Neuro-endocrine mechanisms of Interleukin-1ß-mediated resetting of glucose homeostasis

• Applicant: Professorin Adriana del Rey, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2008 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 94171388

IL-1b induces a long-lasting, insulin-independent, hypoglycemia by increasing glucose utilization and inhibition of gluconeogenesis. However, we have recently found that IL-1b maintains hypoglycemia by acting at brain levels. The aim of this project is to study the mechanisms underlying this central effect of IL-1b. Our hypothesis is that brain-borne IL-1, which is expressed in the hypothalamus following peripheral administration of the cytokine, 1) inhibits counter-regulation to hypoglycemia by switching its initial effects on CRH receptors 1, which stimulate counter-regulation, to CRH receptors 2, which have opposite actions, and/or by affecting glucose-sensing neurons expressing ATP-sensitive K+ channels; 2) restricts the effect of hypoglycemia on brain functions by favouring glucose incorporation into neural cells as part of its neuroprotective actions. To explore this hypothesis, we shall use genetically modified mice (CRH receptors 1 and 2, Kir6.2, MyD88 knockout mice) and normal and type 2 diabetic mice that will receive the corresponding blockers administered in the brain. Our studies include functional tests of glucose- and insulin-tolerance, the evaluation of hormones involved in glucose homeostasis, and hypothalamic aminergic and indolaminergic neurotransmitter content and CRHR and urocortin gene expression. This research should lead to better understanding the effect of brain-borne IL-1b on glucose homeostasis and neuroprotection, and provide the background for clinical studies on the relevance of such effects during inflammation and the metabolic syndrome.

• DFG Programme: Research Grants