The Effect of the GLP-1 Analogue Exenatide on Type 2 Diabetes in CNS and Heart During Hyperglycemia Assessed by PET
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2; Hyperglycemia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      30 type 2 diabetic patients will be PET-scanned twice ( half of the patients heart-PET, half
      of the patients CNS-PET) in random order with infusions of placebo or GLP-1-analogue during
      hyperglycemic clamp to uncover the metabolic effects of GLP-1-analogues in perspectives of
      intervention of macrovascular late diabetic pathology such as stroke and AMI. Earlier studies
      have revealed tendencies towards steady glucose metabolism in the CNS despite fluctuations in
      blood sugar when infusing native GLP-1.
    

Detailed description: 
      Background Type 2 diabetes (T2D) is epidemically increasing throughout the world. T2D is
      frequently associated with multiple complications, where particularly the macrovascular
      complications in the form of myocardial infarction with its possible complication of death or
      heart failure, cerebral infarction and limb amputation are responsible for a vast increase in
      morbidity and mortality in this group of patients. Apart from the individual burden on the
      patient, T2D puts massive pressure on national health economies.

      It is well established that blood glucose lowering drugs, antihypertensive as well as lipid
      lowering drugs all play a pivotal role in the treatment of the type 2 diabetic subjects.
      Regarding glycemia, there are frequently side effects with the 'classic' drugs such as
      hypoglycemia, weight gain, heart failure, and so forth. Another important caveat is that
      employing the anti-hyperglycemic drugs either as monotherapy or in combination does not lower
      blood glucose to the targets as defined by the ADA. In other words novel anti-diabetic drugs
      are urgently required. However, the incretin concept has recently been inaugurated in the
      pharmacological scenario.

      Glucagon-like peptide-1-receptors (GLP-1R) are abundant on alpha- and beta-cells in the
      pancreas, but are also present in the heart and CNS, especially in hypothalamic and
      hippocampal regions. A wide range of extrapancreatic effects of GLP-1 have been observed such
      as slowed gastric emptying and satiety-stimulating effects through hypothalamic mechanisms.
      Recent studies have showed interesting results regarding protection of the heart during
      ischemia, and protection of the brain in the acute phases of stroke have been proposed.
      Over-all GLP-1 seems to display effects in heart, brain, vessels, kidneys, muscles and
      liver(7).

      To our knowledge, our group has in a very recent study been the first, by sophisticated
      metabolic techniques, together with Positron Emission Tomography (PET), to demonstrate that
      GLP-1 per se reduces cerebral glucose transport in total cerebral grey matter as well as
      individual grey matter regions, thereby suggesting that GLP-1 may protect the brain by
      limiting intracerebral glucose fluctuation when plasma glucose is increased. In other words,
      GLP-1 regulates blood brain barrier (BBB) glucose transfer at normal glycemia and presumably
      also during hyperglycemia(19).

      GLP-1 is believed to have cardioprotective actions. A recent study has shown improved
      preservation of cardiac function in patients with acute myocardial infarctions when
      GLP-1-infusion is supplemented to conventional treatment compared to conventional treatment
      alone. Ejection fraction was improved by 10 % in both diabetic and non-diabetic patients(15)
      in the GLP-1 group. It has been shown in animal models by the same research-team that the
      extend of myocardial injury is smaller during coronary occlusion when treated with GLP-1(16).

      Glucagon-like-peptide-1 (GLP-1) T2D is characterized by several hormonal and metabolic
      abnormalities such as dysfunction of insulin secretion, glucagon excess, impaired
      Glucagon-like-peptide-1 (GLP-1) secretion, and insulin resistance.

      GLP-1 is an incretin hormone with numerous documented effects on the glycemic response. It is
      one of the most potent insulinotropic agents known and is secreted from L-cells in the gut
      mucosa in response to food ingestion. Effects on the islet-cells are (I) Amplification of
      glucose dependent stimulation of insulin secretion (II) Inhibition of glucagon secretion. In
      animal and cellular studies GLP-1 stimulates β-cell neogenesis, growth and differentiation,
      and in vitro inhibition of β-cell apoptosis is observed. Thus GLP-1 is also a β-cell growth
      factor. For now, treatment with GLP-1 has seldom caused hypoglycaemia in type 2 diabetic
      patients.

      Hypotheses Based on the findings in the above-mentioned study, we hypothesize that the
      GLP-1-analogue exenatide during hyperglycemia will protect the brain in type 2 diabetic
      patients from hyperglycemia by reducing blood-brain-barrier glucose transport and brain
      glucose metabolism. We also hypothesize that exenatide in a similar fashion through reduction
      of cardiac glucose uptake and metabolism will stabilize cardiac glucose fluctuation, which
      theoretically should protect cardiac tissue from the toxicity of hyperglycemia.

      Aim With well established methodology, to compare the effect of the GLP-1-analogue exenatide
      and placebo, respectively, on the consumption of glucose in the CNS and heart assessed by
      uptake of 18-fluro-deoxy-glucose (FDG) monitored by PET-scan of type-2 diabetic patients
      during hyperglycemic pituitary-pancreatic clamp in the perspective of future prevention of
      macrovascular complications of diabetes and possibly other diseases such as Alzheimer's
      disease and other neurodegenerative and cardiac diseases.

