HypoglycemiaEarly Phase 1NCT02866435
Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes
A Early Phase 1 study testing Insulin, Glucose and Potassium phosphate in people with Hypoglycemia, run by University of Minnesota at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Hypoglycemia
- What is being tested?
- Insulin, Glucose and Potassium phosphate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2016to 30 Dec 2019
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Minnesota
Minneapolis, Minnesota, 55455
About this study
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.
Read the 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.
- Conditions
- Hypoglycemia
- Being tested
- Insulin, Glucose, Potassium phosphate
- Keywords
- MRI
- Medical subject headings
- Hypoglycemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InsulinDrug
Also called Humulin
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.
GlucoseDrug
Also called Dextrose
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.
Potassium phosphateDrug
Also called K Phos
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.
| Study group | Role | What they receive |
|---|---|---|
| Euglycemia pre-conditioning | Experimental | 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. Receives: Drug: Insulin; Drug: Glucose; Drug: Potassium phosphate |
| Hypoglycemia pre-conditioning | Experimental | 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. Receives: Drug: Insulin; Drug: Glucose; Drug: Potassium phosphate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline (i.e., normal glucose levels) functional connectivity, measured as a dimensionless correlation coefficient of MRI signals among brain areas, at hypoglycemia
Functional connectivity will be measured with MRI at 3 Tesla
Measured: Baseline and immediately as hypoglycemia starts
Change from baseline (i.e., normal glucose levels) cerebral blood flow, measured in ml/min/100g, at hypoglycemia
Cerebral blood flow will be measured with MRI at 3 Tesla
Measured: Baseline and immediately as hypoglycemia starts
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Aug 2016 (estimated)
- Study startNov 2016
- Primary completion30 Sep 2019
- Study completion30 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for HypoglycemiaStudies of the same condition, open and under way.
- More trials run by University of MinnesotaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Minnesota
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Silvia Mangia, PhD, Principal investigator, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02866435
- Sponsor's protocol ID
- 1608M92941
- Status last verified
- Jan 2021
- First submitted
- 5 Aug 2016
- Last updated
- 1 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Mangia S, Tesfaye N, De Martino F, Kumar AF, Kollasch P, Moheet AA, Eberly LE, Seaquist ER. Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness. J Cereb Blood Flow Metab. 2012 Nov;32(11):2084-90. doi: 10.1038/jcbfm.2012.117. Epub 2012 Aug 15.
PubMed 22892724Bolo NR, Musen G, Simonson DC, Nickerson LD, Flores VL, Siracusa T, Hager B, Lyoo IK, Renshaw PF, Jacobson AM. Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes. J Neurosci. 2015 Aug 5;35(31):11012-23. doi: 10.1523/JNEUROSCI.0319-15.2015.
PubMed 26245963Wiegers EC, Becker KM, Rooijackers HM, von Samson-Himmelstjerna FC, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Cerebral blood flow response to hypoglycemia is altered in patients with type 1 diabetes and impaired awareness of hypoglycemia. J Cereb Blood Flow Metab. 2017 Jun;37(6):1994-2001. doi: 10.1177/0271678X16658914. Epub 2016 Jan 1.
PubMed 27389175Rooijackers HM, Wiegers EC, Tack CJ, van der Graaf M, de Galan BE. Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from functional and metabolic neuroimaging studies. Cell Mol Life Sci. 2016 Feb;73(4):705-22. doi: 10.1007/s00018-015-2079-8. Epub 2015 Oct 31.
PubMed 26521082Filip P, Canna A, Grohn H, Moheet AA, Kumar AF, Li X, Zhang Y, Eberly LE, Seaquist ER, Mangia S. Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia. J Clin Invest. 2026 Feb 19;136(8):e199725. doi: 10.1172/JCI199725. eCollection 2026 Apr 15.
PubMed 41712301
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT02866435
- Acronym / sponsor ID
- 1608M92941
- Conditions
- Hypoglycemia
- Keywords
- MRI
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- University of MinnesotaUniversity, hospital or other
- Study start
- Nov 2016 (actual)
- Primary completion
- 30 Sep 2019 (actual)
- Study completion
- 30 Dec 2019 (actual)
- First posted
- 15 Aug 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Euglycemia pre-conditioning | Experimental | Drug: Insulin, Drug: Glucose, Drug: Potassium phosphateParticipants 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 | Experimental | Drug: Insulin, Drug: Glucose, Drug: Potassium phosphateParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InsulinAlso: HumulinIn 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. | Drug | Euglycemia pre-conditioning, Hypoglycemia pre-conditioning |
| GlucoseAlso: DextroseGlucose 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. | Drug | Euglycemia pre-conditioning, Hypoglycemia pre-conditioning |
| Potassium phosphateAlso: K PhosPotassium 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. | Drug | Euglycemia pre-conditioning, Hypoglycemia pre-conditioning |
Primary outcome
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2021.
- Background: PubMed 22892724Mangia S, Tesfaye N, De Martino F, Kumar AF, Kollasch P, Moheet AA, Eberly LE, Seaquist ER. Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness. J Cereb Blood Flow Metab. 2012 Nov;32(11):2084-90. doi: 10.1038/jcbfm.2012.117. Epub 2012 Aug 15.
- Background: PubMed 26245963Bolo NR, Musen G, Simonson DC, Nickerson LD, Flores VL, Siracusa T, Hager B, Lyoo IK, Renshaw PF, Jacobson AM. Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes. J Neurosci. 2015 Aug 5;35(31):11012-23. doi: 10.1523/JNEUROSCI.0319-15.2015.
- Background: PubMed 27389175Wiegers EC, Becker KM, Rooijackers HM, von Samson-Himmelstjerna FC, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Cerebral blood flow response to hypoglycemia is altered in patients with type 1 diabetes and impaired awareness of hypoglycemia. J Cereb Blood Flow Metab. 2017 Jun;37(6):1994-2001. doi: 10.1177/0271678X16658914. Epub 2016 Jan 1.
- Background: PubMed 26521082Rooijackers HM, Wiegers EC, Tack CJ, van der Graaf M, de Galan BE. Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from functional and metabolic neuroimaging studies. Cell Mol Life Sci. 2016 Feb;73(4):705-22. doi: 10.1007/s00018-015-2079-8. Epub 2015 Oct 31.
- Derived from this study: PubMed 41712301Filip P, Canna A, Grohn H, Moheet AA, Kumar AF, Li X, Zhang Y, Eberly LE, Seaquist ER, Mangia S. Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia. J Clin Invest. 2026 Feb 19;136(8):e199725. doi: 10.1172/JCI199725. eCollection 2026 Apr 15.
- Description Profile of Principal InvestigatorLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Silvia Mangia, PhD principal investigator
University of Minnesota
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Insulin, Glucose and Potassium phosphate in people with Hypoglycemia, run by University of Minnesota at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02866435, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2021.