Insulin Resistance: the Adipocyte Scene
In insulin resistant states as type 2 diabetes mellitus, the fat cells are resistant to insulin, both for glucose uptake and suppression of lipolysis. J Clin Endocrinol Metab. 1985 Nov;61(5):807-11 The latter defect results in increased lipolysis in adipose tissue with chronically elevated free fatty acids (FFAs) which in turn impairs insulin secretion, decreases glucose uptake in muscles, J Clin Invest. 1983 Nov;72(5):1737-47. stimulates hepatic gluconeogenesis, increases hepatic VLDL production and induces hepatic and muscular insulin resistance. J Biol Chem. 2000 Mar 24;275(12):8456-60. Thus the adipocyte defect might be more crucial in the pathogenesis of insulin resistance? Read further about the role of adipose tissue........Insulin and glucose normally stimulates adipocyte lipoprotein lipase activity while reducing muscle lipoprotein lipase activity, thus directing fatty acids towards adipose tissue rather than muscles. In obese patients, activation of lipoprotein lipase in adipose tissue is delayed while LPL activity in muscle is increased, Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7522-7. resulting in increased lipid accumulation in muscles (increased intramyocellular lipid), with development of the ectopic fat storage syndrome. The role of fatty acid transporter protein (CD36) in regulation of fatty acid uptake in tissues, with implications on development of insulin resistance in states of deficiency Lancet. 2001 Mar 3;357(9257):686-7 remains to be clarified.
Increased reductase activity of 11 beta HSD levels in fat seems to contribute to locally raised cortisol levels which could facilitate increased adipocyte proliferation with resultant adverse effects. Dysregulation of 11β HSD1 in human obesity has been described and seems to be tissue specific. Increasing BMI is associated with impaired 11β-HSD1 activity, with the degree of impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. This down-regulation of 11 β HSD1 activity in the obese could be protective against development of insulin resistance. Type 2 diabetic patients do not show this BMI related change in 11 β HSD1 activity J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack of down-regulation of 11 β HSD1 in obese patients could facilitate development of diabetes.
Increased reductase activity of 11 beta HSD levels in fat seems to contribute to locally raised cortisol levels which could facilitate increased adipocyte proliferation with resultant adverse effects. Dysregulation of 11β HSD1 in human obesity has been described and seems to be tissue specific. Increasing BMI is associated with impaired 11β-HSD1 activity, with the degree of impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. This down-regulation of 11 β HSD1 activity in the obese could be protective against development of insulin resistance. Type 2 diabetic patients do not show this BMI related change in 11 β HSD1 activity J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack of down-regulation of 11 β HSD1 in obese patients could facilitate development of diabetes.