MON-666 Glucokinase Within the Hypothalamic Paraventricular Nucleus Is Important in GLP-1 Release

When glucose is taken orally more insulin is secreted than when glucose is injected directly into the bloodstream. This is known as the incretin effect. Glucagon like peptide 1 (GLP-1) is one of the hormones responsible for this effect. GLP-1 is released from enteroendocrine L-cells in the gut in response to oral glucose intake. GLP-1 increases insulin synthesis and secretion. Release of GLP-1 is thought to be solely dependent upon gastrointestinal tract mechanisms. Here we identify a brain mechanism via the hypothalamic paraventricular nucleus (PVN) which is important in the release of GLP-1 in response to oral glucose. The role of the paraventricular nucleus in glucose homeostasis was previously unknown. We found that a glucokinase dependent glucose sensing mechanism in the PVN works in conjunction with the gut to regulate GLP-1 release. We show that increasing expression of GK (sense GK, sGK) into the PVN improves glucose tolerance (15 minutes glucose: GFP: 8.93±0.27mmol/L, n=11; sGK: 7.72±0.22mmol/L, n=12; p<0.01 and 15 minutes insulin GFP: 2.84±0.14mmol/L, n=11; sGK: 3.73±0.27mmol/L, n=12; p<0.01) and increases GLP-1 release in response to oral glucose (GFP: 6.16±0.18mmol/L, n=11; sGK: 6.90±0.26mmol/L, n=12; p<0.01). On the contrary decreasing expression of GK (antisense GK, asGK) in the PVN worsens glucose tolerance (30 minutes glucose: GFP: 8.22±0.28mmol/L; asGK: 9.46±0.24mmol/L, n=8; p<0.01 and 15 minutes insulin: GFP: 4.07±0.37mmol/L; asGK: 2.25±0.17mmol/L, n=8; p<0.001) and blunts (GLP-1 release 30 minutes GLP-1: GFP: 6.93±0.25pMol/L, n=8; p<0.01 asGK: 5.47±0.13pMol/L, n=8; p<0.001). Our results demonstrate that glucosensitive GK neurones in the PVN, are important to the response to oral glucose and the subsequent release of GLP-1.