SFEBES2018 Oral Communications Obesity & diabetes (6 abstracts)
Hypothalamic arcuate glucokinase and its downstream pathways are critical in glucose homeostasis
Risheka Ratnasabapathy 1 , Yue Ma 1 , Chioma Izzi-Engbeaya 1 , Marie-Sophie Nguyen-Tu 2 , Errol Richardson 1 , Sufyan Hussain 1 , Ivan De Backer 1 , Christopher Holton 1 , Mariana Norton 1 , Gaelle Carrat 2 , Blanche Schwappach 3 , Guy A Rutter 2 , Waljit S Dhillo 1 & James V Gardiner 1
1Section of Endocrinology and Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK; 2Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK; 3Department of Molecular Biology, Center for Biochemistry and Molecular Cell Biology, Heart Research Center Göttingen, University Medicine Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
As the nation gets fatter, the incidence of diabetes is also rising. The brain is now emerging as a critical mediator of blood sugar control, re-directing focus away from the traditional pancreas-centred model. The enzyme glucokinase (GK) acts as a glucose sensor in many tissues including glucose-sensitive neurones within the hypothalamic arcuate nucleus. However, the role of GK here is unclear. We investigated the role of arcuate GK in glucose homeostasis in both healthy and overweight models. We used a recombinant adeno-associated vector (rAAV) expressing either GK (iARC-GK) or antisense GK (iARC-ASGK) to increase or decrease GK activity specifically in the arcuate nucleus of rats. We investigated the subsequent effects on glucose homeostasis. Increased glucokinase activity significantly improved glucose tolerance (7.43±0.23 mmol/L iARC-GFP vs 6.4±0.27 mmol/L iARC-GK, P<0.05). Insulin secretion was also significantly increased (2.68±0.38 ng/ml iARC-GFP vs 3.94±0.33 ng/ml iARC-GK, P<0.001). Conversely, decreased glucokinase activity significantly worsened glucose tolerance (7.27±0.34 mmol/L iARC-GFP vs 8.5±0.34 mmol/L iARC-asGK, P<0.05) and insulin secretion was significantly lower (3.63±0.12ng/ml iARC-GFP vs 2.89±0.20 ng/ml iARC-asGK, P<0.05). The effect of glucokinase upregulation was maintained in a rodent model of Type 2 diabetes. Interestingly, these obese models were also more sensitive to centrally administered sulphonylureas compared with healthy controls. However, the same sulphonylureas were ineffective when administered peripherally. These results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis. Increasing glucokinase activity improved blood glucose levels and increased insulin secretion in both healthy and metabolically dysregulated models thereby making it an attractive potential therapeutic target. Furthermore, centrally acting sulphonylureas appear to be more effective in correcting hyperglycaemia than peripherally administered sulphonylureas. This effect is particularly marked in obese models. Hence development of centrally active ligand-directed glucokinase activators or central sulphonylureas working via the glucokinase activation pathway, may herald a new era in anti-diabetic therapy.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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