The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism - they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism — ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors y (PPARy), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPARy results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted-fey tumour-necrosis factor (TNFa), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPARy. In mature adipocytes, PPARy stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPARy transcriptional activity suggests that this research direction is promising.
Acidic methanolic extracts of haemolymph, cuticle and eyes of larvae and adults of the migratory locust, Locusta migratoria migratorioides (R. et L.), were subjected to thin layer chromatography. The Rf-values as well as the fluorescent colour of the spots under ultraviolet illumination at 350 nm, were compared to those of 12 pteridine standards. Most of the standards showed a major spot, as well as up to 3 additional minor spots, probably due to the presence of isomers and degradation products. The extract of the haemolymph of untreated larvae and adults yielded 6 different spots. Cuticle and eyes had their own specific pattern. Application of methoprene (analogue of juvenile hormone) induced solitary phase-like pigmentation of the cuticle and green-coloured haemolyph. The content of pterin, biopterin, leucopterin, isoxanthopterin, and probably also of lumazin, increased. The melanization of the cuticle nearly completely disappeared. Similar, but weak effects were observed in neem-oil treated locusts. Application of precocene caused a number of changes in the pigment pattern of all extracts. It also induced some melanization of the cuticle in particular in larvae. Many pigment spots were observed which did not correspond to any of the 12 standard pteridines. The classical concept about the pigment composition of locust haemolymph, namely that it is restricted to melanin, carotenes and biliverdin, needs modification.
This article critically examines the arguments against mechanistic neo-Darwinism offered by Thomas Nagel in his recent book Mind and Cosmos. The author argues, in particular, that Nagel’s recognition of teleology in the evolutionary process should make him less sceptical towards a panpsychist understanding of nature., James Hill., and Obsahuje poznámky a bibliografii