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- _2 value "Although the exact mechanism by which these drugs improve peripheral insulin sensitivity and reduce plasma glucose concentration is not fully understood, several general possibilities have emerged. First, TZDs might have a beneficial effect on metabolism by increasing fat-cell number and size, leading to greater lipid storage capacity and increased protection of nonadipose tissues from the deleterious effects of excess lipid accumulation. Second, PPAR? agonists could act on the mature adipocyte to alter the production of adipose-derived hormones or metabolic signals that function to improve metabolic parameters in other tissues and organs, such as muscle, liver and pancreas. Third, it is also possible that TZDs exert their metabolic effects through direct action in nonadipose tissues. The evidence that PPAR? ligands cause the generation of new adipocytes is supported by studies in obese Zucker rats treated with TZDs, where an increased number of small adipocytes, presumably generated by TZD-induced adipogenesis, were observed [34]. An increase in fat-cell size after TZD treatment has also been seen in some rodent models [35] and in patients [36]." provenance.