Controlled Blood Sugar Variation for Stress Response

(Hypo fMRI Trial)

Not currently recruiting at 1 trial location

Overseen By Roy Freeman, MD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Brigham and Women's Hospital

Must not be taking: Corticosteroids, Oral contraceptives

Disqualifiers: Pregnancy, Alcohol abuse, Tobacco, others

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how changes in blood sugar levels affect the nervous system, particularly in response to stress. Participants will undergo various procedures, such as the Hypoglycemic Hyperinsulinemic Clamp and the Normoglycemic Hyperinsulinemic Clamp, which control blood sugar levels. Researchers will then measure the nervous system's responses. This study could provide insights into how non-psychological stress impacts brain function and the autonomic nervous system, which manages automatic body functions like heart rate and breathing. Ideal participants are healthy individuals who are not using certain medications and do not have conditions affecting heart or nervous system functions. As an unphased trial, this study offers participants the chance to contribute to foundational research that could lead to new insights into managing stress-related health issues.

Will I have to stop taking my current medications?

The trial requires that participants do not use medications other than thyroid hormone or hormonal birth control. If you are taking other medications, you may need to stop them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the hypoglycemic hyperinsulinemic clamp is commonly used to study how the body handles stress. This technique involves lowering blood sugar levels while administering insulin to observe the body's reaction to low blood sugar.

Studies have found that this method helps researchers understand the body's stress responses without causing long-term harm. However, short-term side effects can include dizziness, sweating, and hunger due to the temporary drop in blood sugar. These effects usually subside once blood sugar levels return to normal.

Overall, research suggests that the hypoglycemic hyperinsulinemic clamp is generally safe when conducted in a controlled clinical setting. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how controlled blood sugar variations affect the body's stress response. Unlike standard treatments that mainly focus on maintaining blood sugar levels for diabetes management, this study investigates how different blood sugar levels might influence the autonomic nervous system and brain activity. By using techniques like the hypoglycemic and normoglycemic hyperinsulinemic clamps combined with advanced imaging and testing, this research could reveal new insights into stress responses, potentially leading to innovative approaches for managing stress-related conditions.

What evidence suggests that this trial's treatments could be effective for stress response?

Research has shown that low blood sugar, or hypoglycemia, affects the part of the nervous system that automatically controls heart rate, blood pressure, and breathing. In this trial, participants in the hypoglycemia arm will undergo a hypoglycemic hyperinsulinemic clamp procedure to study these effects. Studies have found that sudden drops in blood sugar can increase inflammation and affect heart function by altering heart rhythm and the body's ability to adjust heart rate when blood pressure changes. One study discovered that during low blood sugar, the stress hormone noradrenaline rises more quickly, especially in people with type 2 diabetes. Participants in the normoglycemia arm will undergo a normoglycemic hyperinsulinemic clamp procedure for comparison. These findings suggest that maintaining stable blood sugar levels could influence how the body handles stress. ^{1 6 7 8 9}

Who Is on the Research Team?

Roy Freeman, MD

Principal Investigator

Beth Israel Deaconess Medical Center

Gail K Adler, MD, PhD

Principal Investigator

Brigham and Women's Hospital

David Borsook, MD, PhD

Principal Investigator

Boston Children's Hospital

Are You a Good Fit for This Trial?

This trial is for healthy men and women aged 18-45 with a BMI of 18-35. Participants must not have kidney issues, diabetes, severe depression or anxiety, metal implants, be pregnant or lactating, use tobacco or drugs, have abnormal heart readings or take certain medications.

Inclusion Criteria

You have a body mass index (BMI) between 18 and 35.

People who are in good health

Exclusion Criteria

My kidney function is reduced.

This criterion is too vague to provide a simplified summary. Can you please provide more specific information about the medical condition that needs to be summarized?

I only use thyroid hormone or hormonal birth control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo Autonomic Nervous System (ANS) Testing and a functional MRI (fMRI) scan

1 day

1 visit (in-person)

Intervention

Participants undergo a 120-minute hyperinsulinemic clamp procedure followed by ANS Testing and an fMRI scan

1 day

1 visit (in-person)

Follow-up

Participants undergo repeat ANS Testing and an fMRI scan to assess recovery of brain networks and physiological outcomes

4 days

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Hypoglycemic Hyperinsulinemic Clamp
• Normoglycemic Hyperinsulinemic Clamp

Trial Overview

The study tests how low blood sugar stress affects the nervous system by using two procedures: Normoglycemic Hyperinsulinemic Clamp to maintain normal blood sugar levels and Hypoglycemic Hyperinsulinemic Clamp to lower them.

How Is the Trial Designed?

Group I: Hypoglycemia Active Control 1 Intervention

Participants undergo Autonomic Nervous System (ANS) Testing (measurement of Baroreflex Sensitivity using the Modified Oxford test) followed by a functional MRI (fMRI) scan. The next day, participants undergo one 120-minute hypoglycemic hyperinsulinemic clamp procedure (50mg/dL) in the morning followed by ANS Testing and an fMRI scan. Four days later, participants undergo repeat ANS Testing and an fMRI scan.

Group II: Normoglycemia Placebo Group 1 Intervention

Participants undergo Autonomic Nervous System (ANS) Testing (measurement of Baroreflex Sensitivity using the Modified Oxford test) followed by a functional MRI (fMRI) scan. The next day, participants undergo one 120-minute normoglycemic hyperinsulinemic clamp procedure (90mg/dL) in the morning followed by ANS Testing and an fMRI scan. Four days later, participants undergo repeat ANS Testing and an fMRI scan.

