RESUMEN
Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/biosíntesis , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Proteínas Portadoras/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Circulación Enterohepática/efectos de los fármacos , Humanos , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.
Asunto(s)
Glucosa/biosíntesis , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Depresión Química , HumanosRESUMEN
The difficulties of futurological statement about the role of psychotherapy in the medical care system are seen (1) in the problemacy to define the object, (2) to assess the present state of the situation of psychotherapeutic care, (3) to recognize the environmental conditions of the role of psychotherapy is paramount. The futurological hypotheses are centred on the supposition that psychotherapy is more and more tending not be fixed at medical professional roles.