metabolic disorders after stroke
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Metabolic disorders after Stroke
Dr David StrainPeninsula Medical School
Royal Devon & Exeter Hospital
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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
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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
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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
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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 ins
ulin
(pm
ol/d
l) an
d g
luco
se (m
mol
/dl)
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75g Oral Glucose tolerance test
Time (minutes from IV load)
Uni
ts o
f ins
ulin
(pm
ol/d
l) an
d g
luco
se (m
mol
/dl)
0 20 40 60 80 100 120 1800
10
20
30
40
50
60
70
80
Glucose...
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The Incretin Effect
Time (minutes from IV load)
Uni
ts o
f ins
ulin
(pm
ol/d
l) an
d g
luco
se (m
mol
/dl)
0 20 40 60 80 100 120 1800
10
20
30
40
50
60
70
80
Glucose OGTTInsulin OGTTGlucose IVGTTInsulin IVGTT
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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)
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Food
GLP-1GIP
PromotesInsulin secretion
Guyton and Hall. Textbook of Medical Physiology.
Inhibits gastric emptying
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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
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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 lin
e G
luco
se (m
mol
/l); R
ed li
ne (m
g/kg
/min
)
Data on File
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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
GlucoseInfusion
Time (minutes)
Blu
e lin
e G
luco
se (m
mol
/l); R
ed li
ne (m
g/kg
/min
)
Bolus water administered
Data on File
Drip feed water administered
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Food
GLP-1GIP
PromotesInsulin secretion
Vasodilates perfusing beds Reduces
appetite Inhibits
gluconeogenesis
Inhibits gastric emptying
Inhibits backgroundGlucagon secretion
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Aronoff S L et al. Diabetes Spectr 2004;17:183-190
Effect of diabetes on glucagon response to meal
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The effect of restoring GLP-1 on GlucagonMeal
*
* ***
*
*
*−60
−50
−40
−30
−20
−10
0
10
20
17:00Time
Delta
Glu
cago
n (n
g/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.
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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
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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.
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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.
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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
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Study hypothesis
1 GLP-1 is neuroprotective2 GLP-1 is reduced in patients who are “Nil
By Mouth”3 Replacing and supplementing GLP-1 will
improve outcomes after a stroke
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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
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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
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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
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Thank you for your attention