Type 2 Diabetes Mellitus With Hypoglycemia Clinical Trial
Official title:
A Study to Identify Biomarkers of Hypoglycaemia in Patients With Type 2 Diabetes
Glucose is a sugar carried in the blood stream that body uses for energy. If someone has
diabetes, blood glucose level can be erratic, sometimes becoming very low this is called
Hypoglycaemia (or a "hypo"), and can happen when blood glucose levels drop below 4 mmol/l.
So far in order to prove that a hypo happened for a patient, blood glucose level can only be
measured at time of the hypo and not after it.
In this study we are trying to identify certain chemical substances (biomarkers) in diabetic
patients that may be measured in blood tests of the patient up to after 24 hours of the hypo
and if we could prove that a hypo has happened we could adjust tablets and or insulin dosage
in a way to prevent further hypos.
The study will be conducted in the Diabetes Centre in Hull Royal Infirmary and will involve
three visits to the diabetes centre. The study can finish in a week time after the first
visit.
Visit 1 is the screening visit to identify eligibility to take part in the study. Visit 2
insulin infusion will be given to make participants blood sugar level fall lower than normal
for a short time and corrected quickly afterward. This is a stress for participant's body and
should stimulate certain chemicals that we are trying to identify during hypo.
In Visit 3, the main purpose of this visit which is done 24 hours after insulin infusion is
to take a blood sample and check how participants is after visit 2.
We will recruit 25 Type 2 Diabetic patients and 25 none diabetics to compare both results.
Both groups should not have ischemic heart disease, underactive thyroid or seizures and on
stable dosage of medications.
Background information It is well recognised that patients with both type 1 and type 2
diabetes suffering repeated hypoglycaemia are at risk of death and significant morbidity (1).
This is of major clinical importance as currently, only the recording of a low blood sugar at
the time of hypoglycaemia gives confirmation that a hypoglycaemic event has taken place.
There are many instances when the confirmation or exclusion of a hypoglycaemic event would be
beneficial.
Landmark studies such as the Diabetes Control and Complications Trial (DCCT) )(2) in type 1
diabetes and the in numerous large studies (UKPDS, ACCORD, ADVANCE, VADT(1, 3-7)) designed to
look at whether intensive diabetes control in type 2 diabetes reduced microvascular and
macrovascular cardiovascular events, have helped in establishing glycaemic targets which will
contribute to preventing the development or worsening of retinopathy, nephropathy and
neuropathy. What these studies exemplified was that as glycaemic control became stricter, the
risk of hypoglycaemia increased (defined as a blood glucose fall to less than 3.9mmol/l
according to American Diabetes Association guidelines)(1, 6, 7). For many patients, the main
barrier to achieving optimal glycaemic targets to prevent complications are their increased
risks of hypoglycaemia that remains the most feared complication of intensifying diabetes
therapy for both patients and their health care professional.
Although hypoglycaemia has traditionally been considered a complication of the treatment for
type 1 diabetes, it has recently been recognised as a problem in people with type 2 diabetes
particularly those on intensive insulin therapy (8). In type 1 diabetes, patients on average
experience two symptomatic events per week and one severe event, the latter of which is
responsible for 2-4% of deaths. In type 2 diabetes the risk of a severe hypoglycaemic event
is about 7% in the first few years following diagnosis rising to 25% thereafter. There are
multiple concerns on the impact that a hypoglycaemic event may have leading to pathological,
social and economic consequences. In the ACCORD study, the risk of death was significantly
increased in those with one or more episode of severe hypoglycaemia in both the intensive and
standard study treatment arms (1, 9). As plasma glucose falls to below 4.0mmol/L, a series of
defensive response mechanisms occur, at individualised glycaemic thresholds, to reverse
hypoglycaemia including a rise in catecholamine, cortisol and glucagon levels (10). This may
lead to hypokalemia, prolonged QT interval, and cardiac arrhythmias (11). It may also lead to
increased oxidative stress (12); impaired cardiovascular autonomic function for up to 16
hours afterwards (13); increased inflammatory markers (14); platelet activation (15) and
promote vascular damage. These changes might be clinically relevant as hypoglycaemia was
associated with cardiac ischemia (chest pain) when 72-h continuous glucose monitoring along
with simultaneous cardiac Holter monitoring were performed in people with ischemic heart
disease and type 2 diabetes treated with insulin (16). A few studies, in people with type 1
diabetes and healthy controls, suggested an increase in platelet activation with
hypoglycaemia (15, 17) emphasising the increased risk that hypoglycaemia may have on
cardiovascular events.
