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Platelets from poorly controlled type 2 diabetes patients show impaired
ability to protect against cardiac ischaemia/reperfusion injury
Platelets from poorly controlled type 2 diabetic patients have been shown to have lost their ability to protect against ischaemia/reperfusion injury, but
also induced an increase of infarct size and of lactate dehydrogenase release, a marker of necrosis.
T
his outcome of an investiga-
tion of the direct role of plate-
lets to influence infarct size in
a rat model of ischaemia/reperfusion
after infusion of human platelets
from type 2 diabetic or healthy sub-
jects was reported at the meeting.
Isabella Russo, PhD, of the Uni-
versity of Turin, Italy, explained that
in type 2 diabetes, platelet hyper-
reactivity is partially responsible for
a switch of the coagulation system
toward a prothrombotic state.
Ischaemia and reperfusion are
implicated in a variety of clinical
conditions including thrombolytic
therapy for myocardial infarction.
Reperfusion of previously ischae-
mic tissue, while essential to
prevent irreversible tissue injury,
elicits inflammatory responses with
increased production of reactive oxy-
gen species and soluble mediators,
leading to impaired organ function.
Dr Russo and colleagues perfused
hearts from male Wistar rats in
Langendorff mode with an oxygen-
ated Krebs solution at constant flow
(9 –10 mL/min/g). After 20 minutes
of stabilisation, hearts were divided
into three groups:
1.Controls received 20 minutes of
oxygenated buffer perfusion
2. A group received 20 minutes of
oxygenated buffer containing 30 x
10
6
/mL platelets from healthy
subjects (n=6, four males, two
females, age 49 ± 3 years)
3. A group received 20 minutes of
oxygenated buffer containing
30 x 10
6
/mL platelets from pa-
tients with type 2 diabetes (n=5,
four males/one females, age 55 ± 3
years, haemoglobin A1c 14 ± 1%)
At the end of platelet-perfusion,
the hearts underwent 30 minutes of
normothermic global ischaemia fol-
lowed by 60 minutes of reperfusion.
Lactate dehydrogenase release and
infarct size were assessed. In plate-
let samples from each subject, the
following were also evaluated:
•
platelet aggregation to adenosine
diphosphate 10 µmoL/L, col-
lagen 4 mg/L, arachidonic acid
0.5 mmoL/L (Born’s method)
•
activation of PI-3 kinase/Akt and
MAPK/Erk-1/2 pathways
•
intraplatelet reactive oxygen spe-
cies production
•
cyclooxygenase-1 expression.
Infarct size was 59 ± 2% of risk
area in control hearts and was small-
er in hearts pretreated with platelets
from healthy subjects (49 ± 3% of
risk area; P < 0.05), but higher in
hearts pretreated with platelets from
type 2 diabetic patients (63 ± 4% of
risk area; P < 0.05) than in those
pretreated with platelets-from
healthy subjects.
Lactate dehydrogenase release
corroborated the data on infarct size.
Perfusion pressure was not affected
by any of the treatments. Interest-
ingly, platelets from type 2 diabetic
patients, in comparison with those
from healthy subjects, showed:
•
A higher trend to aggregate in re-
sponse to arachidonic acid (76 ±
11 vs 51 ± 3, P < 0.05); adenosine
diphosphate (78 ± 14 vs 63 ± 2,
difference not significant); and
collagen (89 ± 13 vs 65 ± 2, dif-
ference not significant)
•
A greater increase in basal values
of phosphorylated Akt and Erk-2
in response to collagen (2.9 ± 0.2
vs 1.5 ± 0.6, P = 0.07; and 15.6
± 3.3 vs 5.5 ± 1.2, P < 01.03, re-
spectively) and arachidonic acid
(2 ± 0.3 vs 1.4 ± 0.6, difference
not significant; and 22 ± 4.9 vs 5.4
± 1.5, P < 0.007)
•
Greater reactive oxygen species
production (mean fluorescence
intensity per minute) stimulated
by arachidonic acid (73,708 ± 560
vs 35, 350 ± 720, P < 0.0001)
•
Higher expression of cyclooxyge-
nase-1 (arbitrary units 26,643 ±
210 vs 13,200 ± 350, P < 0.0001).
Dr Russo concluded that platelets
from poorly controlled type 2 diabetic
patients lost not only their ability to
protect against ischaemia/reperfusion
injury but also induced an increase
of infarct size and lactate dehydro-
genase release, a marker of necrosis.
These effects were associated
with an increased tendency of plate-
lets to aggregate in response to the
main physiological proaggregating
agents, as well as increased produc-
tion of reactive oxygen species and
cyclooxygenase-1 expression. These
findings suggest that, in type 2 dia-
betes, platelet hyperreactivity could
hold predictive value of myocardial
dysfunction after ischaemia/reperfu-
sion injury.
In type 2 diabetes, platelet
hyperreactivity could hold
predictive value of
myocardial dysfunction
after ischaemia/reperfusion
injury.
1
1
Dual Action NovoMix
®
30
2,3
NOVMIX0065/CEN/A4
Please review Product Information before prescribing.
The Product Information can be accessed at
www.novonordisk.com.auMinimum Product Information. NovoMix
®
30 (insulin aspart (rys)). Indication:
Treatment of diabetes mellitus.
Contraindications:
Hypoglycaemia. Hypersensitivity to insulin aspart or
excipients.
Precautions:
Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Where blood glucose is greatly
improved, e.g. by intensified insulin therapy, patients may experience a change in usual warning symptoms of hypoglycaemia, and should be advised accordingly. The impact of the rapid onset
of action should be considered in patients where a delayed absorption of food might be expected. Do not use in insulin infusion pumps. No studies in children and adolescents under the age of 18.
No clinical experience in pregnancy. When thiazolidinediones (TZDs) are used in combination with insulin, patients should be observed for signs and symptoms of congestive heart failure, weight gain
and oedema; discontinuation of TZDs may be required. Insulin administration may cause insulin antibodies to form and, in rare cases, may necessitate adjustment of the insulin dose.
Interactions:
Oral hypoglycaemic agents, octreotide, lanreotide, monoamine oxidase inhibitors, non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol,
anabolic steroids, alpha-adrenergic blocking agents, quinine, quinidine, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone,
diazoxide, asparaginase, nicotinic acid.
Adverse Effects:
Hypoglycaemia.
Dosage and Administration:
Dosage as determined
by physician. NovoMix
®
30 should be administered immediately before a meal, or when necessary after the start of a meal.
Resuspend immediately before use. Discard the needle after each injection. Subcutaneous injection only. NovoMix
®
30 must not
be administered intravenously. (July 2014).
References: 1.
Liebl A
et al. Drugs
2012; 72(11): 1495–520.
2.
Wu T
et al. Diabetes
Ther
2015; 6(3): 273–87.
3.
NovoMix
®
30 Approved Product Information (Jul 2014). Novo Nordisk Pharmaceuticals Pty Ltd.
ABN 40 002 879 996. Level 3, 21 Solent Circuit, Baulkham Hills, NSW 2153. NovoCare
®
Customer Care Centre (Australia)
1800 668 626.
www.novonordisk.com.au. ® Registered trademark of Novo Nordisk A/S. AU/NM/0116/0004. January 2016.
PBS Information:
This product is listed on the PBS for the treatment of diabetes mellitus.
insulin aspart (rys)
NOVMIX0065/CEN/A4.indd 1
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