A Study to Identify Biomarkers of Hypoglycaemia in Patients With Type 2 Diabetes
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|ClinicalTrials.gov Identifier: NCT03102801|
Recruitment Status : Recruiting
First Posted : April 6, 2017
Last Update Posted : April 6, 2017
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.
|Condition or disease||Intervention/treatment||Phase|
|Type 2 Diabetes Mellitus With Hypoglycemia||Drug: Humulin S||Not Applicable|
Hide Detailed Description
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
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
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Study to Identify Biomarkers of Hypoglycaemia in Patients With Type 2 Diabetes|
|Study Start Date :||December 2016|
|Estimated Primary Completion Date :||July 2017|
|Estimated Study Completion Date :||July 2017|
Active Comparator: Type 2 diabetes arm
Both arms will be subjected to Hypoglycaemia and compare results
Drug: Humulin S
Active Comparator: Non diabetics arm
Both arms will be subjected to Hypoglycaemia and compare results
Drug: Humulin S
- Measurement of endothelial microparticles (composite number of CD105, CD106, CD142, CD54, CD62 & CD31) following hypoglycemic event [ Time Frame: 6 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03102801
|Contact: Thozhukat Sathyapalan, MD FRCPfirstname.lastname@example.org|
|Contact: Ahmed Al-Qaissi, MRCPemail@example.com|
|Hull and east Yorkshire Hospitals NHS Trust||Recruiting|
|Hull, United Kingdom, HU32RW|
|Contact: Thozhukat Sathyapalan, MD FRCP 01482675312 firstname.lastname@example.org|
|Contact: Ahmed Al-Qaissi, MRCP 01482675314 email@example.com|