose-dependent insulinotropic polypeptide, (Ser(2)-Asp(13))GIP

Structure-function studies suggest that preservation of the N-terminus and secondary structure of glucose-dependent insulinotropic polypeptide (GIP) is important for biological activity. Therefore, a novel di-substituted analogue of GIP, (Ser(2)-Asp(13))GIP, containing a negatively charged Asp residue in place of an Ala in position 13, seas synthesised and evaluated for in vitro biological activity. Incubation with dipeptidyl peptidase IV (DPP IV) showed the half-lives of GIP and (Ser(2)-Asp(13))GIP to be 2.3 and >4 h, respectively. Insulin releasing studies in clonal pancreatic BRIN-BD11 cells demonstrated that (Ser(2)-Asp(13))GIP (10(-12) to 10(-7) mol/l) was significantly less potent (60-90%; P

La parroquia de San Miguel de Sagra y San Gil de Madrid en el siglo XVI. Aportaciones documentales

Una serie de documentos inéditos relativos a la antigua parroquia de San Miguel de Sagra y San Gil, localizada muy próxima a la entrada principal del Alcázar de Madrid, así como su posterior derribo y traslado en 1548 con nuevo edificio en el lado suroriental del Palacio, permite profundizar en un proyecto urbano largo tiempo madurado y culminado en la conformación de un espacio abierto y regularizado, emblemático y representativo, que resultó ser la plaza situada frente a la portada principal del Alcázar.

Roche tomography of cataclysmic variables - IV. Star-spots and slingshot prominences on BV Cen

We present Roche tomograms of the G5-G8 IV/V secondary star in the long-period cataclysmic variable BV Cen reconstructed from Magellan Inamori Kyocera Echelle spectrograph echelle data taken on the Magellan Clay 6.5-m telescope. The tomograms show the presence of a number of large, cool star-spots on BV Cen for the first time. In particular, we find a large high-latitude spot which is deflected from the rotational axis in the same direction as seen on the K3-K5 IV/V secondary star in the cataclysmic variable AE Aqr. BV Cen also shows a similar relative paucity of spots at latitudes between 40° and 50° when compared with AE Aqr. Furthermore, we find evidence for an increased spot coverage around longitudes facing the white dwarf which supports models invoking star-spots at the L1 point to explain the low states observed in some cataclysmic variables. In total, we estimate that some 25 per cent of the Northern hemisphere of BV Cen is spotted. We also find evidence for a faint, narrow, transient emission line with characteristics reminiscent of the peculiar low-velocity emission features observed in some outbursting dwarf novae. We interpret this feature as a slingshot prominence from the secondary star and derive a maximum source size of 75000 km and a minimum altitude of 160000 km above the orbital plane for the prominence. The entropy landscape technique was applied to determine the system parameters of BV Cen. We find M1 = 1.18 +/-0.280.16Msolar and M2 = 1.05 +/-0.230.14Msolar and an orbital inclination of i = 53° +/- 4° at an optimal systemic velocity of ? = -22.3 km s-1. Finally, we also report on the previously unknown binarity of the G5IV star HD 220492.

Alegoría: su pertinencia en la predicación y uso en "La novena maravilla"

En este artículo se focaliza el recurso de la alegoría como método exegético en la composición de los sermones panegíricos de Juan Espinosa Medrano (Perú, siglo XVII). Se traza el recorrido de la alegoría (y las humanidades en general) en relación –siempre tensa– con el cristianismo a lo largo de su historia; y se llega a la Contrarreforma y el uso exacerbado del método en la predicación barroca; particularmente en la oratoria sagrada de Espinosa Medrano, quien abarca elementos diversos y extraídos de distintas fuentes (filosofía natural, mitología clásica, tradición emblemática, relatos bíblicos), a los que hace funcionar como signos de otra verdad mayor, la sagrada. Si bien las preceptivas sagradas impulsaban una predicación más llana y simple, la profusión de alegorías mitológicas, que el autor resemantiza según su interés de guiar la interpretación, pueden explicarse por varias circunstancias, motivos de estudio en este trabajo.

La narrativa indigenista en Argentina. Una doble denuncia

Desde tiempos de José Carlos Mariátegui, la crítica literaria indigenista viene articulando un discurso etnocentrista cuyo eje de producción se sitúa en Perú y los países vecinos, pero rara vez se ha mencionado una obra argentina que trate sobre las desigualdades que sufren los indígenas de ese país. Ni siquiera la academia argentina ha analizado ninguna novela desde la óptica indigenista.En un país cuyos gobiernos, desde el siglo XIX, han tratado de borrar cualquier traza de sangre indígena en su población, ya sea mediante la asimilación, exterminio o invisibilidad, y cuyas zonas de mayor asentamiento indígena se encuentran lejos del hegemónico Buenos Aires, las narraciones de problemas sociales ajenos quedaban encajonadas en el recóndito mundo de la literatura regional.Sin embargo, durante los años de eclosión del movimiento indigenista, escritores argentinos se hicieron eco de los sufrimientos y demandas de sus compatriotas indígenas por medio de novelas que sobrepasaron el peyorativo epíteto regionalista y que incomprensiblemente, han sido olvidadas.En este artículo, que forma parte de un estudio más amplio, se aborda el silencio crítico, se contextualiza la producción indigenista de la época y se analizan brevemente algunas de las obras.

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Effects of antidiabetic drugs on dipeptidyl peptidase IV activity: Nateglinide is an inhibitor of DPP IV and augments the antidiabetic activity of glucagon-like peptide-1

Dipeptidyl peptidase IV (DPP IV) is the primary inactivator of glucoregulatory incretin hormones. This has lead to development of DPP IV inhibitors as a new class of agents for the treatment of type 2 diabetes. Recent reports indicate that other antidiabetic drugs, such as metformin, may also have inhibitory effects on DPP IV activity. In this investigation we show that high concentrations of several antidiabetic drug classes, namely thiazolidinediones, sulphonylureas, meglitinides and morphilinoguanides can inhibit DPP IV The strongest inhibitor nateglinide, the insulin-releasing meglitinide was effective at low therapeutically relevant concentrations as low as 25 mu mol/l. Nateglinide also prevented the degradation of glucagon-like peptide-1 (GLP-1) by DPP IV in a time and concentration-dependent manner. In vitro nateglinide and GLP-1 effects on insulin release were additive. In vivo nateglinide improved the glucose-lowering and insulin-releasing activity of GLP-1 in obese-diabetic ob/ob mice. This was accompanied by significantly enhanced circulating concentrations of active GLP-1(7-36)amide and lower levels of DPP IV activity. Nateglinide similarly benefited the glucose and insulin responses to feeding in ob/ob mice and such actions were abolished by coadministration of exendin(9-39) and (Pro(3))GIP to block incretin hormone action. These data indicate that the use of nateglinide as a prandial insulin-releasing agent may partly rely on inhibition of GLP-1 degradation as well as beta-cell K-ATP channel inhibition. (C) 2007 Elsevier B.V. All rights reserved.