Metabolic disorders after Stroke

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 recognisedcomplicaton

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 Units of insulin (pmol/dl) and glucose (mmol/dl) Time (minutes from IV load)

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

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

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

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 Drip feed water administered Data on File

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

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

15. The effect of restoring GLP-1 on Glucagon Meal 20 Vildagliptin 100 mg (n=16) Placebo (n=16) 10 0 −10 Delta Glucagon (ng/L) −20 * −30 * −40 * * −50 * * * * * −60 17:00 20:00 23:00 02:00 05:00 08:00 Time 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 • GLP-1 is neuroprotective • GLP-1 is reduced in patients who are “Nil By Mouth” • Replacing 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