Challenging the dogma: Tissue specific regulation of insulin action
A role for glucocorticoids (GCs) in the regulation of carbohydrate metabolism and the development of diabetes was first described over 70 years ago. Whilst there is little doubt that systemic GC excess leads to insulin resistance the tissue specific mechanisms underpinning their effect on insulin sensitivity remain to be understood. We have defined tissue specific effects of GCs on insulin sensitivity and lipid metabolism in vitro and in vivo. In skeletal myotubes GCs, in the absence of insulin, decreased glucose uptake and de novo lipogenesis and increased β-oxidation. GC treatment caused insulin resistance, demonstrated by inhibition of insulin signalling and impaired glucose uptake. In human adipocytes, the direct effects of GCs were similar to those in myotubes, with decreased basal glucose uptake and de novo lipogenesis. However, GCs enhanced insulin signalling, insulin-stimulated glucose uptake and de novo lipogenesis. This represents the first description of GC induced insulin sensitisation in human adipose. Observations in human hepatocytes were similar to those in adipocytes, with increased insulin signalling and de novo lipogenesis. Our clinical observations, using a hyperinsulinaemic euglycaemic clamp combined with adipose tissue microdialysis, confirmed that GCs cause global insulin resistance, however, increased insulin stimulated pyruvate generation and enhanced insulin mediated suppression of lipolysis in adipose tissue, demonstrating tissue specific regulation of insulin sensitivity by GCs in vivo. GCs have historically been thought to oppose the actions of insulin in all tissues. The classic view of GCs inhibiting insulin signalling in muscle holds true, but, this is not the case for liver and adipose. These findings reveal new insights into the biology of GC regulation of metabolism, their interaction with insulin and may explain why fatty liver and increased adiposity are associated with GC excess. These observations have the potential to define new therapeutic targets to combat the obesity and diabetes epidemic.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: Medical Research Council (ref. G0802765), Wellcome Trust (075322/Z/04/Z).