Hippocampal Metabolism and Function in Patients With Type 1 Diabetes
Condition: Hypoglycemia; Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia
Study type: Observational

Summary: 
      The hippocampus is an area of brain which plays an essential role in learning and memory
      processing and is thought to be particularly vulnerable to effects of hypoglycemia (low blood
      glucose). The goal of this project is to examine hippocampal neurochemistry and metabolism
      and identify how diabetes and recurrent hypoglycemia alter the hippocampus.
    

Detailed description: 
      In this study we will examine hippocampal neurochemical profile and glucose transport
      kinetics using magnetic resonance spectroscopy (MRS) in patients with type 1 diabetes and
      hypoglycemia unawareness and matched healthy controls. We will also examine hippocampal
      function in these subject groups during euglycemia and hypoglycemia and correlate these
      findings to changes in the neurochemical profile and glucose transport kinetics.

      Study protocol

      MRS experiments On the morning of the MRS experiments, subjects will present to the Center
      for Magnetic Resonance Research (CMRR) at 7 AM in the fasting state to participate in a
      protocol with which our group has significant experience. After arrival, they will be
      prepared for the clamp study by the placement of one intravenous catheter into one vein in
      antecubital fossa for the later infusion of glucose, insulin, and potassium. A second
      intravenous catheter will be placed retrograde into a vein in the distal leg for later blood
      sampling. An intravenous infusion of insulin will then be started and adjusted as necessary
      to bring blood glucose to 95 mg/dl. Blood will be collected every 10 minutes for measurement
      of glucose on a nearby Analox machine to guide adjustments in the insulin infusion rate. The
      experiment will begin when the subject is at 95 mg/dl. At time 0, the intravenous insulin
      infusion will be fixed at 1 mU/kg/min, samples for blood glucose will be collected every 5
      minutes and an intravenous infusion of glucose (20% dextrose) will be administered as
      necessary to maintain blood glucose at 95 mg/dl. At +5 minutes, subjects will be placed into
      the magnet. Blood glucose will be maintained at 95 mg/dl during the next 25 minutes as the
      hippocampal volume-of-interest (VOI) is selected and baseline MRS data are acquired. At + 30
      min, subjects will be given an intravenous bolus injection of glucose over 1-2 minutes using
      the formula of administering 2 mg glucose/kg body weight for each 1 mg/dl increase desired
      that our group have used with success previously. Immediately after the bolus injection, a
      continuous infusion of 20% dextrose will be started and the rate of administration will be
      adjusted to maintain the desired glucose target of 200 mg/dl, 300 mg/dl, or 400 mg/dl. MRS
      data will be collected continuously starting 10 minutes before the bolus injection (baseline)
      until the end of the study ~60 minutes after the bolus, which is sufficient to reach
      steady-state glucose concentrations in the brain and maintain them for at least 20 minutes.
      At the completion of the study, the infusions will be discontinued; the subject will resume
      their usual insulin regimen, and be fed a meal. The subjects with diabetes will be prepared
      for this protocol by instructing them to manage their diabetes in such a way as to minimize
      the amount of subcutaneous insulin present at the time of the study without creating
      hyperglycemia on the day before the study (i.e. pump patients will stop their pump on
      arrival, glargine treated patients will take last glargine dose 24 hours before study start).
      At the conclusion of the study, subjects will be allowed to resume their usual insulin
      regimen.

      Neurocognitive testing On the morning of the Neurocognitive testing, subjects will present to
      the Clinical and Translational Science Institute at 7 AM in the fasting state. Subjects with
      diabetes will have their blood glucose checked to ensure that blood glucose is between 90-200
      mg/dl. If the blood glucose is not in target range, treatment will be given to correct
      glucose or the study will be rescheduled. Subjects will undergo neurocognitive testing with
      the California Verbal Learning Test - Second Edition (CVLT-II) and subtests from the
      Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Story Memory
      (immediate and delayed), Digit Span, and Coding. After completion of neurocognitive testing,
      an intravenous catheter will be placed antegrade in each forearm for subsequent infusions and
      for blood sampling. Insulin will be infused at a rate of 2.0 mU/kg/min along with potassium
      phosphate (4 mEq/hour) and blood glucose will reduced to and then maintained at 55 mg/dl by
      the variable infusion of 20% dextrose. Samples for blood glucose will be collected every 5
      minutes for measurement of glucose. Once the blood glucose target of 55 is achieved subject
      will undergo neurocognitive testing again. At the completion of the neurocognitive testing
      subjects will be fed and euglycemia will be restored.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        University of Minnesota Endocrine Clinic, univeristy of Minnesota community and a registry
        of volunteers maintained by the investigators.
      
Biospecimen description: 
      blood smaple will be drawn measurement of blood glucose, HgbA1C, insulin and hormone levels
    
Keywords: hypoglycemia; hypoglycemia unawareness; type 1 diabetes, hippocampus; glucose transport; cognitive dysfunction