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Cardiovascular risk in patients with diabetes mellitus is increased 3 to 5-fold. Haffner et al. (1998) have shown recently, that diabetic patients without previous myocardial infarction have a similar risk of myocardial infarction as non-diabetic patients with previous myocardial infarction (Haffner et al., 1998). This study compared the 7-year incidence of cardiovascular mortality among 1373 non-diabetic subjects with the incidence among 1950 diabetic subjects in Finland. Therefore, it is a current issue of discussion, that type 2 diabetes and coronary heart disease have some common predisposing environmental and genetic factors in their pathogenesis. Several recent studies indicate that arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity with consecutive hyperinsulinaemia called "metabolic syndrome" or "syndrome X".

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Concerning a possible molecular link between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between lipid metabolism, insulin action, and obesity at a gene regulatory level. Alterations in the structure, function and regulation of transcription factors appear to be such signalling steps which might play an essential role in the pathogenesis and therapy of cardiovascular risk factors associated with insulin resistance. Recent examples are members of the nuclear hormone receptor superfamily, e. g. peroxisome proliferator-activated receptor (PPAR) isoformes and sterol regulatory element-binding proteins (SREBPs). Beside their regulation by different metabolites, these transcription factors are also targets of hormones, like insulin and leptin, growth factors, and inflammatory signals. Therefore, they appear to be a point of signalling convergence at a gene regulatory level. Therefore, these studies may identify novel pathways which play a role in the control of body weight, insulin sensitivity and cardiovascular risk.

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The release of SREBPs from the endoplasmatic reticulum or nuclear envelope is a complex cholsterol-regulated proteolytic cascade and a key step in gene regulation by metabolites (Brown and Goldstein, 1999). However, beside mechanisms controlling intracellular abundance of the trans-active N-terminal domain of SREBPs, there is growing evidence that an additional major mechanism of control is regulating trans-activity of SREBPs directly, e. g. via posttranslational modification mediated by MAP kinases (Salter et al., 1987; Brindley et al., 1989; Wade et al., 1988, 1989; Lloyd and Thompson, 1995; Streicher et al., 1996; Wang and Sul, 1997; Kim et al., 1998a; Kotzka et al., 1998, 2000; Kumar et al., 1998; Singh et al., 1999; Gierens et al., 2000). In accordance to that it has been shown, that SREBP-1a, -1c, and -2 are substrates of the ERK-familiy of MAP kinases, in vitro (Kotzka et al., 1998, 2000; Roth et al., 2000). The best characterisation of phosphorylation sites has been obtained for SREBP-1a. The N-terminal domain was investigated after phosphorylation by ERK-2, in vitro. A protein chemistry approach using mass spectrometry and peptide sequencing identified serine 117 as the major phopshorylation site, which was verified by corresponding mutation of this site to alanine. In accordance to that, LDL receptor promotor reporter gene analyses have shown, that mutation of serine 117 to alanine abolishes the stimulatory effect of insulin and PDGF (Roth et al., 2000).

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There are three SREBP-isoforms, so called SREBP-1a, SREBP-1c as well as SREBP-2 (Briggs et al., 1993, Wang et al., 1993, Hua et al., 1993, Tonotonoz et al., 1993), two of which are products of a single SREBP-1 gene (Yokoyama et al., 1993, Hua at al., 1995b, Shimomura et al., 1997). SREBP-1a and SREBP-1c are generated by the recruitment of two distinct promotors and different first exons. Exon-1 of SREBP-1a codes for 29 amino acids, whereas SREBP-1c contains only 5 amino acids. The protein structure contains three essential domains, the N-terminal domain (SREBP-1a: ca. 460 aa, SREBP-1c: ca. 435 aa, SREBP-2: ca. 460 aa), two transmembrane domains containing a short loop of approximately 80 aa and a C-terminal domain (SREBP-1a: ca. 600 aa, SREBP-1c: ca. 585 aa, SREBP-2: ca. 600 aa). The N-terminal domain contains several regions beginning with a so called acidic region (SREBP-1a: 51 aa, SREBP-1c: 27 aa, SREBP-2: 61 aa), which is typical for transcription factors and appears to have a trans-activating role (Ma & Ptashne, 1987). According to this hypothesis it has been shown that SREBP-1a, which contains a 24 amino acid longer sequence in this region than SREBP-1c, is a stronger activator of transcription in liver. SREBPs are key players in the control of intracellular lipid accumulation, which might impair the function of the corresponding cell, e.g. insulin secretion in the case of pancreatic ß-cells, or insulin-stimulated glucose uptake or insulin sensitivity in the case of adipose tissue, skeletal muscle, and liver (Unger & Orci, 2001; Unger & Zhou, 2001).

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The paper by Marchesini et al. (2001) provides direct clinical evidence, that intracellular lipid accumulation in the liver appears to be related to decreased systemic sensitivity for insulin-stimulated glucose uptake. Accordingly, patients with NAFLD appear to be insulin resistant comparable to patients with overt type 2 diabetes.

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In this respect it is interesting to note, that a recent posthoc analysis of the WOSCOP study indicates that in the statin treated group incidence of overt type 2 diabetes was reduced by 30 %. This evidence implies, that plasma cholesterol lowering by induction of the hepatic LDL receptor gene is only one effect of statin-mediated reduction of cholesterol synthesis in the liver. Beside induction of the LDL receptor gene, inhibition of HMG-CoA reductase by statins might affect the expression of many other genes and signalling pathways, e. g. involved in reaction to stress and other extracellular stimuli, proliferation and apoptosis. Apparently, as mentioned above, these so called pleiotropic effects have different implications for different cells and might lead to novel perspectives and clinical indications for statins in the near future.

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Intracellular lipid accumulation, called lipid toxicity, might be a link between insulin resistance, visceral obesity and increased lipid deposition in non-adipose tissue, perhaps even including cells of the arterial vessel wall being a feature of atherosclerosis. Therefore, it is interesting to note that SREBPs regulate not only lipid metabolism, but also appear to be target of insulin action, and therefore possibly a key link for different features of the metabolic syndrome.

Discovery and elucidation of complex gene regulatory networks will ultimately lead to the identification of master regulators like transcription factors, which will give new insights into the pathophysiology of complex clinical phenotypes like syndrome X, and provide medicine with new potential drug targets. Therefore, the relationship between structure and function of these transcription factors, their regulation, gene targets as well as the role in different cells or tissues have to be understood.