CIRCADIAN REGULATION · Circadian regulation in the control of insulin and glucagon release and its role in Type 2 diabetes

Circadian regulation in the control of insulin and glucagon release and its role in Type 2 diabetes

Many organisms have 24 hours rhythms in metabolism physiology and behaviour that are driven by cell circadian pacemakers. These circadian rhythms allow organisms to coordinate many physiological processes in response to environmental changes. In mammals, the central pacemaker is localised in the suprachiasmatic nuclei in the hypothalamus and it is controlled by a transcriptional / translational feedback loops involving a set of clock genes. Recent studies, however, indicate that besides the central clock in the brain, peripheral molecular clocks exist in several organs, such as liver, kidney, heart, adipose tissue and pancreas. Studies in human showed that disturbances in the regulation of central and peripheral biological clocks by sleep loss among other factors, can lead to a decrease in insulin sensitivity and increased risk of obesity and diabetes Mellitus whereas long-term shift work has been associated with dislipidaemia and an increased risk of diabetes and cardiovascular disease. Because of the strong association between increased risk of obesity and type 2 diabetes and disturbances in the biological clocks, this proposal was aimed to determine whether clock genes can regulate insulin and glucagon secretion and whether alterations in the pancreatic circadian clock is involved in the irregular pattern of secretion of these hormones in diabetes. We demonstrated that all clock genes are expressed in the pancreatic islet of Langerhans, in a mouse beta cell line (MIN-6) and in a mouse alpha cell line (alpha-TC1-9). Among the clock genes, we discovered that Bmal1 is one of the most important clock genes that regulate glucagon mRNA expression. However, the main outcome of this fellowship was the identification of the clock gene Rev-erb-alpha as a regulator of pancreatic beta-cell function. Down-regulation of Rev-erb-alpha expression in islet-cells as well as in MIN-6 cells decreased the mRNA levels of lipogenic genes, decreased beta cell proliferation and impaired glucose-induced insulin secretion. In addition, we demonstrated that pancreatic beta cells exhibit oscillations of Rev-erb-alpha gene expression along the day and these oscillations are an intrinsic property of these endocrine cells, which occurs in vitro independently of the main clock located in the brain supraschiasmatic nucleus. Furthermore, we found that Rev-erb-alpha expression is modulated by high-fat diet (HFD) and by the hormone leptin. Among the different clock genes analysed, Rev-erb-alpha was the only one that had altered expression in all the times of the day due to HFD treatment. In vivo and in vitro leptin treatment increased Rev-erb-alpha expression in isolated islets through a mitogen activated protein kinase pathway. Our results indicate that the clock gene Rev-erb-alpha plays multiple functions in the pancreatic beta-cell. While the increase in Rev-erb-alpha expression during obesity may promote beta-cell adaptation, its dysregulation may lead to altered beta-cell function and, eventually, type 2 diabetes. The significance of our results will impact both the scientific community and the public because we identify the clock gene Rev-erb-alpha as a new regulator of glucose-induced insulin secretion, lipogenic genes and proliferation in the beta-cell. These findings will help to understand the regulation between disturbances of circadian rhythms and metabolic disorders which are becoming a priority in prevention and management of these diseases. Contact details: Dr Elaine Vieira Instituto de Bioingeniería, Universidad Miguel Hernandez, Avenida de la Universidad s/n, 03202 Elche, Spain Phone: +34-96-522-2012, Fax: +34-9652-22033, Email: evieira@umh.es.

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