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2012, Number 4

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Rev Endocrinol Nutr 2012; 20 (4)

Epigenetics and Diabetes: The role of DPP-4

Storino-Farina MA, Contreras-Zambrano MÁ

Language: Spanish
References: 31
Page: 169-174
PDF size: 276.58 Kb.


ABSTRACT

Diabetes is currently one of the most frequent diseases and its incidence is rising at amazing speed. It constitutes one of the main causes of death worldwide. The uprising incidence rate is due partly because of better diagnostic methods and more effective treatment, all of which has enhanced the diabetic patient life expectancy. Nevertheless, 50% of all cases remain undiagnosed, which translates into one undiagnosed diabetic patient for every diagnosed one. There are many treatments for Diabetes, amongst which there are the dipeptidyl peptidase-4 inhibitors. DPP-4 has a wide distribution on the human body and exerts pleiotrophyc effects through its peptidase activity. The most representative target peptide is the glucagon-like peptide 1 (GLP-1) and its inhibition re sults in glucose intolerance, diabetes mellitus and hepatic steatosis. Recent studies have identified a series of genetic factors that explain in part the interindividual variability of susceptibility to diabetes. Epigenetics can be defined as the process of changing the function of a gene (probably transferable) without any change on the nucleotide sequence. The epigenetics effects can be altered by the environment, turning them into potentially important pathogenic mechanisms in complex and multifactorial diseases such as type 2 diabetes. The epigenetic mechanisms are closely related. They all work at different levels of the genetic organization providing altogether relevant modifications of the chromatin structure. A narrow chromatin is less accessible to transcription, hence the target gen is silenced and the product is not codified, because when a gene is «shut down», methylated, or suppressed, its genetic information will not be transcribed. This process is reversible, so that a «shut down» gene can be reactivated. DNA methylation is the main epigenetic modification of human genoma and it regulates key aspects of its features. It is a gene silencing mechanism with an evident role in transcriptional suppression. The nucleosome is the basic unit of the chromatin and the histones are part of the core of this functional unit. Histones are subject of chemical modifications on both its domains: the globular and the N-terminal tails. The effects of these modifications transform the nature of the nucleosome so it «opens» or «shuts down» the chromatin in order for the transcription to take place. Acetylation is one of the best studied histone modifications and it is catalyzed by «histone acetyltransferases». Another well-known mechanism is histone methylation which is catalyzed by enzymes called «histone methyltransferases». One of the most important breakthroughs in latest biology has been the discovery of RNA molecules that regulate gene expression. These are called «short interfering RNA» or «silencing RNA», and are small RNA molecules that unchain the process of silencing by interference. DPP-4 is a 110 kDa peptidase associated to the membrane of epithelial and endothelial cells, fibroblasts and lymphocytes. Besides the immunologic role, DPP-4 is associated with the sensitivity to anti-cancer agents on hematologic malignancies. The epigenetic changes associated with type 2 diabetes remain poorly known. However, epigenetics plays an important role in the rising of the incidence of type 2 diabetes and in the years to come it will be a great challenge to unveil the meddling of histones modifications and DNA methylation in the pathogenesis of this disease.


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