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4) Mechanisms of insulin resistance in the CNS. Aged Irs2-deficient mice present various manifestations of neurodegeneration including neuronal loss and deposits of hyperphosphorylated tau. Through the use of genomics and proteomics, we hope to identify new markers of neurodegeneration that are regulated by insulin signaling. given that we seek to identify the molecular basis of obesity and insulin resistance, our research may provide the rational basis for the development of new and innovative strategies for the detection, treatment and prevention of metabolic disorders including lifestyle changes or drugs that promote IRS2 expression or function.
Most relevant scientific articles
• Martorell S., Hueso L., González-Navarro H., Collado A., Sanz M.-J., Piqueras L. Vitamin D Receptor Activation Reduces Angiotensin-II–Induced Dissecting Abdominal Aortic Aneurysm in Apolipoprotein E– Knockout Mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2016.
• Lao-Peregrin C., Ballesteros J.J., Fernández M., Zamora-Moratalla A., Saavedra A., Gómez Lázaro M. et al. Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling. Addiction Biology. 2016.
• Andrés-Blasco I., Vinue A., Herrero-Cervera A., Martínez-Hervás S., Nunez L., Piqueras L. et al. Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIgHT/ lymphotoxin β-receptor pathway. Thrombosis and Haemostasis. 2016;116(2):379-393.
• Martínez-Hervás S., Navarro I., Real J.T., Artero A., Peiro M., González-Navarro H. et al. Unsaturated oral fat load test improves glycemia, insulinemia and oxidative stress status in nondiabetic subjects with abdominal obesity. PLoS ONE. 2016;11(8).
• Martínez-Hervás S., Artero A., Martínez-Ibánez J., Tormos M.C., González-Navarro H., Priego A. et al. Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia. European Journal of Clinical Investigation. 2016;46(7):636-642.
Highlights
During this year, our laboratory has received funding from the pharmaceutical industry to screen potential anti-diabetic compounds in the Irs2-deficient mouse model, a model of insulin resistance combined with pancreatic beta cell failure. One of these test drugs delayed the development of hyperglycemia in female Irs2-null mice and was associated with improved hepatic metabolism. However, the potential anti-diabetic properties of the other test drug may be dependent on IRS2 signaling since it had no beneficial effects in Irs2-deficient mice.
IRS2 signals are required for hepatic insulin action. Our recent studies suggest that local IRS2 signaling is also essential for hepatic regeneration in response to chronic injury. Irs2-deficiency undermines a full regeneration response that includes upregulation of inflammatory and repair genes. Our observations suggest that IRS2 may modulate a balance between regeneration and the uncontrolled proliferation of hepatocellular carcinoma.
We have also generated a new tool for studying the role of Irs2 in vivo: a transgenic mouse model where the expression of gFP and luciferase are under the control of the Irs2 promoter. Although IRS2 signals are critical for the development and function of the endocrine pancreas, little is known about the spatial/ temporal expression during embryonic development and the regulation of the Irs2 gene in the adult pancreas. The new Irs2-GFP-luc model will permit us to define the spatiotemporal regulation of Irs2 during fetal and adult life and during the aetiology of metabolic disease. Additionally, this new mouse model will facilitate identification of compounds or drugs which protect and/or restore beta cell compensation as mediated by the IRS2 pathway.
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