RESUMO
The glucose-sensing enzyme glucokinase (GK) plays a key role in glucose metabolism. We report here the effects of a novel glucokinase activator, LY2121260. The activator enhanced GK activity via binding to the allosteric site located in the hinge region of the enzyme. LY2121260 stimulated insulin secretion in a glucose-dependent manner in pancreatic beta-cells and increased glucose use in rat hepatocytes. In addition, incubation of beta-cells with the GK activator resulted in increased GK protein levels, suggesting that enhanced insulin secretion on chronic treatment with a GK activator may be due to not only changed enzyme kinetics but also elevated enzyme levels. Animals treated with LY2121260 showed an improved glucose tolerance after oral glucose challenge. These results support the concept that GK activators represent a new class of compounds that increase both insulin secretion and hepatic glucose use and in doing so may prove to be effective agents for the control of blood glucose levels in patients with type 2 diabetes.
Assuntos
Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hepatócitos/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Sulfonas/farmacologia , Tiazóis/farmacologia , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Cristalografia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Glucoquinase/química , Hepatócitos/citologia , Hepatócitos/enzimologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/enzimologia , Masculino , Estrutura Terciária de Proteína , Ratos , Ratos Wistar , Sulfonas/química , Tiazóis/químicaRESUMO
Pleural mesotheliomas, especially pure epithelioid mesotheliomas, may histologically be easily confused with peripheral pulmonary adenocarcinomas or pleural carcinosis. As there is no specific antibody for mesotheliomas, today a panel of immunohistochemical markers is used for the differential diagnosis of these two tumour entities. In search of further significant antibodies for application onto formalin-fixed, paraffin-embedded tissue, we immunohistochemically investigated the expression pattern of three adhesion molecules: vascular cell adhesion molecule (VCAM), E-selectin and E-cadherin. A comparatively large number of 44 mesotheliomas (15 epithelioid, 15 biphasic, 14 sarcomatoid) and 18 peripheral pulmonary adenocarcinomas were analysed. While for these two tumour entities there were no significant differences of the staining patterns for VCAM and E-selectin, there were significant differences in the expression of E-cadherin: while nearly all adenocarcinomas stained positively, there was almost no staining reaction of the mesotheliomas. Therefore, E-cadherin -- in contrast to E-selectin and VCAM -- appears to be a further relevant immunohistochemical marker for the distinction between adenocarcinomas and mesotheliomas.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais , Caderinas/metabolismo , Selectina E/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico , Mesotelioma/patologia , Pessoa de Meia-IdadeRESUMO
A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.