metabolic disorders after stroke dr david strain peninsula medical school royal devon & exeter...
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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
0 20 40 60 80 100 120 1800
10
20
30
40
50
60
70
80
GlucoseInsulin
Time (minutes from IV load)
Uni
ts o
f in
suli
n (p
mol
/dl)
and
glu
cose
(m
mol
/dl)
75g Oral Glucose tolerance test
Time (minutes from IV load)
Uni
ts o
f in
suli
n (p
mol
/dl)
and
glu
cose
(m
mol
/dl)
0 20 40 60 80 100 120 1800
10
20
30
40
50
60
70
80
Glucose...
The Incretin Effect
Time (minutes from IV load)
Uni
ts o
f in
sulin
(pm
ol/d
l) an
d g
luco
se (
mm
ol/d
l)
0 20 40 60 80 100 120 1800
10
20
30
40
50
60
70
80
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
0 20 40 60 80 100 1200
5
10
15
20
25
after 1 hour stabilisation period
Glucose Infusion
Time (minutes)
Blu
e li
ne
Glu
cose
(m
mol
/l);
Red
lin
e (m
g/k
g/m
in)
Data on File
Serum Glucose and intravenous glucose disposal
0 20 40 60 80 100 120 140 160 180 200 220 2400
5
10
15
20
25
30
35
40
Glucose
Infusion
Time (minutes)
Blu
e li
ne
Glu
cose
(m
mol
/l);
Red
lin
e (m
g/k
g/m
in)
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
*
* **
*
*
*
*−60
−50
−40
−30
−20
−10
0
10
20
17:00
Time
Del
ta G
luca
gon
(ng/
L)
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
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