Diabetes mellitus (DM) is the most common endocrine disorder in man, currently affecting over 170 million people world-wide and, potentially, over 365 million in the year 2030. Type 2 DM is rapidly emerging as one of the greatest global health challenges of the 21st century. This looming epidemic is also expected to trigger a steep rise in the complications associated with diabetes, such as ischemic heart disease, stroke, neuropathy, retinopathy, and nephropathy.
Besides β cell failure, the major pathophysiological event contributing to the development of type 2 DM is the resistance of target tissues to insulin, which is usually associated with abnormal insulin secretion. Clinically, the term “insulin resistance” implies that higher-than-normal concentrations of insulin are required to maintain normoglycemia. On a cellular level, it defines the inadequate strength of insulin signaling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic and mitogenic aspects of cellular function.
The pathogenesis of type 2 diabetes involves abnormalities in both insulin action and secretion. Although the precise pathophysiological sequence which leads to insulin resistance is still largely unknown, recent studies have contributed to a deeper understanding of the underlying molecular mechanisms. This review deals with the mechanisms related to type 2 diabetes. A detailed understanding of these basic pathophysiological mechanisms is critical for the development of novel therapeutic strategies to treat diabetes.
In order to understand the molecular basis of the regulation of IR gene expression, the promoter region of the human IR gene has been identified and studied by several groups[62]. Two unique AT-rich sequences, C2 and E3, within the IR gene promoter have been identified, and both these sequences are positively regulated by transcription factor HMGA1 (earlier known as HMG1-Y)[63]. HMGA1 interacts with the AT rich regions and regulates transcriptional activation of many genes by modifying DNA conformation, which permits recruitment of transcriptional factor to the transcription start site.
HMGA1 induces transcriptional activation of the human IR gene by permitting the recruitment of SP1and cEBPβ, the ubiquitously expressed transcription factors, to the promoter region. A recent report demonstrates that a genetic flaw which reduces the intracellular expression of HMGA1 protein can adversely affect IR expression in cells and tissues from subjects with insulin resistance and type 2 diabetes.
There is also a possibility that activated PKCε phosphorylates HMGA1, which inhibits its mobilization to the promoter region IR gene. It has been shown that phosphorylation of the HMGA1 protein reduces its DNA-binding ability. Without the mobilization of HMGA1 to the IR promoter there is no recruitment of additional transcription factors to the promoter region of the IR gene and therefore no expression of the IR gene.
Source: ncbi.nlm.nih.gov
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