Molecular characterization of insulin resistance in the adipose tissue and the effects of thiazolidinediones

Abstract: Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many contries. Insulin resistance plays a central role in the pathogenesis of Type 2 diabetes and can be present for a decade or more before onset of the disease. During this time, many of the abnormalities and complications associated with Type 2 diabetes are initiated. Studies in, and identification of, pre-diabetic individuals are therefore important for the prevention and understanding of the cause of Type 2 diabetes. Thiazolidinediones (TZD) is a group of agents used in the treatment of Type 2 diabetes. However, our knowledge about their mode of action is still incomplete.The aims of this thesis were: 1) To study the effect of TZD treatment on key insulin signaling molecules in cultured skeletal muscle cells (Paper I); 2) To examine the expression of PGC-alpha in adipose tissue of non-diabetic but insulin-resistant individuals as well as its relation to insulin sensitivity and different markers involved in insulin action (Paper II); 3) To characterize the IRS-1 expression in the adipose tissue and its potential role as a marker for insulin resistance and early atherosclerosis (Paper III); 4) To examine if short-term treatment with TZD improves insulin sensitivity in non-diabetic but insulin-resistant individuals, and if this is associated with an improvement in the dysregulated adipose tissue that we have documented to be associated with insulin resistance (Paper IV). In Paper I, L6 skeletal muscles were used to study the effects of TZD on gene and protein expression of major insulin signaling molecules. TZD treatment increased the expression of IRS-1, possibly through an indirect mechanism. In Paper II, we show that PGC-alpha is expressed in human isolated adipocytes and that its expression is decreased in individuals characterized by low protein expression of IRS-1 in the adipose cells and reduced insulin sensitivity. In Paper III, we report that a low IRS-1 protein expression in the adipose cells seems to be a more sensitive marker for identifying individuals at risk of developing Type 2 diabetes and atherosclerosis, compared to a known genetic predisposition for the disease. Furthermore, the individuals expressing low IRS-1 protein in the adipose cells display lower circulating levels of adiponectin and show attenuated expression of several genes related to adipogenesis in the adipose tissue. In Paper IV, we show that short-term treatment with TZD increases the insulin sensitivity and that this is associated with an improvement in some, but not all, markers of a dysregulated adipose tissue.In conclusion, low IRS-1 protein expression in the adipose cells is a marker for identifying individuals with reduced insulin sensitivity. These individuals are also characterized by a reduced expression of PGC-alpha, attenuated adipocyte differentiation and low levels of circulating adiponectin. TZD increases the expression of IRS-1 in vitro in cultured skeletal muscle cells. In vivo, however, short-term treatment (3 wks) with TZD does not increase the expression of IRS-1 in the adipose cells. Nevertheless, the improved insulin sensitivity after TZD treatment was associated with an increased expression of a number of other genes and proteins involved in insulin-signaling and adipocyte differentiation.The impaired adipocyte differentiation seen in these individuals can provide a potential link between the cellular markers and the in vivo phenotype. Further studies of the underlying mechanisms for the impaired adipogenesis are now warranted.