All of these changes may therefore result in the generation of biomarkers that may be able to
identify the occurrence of a hypoglycaemia event after the blood glucose has reversed to
normal or rebound hyperglycaemic levels have resulted. This will be of particular value in
hypoglycaemic unawareness, nocturnal hypoglycaemia and events of uncertain aetiology where
hypoglycaemia is part of the differential diagnosis.
An ability to determine whether a hypoglycaemic event has occurred through measurement of a
biomarker will be of major impact for the confidence of patients and their healthcare
providers allowing glycaemic control to be optimised and glycaemic targets to be reached
through more stringent diabetes therapeutic treatment regimens.
The ability to identify nocturnal hypoglycaemia will be of particular value in all patients
and will circumvent the need for continuous glucose monitoring or enforced waking at 3am to
do blood glucose measurements that we currently have to rely on. Identification of biomarkers
for hypoglycaemia will be of great value in the elderly population where it is often
difficult to determine causes of, for example, feeling non specifically unwell, poor
concentration, falls or faints, particularly as there are often multiple morbidities that are
being treated at the same time (18).
From an economic perspective it is recognised that hypoglycaemia directly accounts for 95% of
endocrine related emergency hospitalisations (19)and it is recognised that severe
hypoglycaemia is associated with a total cost of around £2,152 (20) It can then be seen that
a new method to determine hypoglycaemia through biomarker determination may help prevent
severe hypoglycaemia by earlier recognition and prevent death and morbidity.
One promising biomarker is that of endothelial Microparticles which are heterogeneous
population of vesicles playing a relevant role in the pathogenesis of vascular diseases,
cancer and metabolic diseases such as diabetes mellitus.
They are released by virtually all cell types by shedding during cell growth, proliferation,
activation, apoptosis or senescence processes.(21) Microparticles are consistently present in
blood stream (22) they are the main regulators of cell to cell interactions, by carrying
specific membrane antigens from their host cells, thereby acting as diffusible vectors in the
trancellular exchange of biological information(23).
Microparticles expose membrane proteins of their mother cell for example CD31 is for
endothelial cells and a proportion of platelets.(24) CD105,CD106, CD142, CD54, CD62E all
Endothelial cells in nature.(25-28) An increased level of circulating Microparticles has been
suggested to be one of the procoagulant determinants in patients with type 2 diabetes
mellitus (29)Circulating levels of CD31+ (PECAM-1), CD105+, CD106+ and 62E+
endothelial-derived MPs as well as increased concentrations of fibrinogen+, tissue factor,
P-selectin+ platelet-derived MPs have been shown to be significantly increased in T2DM
patients as compared with non-diabetic controls (25, 26)Indeed, platelets of patients with
T2DM are characterised by an hyperreactive phenotype with enhanced adhesion, aggregation, and
activation(30), that may contribute to the pathogenesis of atherothrombotic
complications(31-33). Therefore, high levels of specific endothelial and platelets
Microparticles circulate in the blood of patients with atherosclerotic diseases, and can be
used as biomarkers of vascular injury and potential predictors of cardiovascular outcome,
especially in diabetic patients(34-37).
Aims and Objectives
Objectives :
Identification and comparison of Microparticles (CD105, CD106, CD31, CD54, CD62E, CD142)
following a hypoglycemic event in patients with type 2 diabetes and in subjects without type
2 diabetes.
Study Design Prospective parallel study performed in the Diabetes research centre, Hull Royal
Infirmary involving patients with type 2 diabetes and a control group without diabetes
;
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