Metabolic disorders after Stroke

Dr David Strain

Peninsula Medical School

Royal Devon & Exeter Hospital

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

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

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

75g Intra-venous Glucose tolerance test

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75g Oral Glucose tolerance test

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Glucose...

The Incretin Effect

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Glucose OGTTInsulin OGTTGlucose IVGTTInsulin IVGTT

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)

Food

GLP-1GIP

PromotesInsulin secretion

Guyton and Hall. Textbook of Medical Physiology.

Inhibits gastric emptying

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

Serum Glucose and intravenous glucose disposal

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after 1 hour stabilisation period

Glucose Infusion

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Data on File

Serum Glucose and intravenous glucose disposal

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Infusion

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Bolus water administered

Data on File

Drip feed water administered

Food

GLP-1GIP

PromotesInsulin secretion

Vasodilates perfusing beds Reduces

appetite Inhibits

gluconeogenesis

Inhibits gastric emptying

Inhibits backgroundGlucagon secretion

Aronoff S L et al. Diabetes Spectr 2004;17:183-190

Effect of diabetes on glucagon response to meal

The effect of restoring GLP-1 on Glucagon

Meal

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Time

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20:00 23:00 02:00 05:00 08:00

Placebo (n=16)Vildagliptin 100 mg (n=16)

*

Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.

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

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.

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.

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

Study hypothesis

1 GLP-1 is neuroprotective

2 GLP-1 is reduced in patients who are “Nil By Mouth”

3 Replacing and supplementing GLP-1 will improve outcomes after a stroke

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

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

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

Thank you for your attention