      The project comprises two separate substudies focusing on the effects of exenatide in the CNS
      and heart, respectively. Accordingly, each substudy will have its own primary endpoint: 1)
      glucose-uptake in the brain and 2) glucose-uptake in the heart.

      Design Randomized, double-blinded crossover design. Every participant will be CNS-PET-scanned
      twice or heart-PET-scanned twice in random order with GLP-1 and placebo-infusions interrupted
      by a 4 week wash-out period between study days.

      The study will be performed similarly to our previously conducted FDG/PET-study(21) and
      pancreatic clamp as done by Nielsen et al.(22)

      Methods

      GLP-1 is a natural peptide hormone that is degraded by the enzyme DPPIV after few minutes in
      the circulation. In this study we use the GLP-1 analogue exenatide that is a slower
      degradable peptide due to resistance towards DPPIV. The remaining hormones utilized in this
      study, are used as tools in the investigational design and will not be used as medical
      compounds themselves.

      Hormone doses

        -  Somatostatin (Ferring) 300 μg/hour(22)

        -  Insulin Actrapid (NOVO Nordisk) 1,0 mU/kg/minute (0-60 min.)(22)

        -  Insulin Actrapid (NOVO Nordisk) 0,3 mU/kg/minute (60min - )(22)

        -  Glucagon (NOVO Nordisk, Glucagen) 0.6 ng/kg/minute(22)

        -  Growth hormone (NOVO Nordisk) 2 ng/kg/minute(22)

        -  GLP-1-analogue, Exenatide (Eli Lilly/Amylin Pharmaceuticals) 0.066 pmol*kg-1*min-1 (23)

      Pancreatic and hyperglycemic clamp Somatostatin is administered to inhibit endogenous
      production of GLP-1, insulin, glucagon, and growth hormone. Insulin, glucagon, and growth
      hormone are administered to achieve basal hormone levels. 20% glucose is infused to achieve
      hyperglycemic clamp with plasma glucose at 9 mM which is by experience the highest level of
      hyperglycemia possible while still avoiding breakthrough of natural counterregulatory
      hormones.

      Ethics Apart from its documented effect on glycemic control, GLP-1 has potential protective
      impact in the heart and brain. Patients with type-2 diabetes carry a significantly increased
      risk of ischemic heart disease and stroke that has not been substantially reduced by current
      treatments. Preliminary data suggest that clinical use of GLP-1 or GLP-1 analogues can lead
      to improved prophylaxis against late diabetic complications, which can be achieved in this
      patient group in addition to improved glycemic control.

      We believe the current study will provide deeper insight into the extra-pancreatic effects of
      GLP-1, with the particular aim to develop efficient prophylaxis against late diabetic
      cerebrovascular and cardiovascular complications, which outweighs the known adverse effects
      of the elements of the study.

      The study will be conducted in accordance with the principles described in the Helsinki
      Declaration II and will not be initiated before acceptance is granted from the local Ethics
      Committee.

      Written consent from participants is required before studies can be commenced, and all
      participants are covered by insurance according to "Bekendtgørelse af lov om
      patientforsikring" and "Lov om erstatning for lægemiddelskader".

      Informed consent All participants will receive written and oral information about the purpose
      and the expected scientific value of the project as well as detailed description of all
      procedures and risks involved. Specifically, the participant will be told that participation
      is completely voluntary, and withdrawal is accepted at any stage during the investigation.

      The project coordinator, Dr. Chalotte Stecher, will provide oral information and hand out
      written material including the general information brochure "Before you decide….." ("Før du
      beslutter dig…"). The participant is allowed an accompanying person for the duration of the
      meeting.

      Written consent is collected after a minimum of 24 hours for further consideration. Both the
      responsible physician and the participant sign the consent, and the latter will be provided a
      copy.

      Data management Source data (original documentation of clinical findings, printouts, lab
      results, and other details necessary to completely reconstruct each study) are stored in case
      report forms and a common database. All personal information is locked away and inaccessible
      to all but the investigators. Screening ID, randomization ID, and initials in the database
      identify participants. The initials will be erased from the database after completion of the
      study to ensure anonymity. A separate chart containing screening ID, randomization ID,
      initials, and personal data will be stored at another location to allow re-identification of
      source data. Social security numbers (Danish: CPR-numbers) are present on electronical
      charts, which are kept in the individual electronical patient charts on the hospital server.
      This information will only be accessible to personnel in the study-group and not to doctors
      treating the patients in any future hospitalization. Data will automatically be erased from
      the server after 15 years. The study will be disclosed to the local Data Monitoring Board.

      Financial aspects Each participant will receive dkr 4.000 as compensation. Furthermore,
      transport expenses will be reimbursed according to official rates.

      The applicant will provide the needed work in accordance with present rules and contracts
      concerning research fellows at Institute of Pharmacology, University of Aarhus and the
      Research Unit, Department of Endocrinology (M), Aarhus University Hospital.

      Eli Lilly/Amylin Pharmaceuticals and relevant public foundations will be applied for
      financial support for the present study.
    

Intervention name(s): Byetta, Exenatide
Intervention type(s): Drug
Intervention description(s): Drug: Exenatide or placebo Dosage form: Infusion Dosage: Exenatide (Eli Lilly/Amylin Pharmaceuticals) 0.066 pmol*kg-1*min-1 Duration: 5 hours Frequency: Drug given once, placebo given once
Other intervention name(s): placebo
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science