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Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT02866435
Recruitment Status : Recruiting
First Posted : August 15, 2016
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute

Brief Summary:
The purpose of this study is to investigate how the brain responds to low blood glucose in non-diabetic individuals. The ultimate goal is to understand the brain substrates of hypoglycemia unawareness, a condition that can occur in patients with type1 diabetes undergoing insulin treatment.In the present study, the investigators focus on differences between two groups of non-diabetic subjects: one group who experienced two episodes of hypoglycemia the day prior to the study (and supposedly developed some level of unawareness to hypoglycemia), and one group who did not. In this study, a 3 tesla MRI scanner is used to acquire brain images. The imaging system is identical to the ones used in hospitals.

Condition or disease Intervention/treatment Phase
Hypoglycemia Drug: Insulin Drug: Glucose Drug: Potassium phosphate Early Phase 1

Detailed Description:
Hypoglycemia, also called low blood glucose or low blood sugar, occurs when blood glucose drops below normal levels. When blood glucose starts to drop, the body reacts to this drop, trying to restore the blood glucose level. Symptoms of hypoglycemia are usually easily recognized. Hypoglycemia can be treated quickly and easily by eating or drinking a small amount of glucose-rich food. However some people with long history of diabetes can have an impaired response to hypoglycemia and therefore don't recognize the symptoms of hypoglycemia, condition called hypoglycemia unawareness. If not treated hypoglycemia can get worse and cause confusion, clumsiness, fainting etc. Currently, it is not fully understood which brain areas are involved in sensing the drop of glucose levels. Absence of such knowledge is a critical barrier to the design and monitoring of effective intervention strategies to avoid and/or reverse hypoglycemia unawareness. The purpose of this study is to investigate how the brain responds to low blood glucose in non-diabetic individuals. Specific focus is given to differences between two groups of non-diabetic subjects: one group who experienced two episodes of hypoglycemia the day prior to the study (and therefore supposedly developed some level of unawareness to hypoglycemia), and one group who did not.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes
Actual Study Start Date : November 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Euglycemia pre-conditioning
Participants will undergo two euglycemia (normal blood sugar) clamps (8-10 am and 1-3 pm) on day 1, where the target glucose during the clamp will be 95 mg/dl. For each clamp, participants will be given intravenous insulin for two hours and blood glucose will be maintained at target by the infusion of 20% dextrose, the rate of which will be adjusted based on measured blood glucose values collected every 5 minutes. Potassium phosphate will also be infused during each clamp. On next day (day 2), participants will undergo MRI session during experimental hypoglycemia, i.e., while their blood sugar is clamped from normal value to low value.
Drug: Insulin
In each clamp, a small intravenous catheter is placed in participant's arm for infusion of insulin together with potassium phosphate and glucose. Insulin is a hormone that body makes naturally and it causes blood sugar to decrease. Insulin (and glucose) will be infused in calculated doses to maintain blood sugar level in the target range of 95 mg/dl or 50 mg/dl depending on the clamp.
Other Name: Humulin

Drug: Glucose
Glucose is administered together with insulin and potassium phosphate during each clamp via the intravenous catheter. Glucose is a sugar and it is used to carefully regulate blood sugar level.
Other Name: Dextrose

Drug: Potassium phosphate
Potassium phosphate is administered together with glucose and insulin during each clamp via the intravenous catheter. Potassium is a salt-like substance that is present in the blood.
Other Name: K Phos

Experimental: Hypoglycemia pre-conditioning
Participants will undergo two hypoglycemia (low blood sugar) clamps (8-10 am and 1-3 pm) on day 1, where target glucose during the clamp will be 50 mg/dl. For each clamp, participants will be given intravenous insulin for two hours and blood glucose will be maintained at target by the infusion of 20% dextrose, the rate of which will be adjusted based on measured blood glucose values collected every 5 minutes. Potassium phosphate will also be infused during each clamp. On next day (day 2), participants will undergo MRI session during experimental hypoglycemia, i.e., while their blood sugar is clamped from normal value to low value.
Drug: Insulin
In each clamp, a small intravenous catheter is placed in participant's arm for infusion of insulin together with potassium phosphate and glucose. Insulin is a hormone that body makes naturally and it causes blood sugar to decrease. Insulin (and glucose) will be infused in calculated doses to maintain blood sugar level in the target range of 95 mg/dl or 50 mg/dl depending on the clamp.
Other Name: Humulin

Drug: Glucose
Glucose is administered together with insulin and potassium phosphate during each clamp via the intravenous catheter. Glucose is a sugar and it is used to carefully regulate blood sugar level.
Other Name: Dextrose

Drug: Potassium phosphate
Potassium phosphate is administered together with glucose and insulin during each clamp via the intravenous catheter. Potassium is a salt-like substance that is present in the blood.
Other Name: K Phos




Primary Outcome Measures :
  1. Change from baseline (i.e., normal glucose levels) functional connectivity, measured as a dimensionless correlation coefficient of MRI signals among brain areas, at hypoglycemia [ Time Frame: Baseline and immediately as hypoglycemia starts ]
    Functional connectivity will be measured with MRI at 3 Tesla

  2. Change from baseline (i.e., normal glucose levels) cerebral blood flow, measured in ml/min/100g, at hypoglycemia [ Time Frame: Baseline and immediately as hypoglycemia starts ]
    Cerebral blood flow will be measured with MRI at 3 Tesla



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Participants will be included in the study, if they

  • are non-diabetic
  • are evaluated as not contraindicated (based on exclusion criteria)
  • are age (within 5 years), gender, and body mass index (within 4 kg/m2) matched to patients with type 1 diabetes who have participated to a similar study which involved only the second part (day 2) of the current protocol.

Exclusion Criteria:

Participants will be excluded from the study, if they

  • have any type of bio‐implant activated by mechanical, electronic, or magnetic means (e.g. cochlear implants, pacemakers, neurostimulators, bio stimulators, electronic infusion pumps)
  • have any type of ferromagnetic bio‐implant that could potentially be displaced or damaged, such as aneurysm clips, metallic skull plates, etc
  • have any retained metal in their body, either from a medical procedure or an injury
  • have history of stroke, seizures, neurosurgical procedures, or arrhythmias
  • are pregnant
  • are currently using medication that can alter glucose metabolism or brain perfusion
  • weight more than 300lbs (limit for MRI scanner)
  • have concomitant medical problems that may prevent them from successfully completing the protocol
  • lack capacity to consent

Information from the National Library of Medicine

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): NCT02866435


Contacts
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Contact: Anjali F Kumar, PA-C 612-624-0470 kumar045@umn.edu

Locations
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United States, Minnesota
University of Minnesota Not yet recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Anjali F Kumar, PA-C    612-624-0470    kumar045@umn.edu   
Sub-Investigator: Elizabeth R Seaquist, MD         
Sub-Investigator: Amir A Moheet, MD         
Sub-Investigator: Essa Yacoub, PhD         
Sub-Investigator: Lynn E Eberly, PhD         
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Investigators
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Principal Investigator: Silvia Mangia, PhD University of Minnesota - Clinical and Translational Science Institute

Additional Information:
Publications:
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Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT02866435     History of Changes
Other Study ID Numbers: 25007
First Posted: August 15, 2016    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
MRI

Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Hypoglycemia
Unconsciousness
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Insulin
Insulin, Globin Zinc
Potassium phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Cariostatic Agents
Protective Agents