The main objectives of this thesis are to investigate and analyze the expression of various genes of the biological clock, 6-phosphofructo-2-kinase/fructoso-2,6-bisphosphatase, and a number of other key regulatory enzymes and factors in the subcutaneous adipose tissue in obesity and its complications. Accumulating evidence raises the hypothesis that dysregulation of intrinsic clock mechanisms which control most metabolic processes are involved in the development of obesity, metabolic syndrome, and type 2 diabetes mellitus, the most profound public health problems. We sought to identify the dysregulation of molecular components of circadian clock system and its connection with the expression of different PFKFB, a key regulatory enzyme of glycolysis and proliferation, in adipose tissue of obese individuals with type 2 diabetes and prediabetic traits versus lean and obese patients. The results of this study provide strong evidence that key circadian genes are deregulated in adipose tissue of obese individuals as well as in obese patients with type 2 diabetes and prediabetic traits. This dysregulation of the intrinsic clock mechanisms is accompanied by the suppression of a key regulatory enzyme of glucose and lipid metabolism. It is possible that a significant increase of PER2, CLOCK, CRY1, PFKFB4, PFKFB3, HK2 and IRS1 gene expression as well as a decrease of PER2, CLOCK, CRY1, PFKFB4, SPARC and E2F1 gene expression in adipose tissue of individuals with type 2 diabetes mellitus versus patients with prediabetic traits can participate in the development of diabetes and its complications. Additionally, results of this study provide strong evidence that expression of genes encoded the key regulatory factors with pleiotropic functions, related to the control of proliferation and angiogenesis, in subcutaneous adipose tissue of the obese individuals with normal glucose tolerance as well as in obese patients with glucose intolerance and type 2 diabetes is deregulated. It is possible that these changes in the expression of TIMP and THBS genes in adipose tissue in obesity as well as in obese individuals with impaired glucose tolerance and type 2 diabetes can contribute to fat tissue storage, insulin and VEGF resistance as well as the development of diabetic complications determined both by insulin resistance and endoplasmic reticulum stress. Collectively, results of this study underscore the crucial role of the biological clock, PFKFB, THBS, TIMP and some other regulatory factors in developing the obesity as well as glucose intolerance, insulin resistance and type 2 diabetes mellitus in obese individuals.
