A Study to Identify Biomarkers of Hypoglycaemia in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus With Hypoglycemia
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemia
Study type: Interventional

Summary: 
      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.
    

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

      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
    

Intervention name(s): Humulin S
Intervention type(s): Drug
Intervention description(s): Humulin S used to induce hypoglycaemia
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other