Download Time (minutes) Blue line Glucose (mmol/l)

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
Units of insulin (pmol/dl) and
glucose (mmol/dl)
75g Intra-venous Glucose tolerance
test
80
70
60
50
Glucose
Insulin
40
30
20
10
0
0
20
40
60
80
100 120 140 160 180
Time (minutes from IV load)
75g Oral Glucose tolerance test
Units of insulin (pmol/dl) and
glucose (mmol/dl)
80
70
Glucos…
Insulin…
60
50
40
30
20
10
0
0
20
40
60
80
100
Time (minutes from IV load)
120
140
160
180
The Incretin Effect
80
Glucose OGTT
Insulin OGTT
Glucose IVGTT
Insulin IVGTT
Units of insulin (pmol/dl) and
glucose (mmol/dl)
70
60
50
40
30
20
10
0
0
20
40
60
80
100
Time (minutes from IV load)
120
140
160
180
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
Promotes
Insulin secretion
Inhibits
gastric emptying
GIP
GLP-1
Guyton and Hall. Textbook of Medical Physiology.
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
after 1 hour stabilisation period
Blue line Glucose (mmol/l); Red line
(mg/kg/min)
25
20
15
10
5
Glucose
Infusion
0
0
20
40
60
Time (minutes)
80
100
120
Data on File
Serum Glucose and intravenous glucose
disposal
Blue line Glucose (mmol/l); Red line
(mg/kg/min)
40
35
Glucose
30
Infusion
25
20
15
10
5
Drip feed water administered
Bolus water administered
0
0
20
40
60
80
100
120
140
Time (minutes)
160
180
200
220
240
Data on File
Promotes
Insulin secretion
Food
Inhibits background
Glucagon secretion
Inhibits
gastric emptying
GIP
GLP-1
Vasodilates
perfusing beds
Reduces
appetite
Inhibits
gluconeogenesis
Effect of diabetes on glucagon response to
meal
Aronoff S L et al. Diabetes Spectr 2004;17:183-190
The effect of restoring GLP-1 on Glucagon
20
Meal
Vildagliptin 100 mg (n=16)
Placebo (n=16)
Delta Glucagon (ng/L)
10
0
−10
−20
*
−30
*
−40
−50
−60
17:00
*
*
*
*
*
*
*
20:00
23:00
02:00
Time
Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.
05:00
08:00
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