Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes

Early Phase 1

Completed

• Conditions: Hypoglycemia
• Interventions: Drug: Insulin; Drug: Glucose; Drug: Potassium phosphate

• Registration Number: NCT02866435
• Lead Sponsor: University of Minnesota

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.

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.

Study Timeline

• Study First Submitted: 2016-08-05
• Study First Submitted QC: 2016-08-10
• Study First Posted: 2016-08-15
• Study Start: 2016-11
• Primary Completion: 2019-09-30
• Study Completion: 2019-12-30
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-29
• Last Update Posted: 2021-02-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 27

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Euglycemia pre-conditioning	Insulin	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.
Hypoglycemia pre-conditioning	Insulin	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.
Hypoglycemia pre-conditioning	Glucose	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.
Euglycemia pre-conditioning	Glucose	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.
Euglycemia pre-conditioning	Potassium phosphate	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.
Hypoglycemia pre-conditioning	Potassium phosphate	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.

Primary Outcome Measures

Name	Time	Method
Change from baseline (i.e., normal glucose levels) functional connectivity, measured as a dimensionless correlation coefficient of MRI signals among brain areas, at hypoglycemia	Baseline and immediately as hypoglycemia starts	Functional connectivity will be measured with MRI at 3 Tesla
Change from baseline (i.e., normal glucose levels) cerebral blood flow, measured in ml/min/100g, at hypoglycemia	Baseline and immediately as hypoglycemia starts	Cerebral blood flow will be measured with MRI at 3 Tesla

Trial Locations

Locations (1)

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States