Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes

NCT02866435 | Completed Early Phase 1 DMC FDA Drug

• 1 other identifier: 1608M92941
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypoglycemia

Keywords

MRI

Outcome Measures

Primary Outcomes (2)

• 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

  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

  Baseline and immediately as hypoglycemia starts

Study Arms (2)

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.

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.

Drug: Insulin; Drug: Glucose; Drug: Potassium phosphate

Interventions

Insulin DRUG

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.

Also known as: Humulin

Euglycemia pre-conditioning; Hypoglycemia pre-conditioning

Glucose DRUG

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.

Also known as: Dextrose

Euglycemia pre-conditioning; Hypoglycemia pre-conditioning

Potassium phosphate DRUG

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.

Also known as: K Phos

Euglycemia pre-conditioning; Hypoglycemia pre-conditioning

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants will be included in the study, if they
• are non-diabetic

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (4)

• 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.

  PMID: 22892724 BACKGROUND

• Bolo 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.

  PMID: 26245963 BACKGROUND

• Wiegers 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.

  PMID: 27389175 BACKGROUND

• Rooijackers 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.

  PMID: 26521082 BACKGROUND

Related Links

• Description Profile of Principal Investigator

MeSH Terms

Conditions

Hypoglycemia

Interventions

Insulin; Insulin, Regular, Human; Glucose; potassium phosphate

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Silvia Mangia, PhD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2016
• First Posted: August 15, 2016
• Study Start: November 1, 2016
• Primary Completion: September 30, 2019
• Study Completion: December 30, 2019
• Last Updated: February 1, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)