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

Mclean Hospital

Collaborator

Trials

221

Recruited

22,500+

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

Published Research Related to This Trial

The Biostator GCIIS effectively maintained stable blood glucose levels at hypoglycemic, euglycemic, and hyperglycemic states in normal subjects during a 2-hour insulin infusion study, demonstrating its utility in glucose clamp studies.

Despite some technical challenges, such as interruptions in blood flow and occasional discrepancies in glucose measurements, the system achieved low coefficients of variation in blood glucose levels, indicating reliable performance for glucose regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose clamping using the Biostator GCIIS. Verdonk, CA., Rizza, RA., Westland, RE., et al.[2015]

A new control system was successfully developed to maintain steady blood glucose levels in hyperglycemic dogs, validating a mathematical model of how dogs regulate glucose.

This glucose clamp system can be used clinically to measure glucose turnover and in research to study how varying insulin levels affect glucose levels, without needing radioisotopes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development of a glucose clamp. Norwich, KH., Fluker, G., Anthony, J., et al.[2019]

The hyperinsulinemic normoglycemic clamp technique effectively maintained normal blood glucose levels during elective cardiac surgery in both nondiabetic and diabetic patients, achieving significantly better glucose control compared to conventional insulin infusion methods.

In the clamp group, blood glucose levels remained within the target range (4.0-6.0 mmol/L) throughout the surgery, while control group patients experienced hyperglycemia, highlighting the technique's efficacy in preventing perioperative hyperglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance of normoglycemia during cardiac surgery. Carvalho, G., Moore, A., Qizilbash, B., et al.[2022]

The improved algorithm implemented in the ClampArt device significantly reduced blood glucose (BG) and glucose infusion rate (GIR) oscillations, as demonstrated through in silico, in vitro, and in vivo experiments.

In a clinical study, the coefficient of variation for BG decreased from 6.0% to 4.2% and for GIR from 60.7% to 43.5%, indicating enhanced stability in glucose clamp quality without major changes to other parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Algorithm for Automated Glucose Clamps. Kuhlenkötter, M., Heise, T., Benesch, C.[2017]

In a study involving 10 healthy subjects, prior exposure to hypoglycemia was found to reduce basal levels of ACTH and cortisol, but it enhanced the cortisol response to subsequent ACTH infusion, indicating that adrenal function is not impaired by previous hypoglycemic episodes.

The findings suggest that the adrenal glands may be primed by endogenous ACTH during hypoglycemia, and therefore, adrenal function testing using ACTH is reliable even after hypoglycemic events, which is important for understanding hormonal responses in patients with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent hypoglycemia does not impair the cortisol response to adrenocorticotropin infusion in healthy humans. Welt, CK., Kinsley, BT., Simonson, DC.[2019]

In a study involving eight patients with insulin-dependent diabetes, hypoglycemia led to prolonged insulin resistance lasting 6.5 to 7.5 hours, as evidenced by significantly lower glucose infusion rates after hypoglycemia compared to a control group.

The insulin resistance observed post-hypoglycemia was primarily due to a decreased effect of insulin on glucose utilization, while its effect on glucose production remained unchanged.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the late posthypoglycemic insulin resistance in insulin-dependent diabetes mellitus. Fowelin, J., Attvall, S., von Schenck, H., et al.[2022]

The study developed 17 virtual healthy subjects to simulate glucose clamp experiments, which can help train personnel in adjusting glucose infusion rates without needing real patients.

The virtual subjects accurately predicted plasma glucose and insulin levels during hyperglycemic clamp conditions, showing their potential for training and testing automated glucose clamp algorithms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Computer Simulation Model to Train Medical Personnel on Glucose Clamp Procedures. Maghoul, P., Boulet, B., Tardif, A., et al.[2018]

The study involving 110 patients (70 non-diabetic and 40 diabetic) demonstrated that using a hyperinsulinemic-normoglycemic clamp technique effectively maintained blood glucose levels within the target range during and after cardiac surgery, achieving normoglycemia in 92.8% of non-diabetic and 87.4% of diabetic patients intraoperatively.

The incidence of severe hypoglycemia was very low, at only 2.7% overall, with non-diabetic patients experiencing just 0.2% during surgery, indicating that this method is both effective and safe for managing glucose levels in surgical patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative tight glucose control with hyperinsulinemic-normoglycemic clamp technique in cardiac surgery. Sato, H., Carvalho, G., Sato, T., et al.[2010]

A systematic review of 383 studies using the hyperinsulinaemic-hypoglycaemic clamp technique revealed significant variability in methodology, including insulin dosing (with a 49-fold difference), number of hypoglycaemic steps, and duration of the clamps, which could affect study outcomes.

Despite being the gold standard for studying hypoglycaemia, the lack of uniform standards in conducting these experiments means that results from different studies may not be directly comparable, highlighting the need for standardized protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperinsulinaemic-hypoglycaemic glucose clamps in human research: a systematic review of the literature. Fabricius, TW., Verhulst, CEM., Kristensen, PL., et al.[2023]

In a study involving nine patients with insulin-dependent diabetes, higher insulin infusion rates during hypoglycemia led to reduced awareness and symptoms of low blood sugar, indicating that insulin may dampen the body's natural response to hypoglycemia.

Cognitive function was significantly impaired at lower blood glucose levels, particularly at 2.8 mM and 2 mM, highlighting the risks of cognitive decline during severe hypoglycemic episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Importance of insulin in subjective, cognitive, and hormonal responses to hypoglycemia in patients with IDDM. Kerr, D., Reza, M., Smith, N., et al.[2022]

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