1. Metabolic disorders after Stroke Dr David Strain Peninsula Medical School Royal Devon & Exeter Hospital

2. Acute Stroke There are many known effects of stroke on the neuroendocrine system These include release of adrenaline, noradrenaline, cortisol, growth hormone. Further, inflammatory markers are also elevated. All of these are known to antagonise the effects of insulin therefore acute hyperglycaemia is a well recognised complicaton

3. Hyperglycaemia post stroke The prevalence of hyperglycaemia is greater post stroke than post other vascular events Further, if a patient is placed Nil by mouth or NG fed, the prevalence almost doubles again This raises the question of stroke specific mechanisms

4. The Incretin system Main role of the pancreas is secreting digestive enzymes -Trypsin, pepsin, VIP… Also has small groups of cells that form “Islands” not connected to the gut These islets of Langerhans control sugar levels in the body No direct supply/connection between intestine and pancreas

5. 75g Intra-venous Glucose tolerance test Time (minutes from IV load) Units of insulin (pmol/dl) and glucose (mmol/dl)

6. 75g Oral Glucose tolerance test Time (minutes from IV load) Units of insulin (pmol/dl) and glucose (mmol/dl)

7. The Incretin Effect Time (minutes from IV load) Units of insulin (pmol/dl) and glucose (mmol/dl)

8. Incretins Messengers exist to stimulate insulin release and prepare vasculature for glucose/insulin combination Glucagon-like peptide -1 (GLP-1) Glucose-dependent insulinotropic polypeptide (GIP)

9. Food GLP-1GIP Promotes Insulin secretion Guyton and Hall. Textbook of Medical Physiology. Inhibits gastric emptying

10. Pilot study to determine the stimulating mechanism of incretins Take 1 willing fasted volunteer ?!?... Infuse intravenous Glucose until Plasma glucose is in the diabetic range (~11mmol/l) Measure infusion requirements

11. Serum Glucose and intravenous glucose disposal Data on File

12. Serum Glucose and intravenous glucose disposal Data on File Drip feed water administered

13. Food GLP-1GIP Promotes Insulin secretion Vasodilates perfusing beds Reduces appetite Inhibits gluconeogenesis Inhibits gastric emptying Inhibits background Glucagon secretion

14. Aronoff S L et al. Diabetes Spectr 2004;17:183-190 Effect of diabetes on glucagon response to meal

15. The effect of restoring GLP-1 on Glucagon Meal * * * * * * * * −60 −50 −40 −30 −20 −10 0 10 20 17:00 Time Delta Glucagon (ng/L) 20:0023:0002:0005:0008:00 Placebo (n=16) Vildagliptin 100 mg (n=16) * Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.

16. Relevance in acute stroke Insulin has purported neuro-protective effects Glucagon increases glucose utility therefore may increase infarct size GLP-1 has proven benefits in animal models

17. GLP-1 in acute stroke animal studies GLP-1 –mediates endothelial dependent relaxation –Mediates endothelial independent relaxation –is protective against ischaemia-reperfusion injury –is renoprotective Finally, it protects mouse brain against traumatic stroke when administered after the event for 7 days. Importantly this did not require pre-treatment.

18. Study Rationale GLP-1 is produced by gastric stretch GLP-1 is neuroprotective in animals By putting patients NBM we reduce endogenous GLP-1 Therefore we reduce the potential protective mechanism We wish to replace this.

19. Liraglutide Liraglutide is synthetic GLP-1 1 amino acid different from naturally occurring GLP-1 Therefore has an action >24 hours by binding to albumin Licensed for the management of type 2 diabetes Licensed in states for obesity Not licensed for treatment of stroke

20. Study hypothesis 1GLP-1 is neuroprotective 2GLP-1 is reduced in patients who are “Nil By Mouth” 3Replacing and supplementing GLP-1 will improve outcomes after a stroke

21. PILOT study plan To recruit 40 individuals –within 6 hours –Ischaemic stroke –Anticipated to be “Nil By Mouth” for at least 12 hours –With or without thrombolysis

22. Outcomes The principle outcome from this is study is to inform the definitive outcome trial Therefore we aim to –Assess recruitment feasibility –Assess numbers –Determine Standard Deviations of MRI measures and NIHSS scores –Follow attrition –Inform costs of definitive study

23. Secondary outcomes In animal models Infarct was reduced by 75% If this is replicated we will see –Reduced MRI infarct volume –Greater improvement in NIHSS BUT not the principle outcome. Therefore, study will not be a failure if no difference demonstrated

24. Thank you for your attention