Fogorvosi szemle, 2007 (100. évfolyam, 1-6. szám)
2007-10-01 / 5. szám
251 FOGORVOSI SZEMLE ■ 100. évf. 5. sz. 2007. sulin mediated glucose uptake of the peripheral tissues (insulin resistance) and the compensatory hyperinsulinism are common soils of different human diseases [46], This discovery yielded revolutionary changes in the knowledge concerning DM2. Earlier, the micro- and macrovascular lesions and the ischemic hard diseases were regarded as complications of the DM but the new concept suggested a common source, namely the insulin resistance. The predecessor of DM2 is an insulin resistant state: the metabolic syndrome. It is composed of increased body mass index, hypertension and elevated plasma glucose, triglyceride and low-density lipoprotein cholesterol levels. The essence of the metabolic syndrome lies in the clustering of these risk factors, which are all associated with cardiovascular diseases [6], Interestingly, most of these factors have individually been linked in some way to the cancer development [11], Metabolic syndrome and DM2 show an increasing prevalence all over the world. The “western lifestyle” (energy-rich diet, obesity, lack of physical exercise) has an important role in its widespread occurrence. Surprisingly, there are several unique features of the metabolic syndrome in women. Estrogen deficient states, such as polycystic ovarian syndrome of premenopausal female patients and menopause may increase the inclination to insulin resistance [53]. At the end of the 20th century, strong correlations have also emerged between the defects of insulin mediated glucose uptake and risk of malignancies. The recognition of this new correlation suffered some delay, as clinical manifestation of cancer from tumor initiation requires a longer period, frequently decades. Clinical epidemiological studies supported that both the earlier phases of glucose metabolism disorders, such as metabolic syndrome and DM2 are important cancer risk factors [21,23, 28, 45, 56], The correlation between insulin resistance and tumors was first described in breast and colon cancer cases [6]. These observations were followed by many data supporting the tumor provoking effect of insulin resistance at different sites [1, 16, 18, 29 57, 60]. Our working group described first the epidemiological correlations of oral tumors and type-2 diabetes [57, 60]. Moreover, there are gender related differences for OC risk depending on the hormonal milieu and the grade of insulin sensitivity [58], Correlations of insulin resistance and tumor promotion Insulin resistance has a first, compensated phase when the serum glucose level is maintained within the normal range at the expense of a reactive hyperinsulinemia. Insulin has crucial metabolic effects and at the same time it is a growth factor. An elevated serum insulin level enhances the production and mitogenic activity of other, insulin-like growth factors, such as IGF-I and IGF-II [49, 63], Excessive insulin supply and IGFs have important impact on cell proliferation activity and have proven role in cancer risk at several sites. In the second, uncompensated phase of insulin resistance the secretor capacity of the insular ß-cells becomes exhausted and the serum insulin level is not enough to maintain euglycemia. The increased plasma glucose level results in DM2. Hyperglycemia also promotes the tumor genesis by several pathways. Excessive glucose supply may play a direct role in neoplastic cell proliferation through the pentose phosphate pathways, which are characteristic of unrestrained DNA synthesis of malignancies [7]. Elevated serum glucose level and glucose auto-oxidation provoke deliberation of free radicals and oxidative stress, which cause derangement of both DNA and the enzymes having important role in repair mechanisms [62]. Hyperglycemia leads to a non-enzymatic glycation of protein structures, and these glycated products have crucial role in tumor promotion and spread [5], Insulin stimulates cellular glucose uptake by inducing the expression of a protein family called glucose transporters (GLUTs). GLUT4 is the only isoform of these proteins that responds to insulin and constitutes the rate limitation of insulin-induced glucose uptake. In hyperglycemia GLUT1, which is another member of this glucose transporter family, shows an enhanced expression and activity, which results in an uncontrolled glucose transport. High expression of GLUT1 and its excessive glucose transporter activity is an important contributing factor to tissue injury in hyperglycemic patients [37], Recent literary results support that GLUT1 has crucial correlation with human malignancies. In oral cancer cases a significant relationship between cancer related death and GLUT1 expression has been observed; a high GLUT1 level predicted shorter survival [27, 42], Extracellular matrix alterations in DM2 and OC risk Sustained hyperglycemia is in correlation not only with glucose metabolism but also with alterations in lipid metabolism as well as non-enzymatic glycation of proteins, such as collagens. These changes alter the function of the cell membranes and their receptor proteins and cause thorough changes in cell-cell and cell-matrix interactions. Non-enzymatic glycation of proteins, lipids and nucleic acids in DM patients causes serious complications [8], Glycated proteins, known as advanced glycation end-products (AGEs) may be formed both in DM and non-diabetic cases, however, their accumulation is greatly increased in DM patients with sustained hyperglycemia.
