Controlled Blood Sugar Variation for Stress Response

(Hypo fMRI Trial)

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

44 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to examine the effect of a moderately low blood sugar stress on the nervous system. The investigators hope that information obtained from completing this study will help to reveal information about how a non-psychological stress impacts the parts of the brain that react to stress and the autonomic nervous system. The autonomic nervous system is the part of the nervous system that provides the body with involuntary or automatic control of heart rate, blood pressure, and breathing.

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.

What data supports the effectiveness of the treatment Controlled Blood Sugar Variation for Stress Response?

The hyperinsulinemic normoglycemic clamp technique has been shown to effectively maintain normal blood sugar levels during cardiac surgery, preventing high blood sugar in both diabetic and non-diabetic patients. This suggests that the treatment can help control blood sugar levels under stress, which may be beneficial for managing stress responses. ^{1 2 3 4 5}

Is the glucose clamp technique generally safe for humans?

The glucose clamp technique, used to study insulin and blood sugar levels, has been widely used in research and is generally considered safe when conducted by trained professionals. However, it can cause low blood sugar (hypoglycemia), which may lead to symptoms like hunger, sweating, and confusion, especially if not carefully monitored. ^{1 2 6 7 8}

How is the Hypoglycemic Hyperinsulinemic Clamp treatment different from other treatments for blood sugar control?

The Hypoglycemic Hyperinsulinemic Clamp treatment is unique because it precisely controls blood sugar levels by infusing insulin and glucose at specific rates to maintain a steady state, allowing researchers to study the body's response to controlled blood sugar variations. This method is different from standard treatments that typically involve fixed doses of insulin or oral medications without such precise control. ^{1 4 5 9 10}

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

Eligibility Criteria

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

I am between 18 and 45 years old.

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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]

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Hyperinsulinaemic-hypoglycaemic glucose clamps in human research: a systematic review of the literature. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Characterization of the late posthypoglycemic insulin resistance in insulin-dependent diabetes mellitus. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Recurrent hypoglycemia does not impair the cortisol response to adrenocorticotropin infusion in healthy humans. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Glucose clamping using the Biostator GCIIS. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Maintenance of normoglycemia during cardiac surgery. [2022]

6. Canada pubmed.ncbi.nlm.nih.gov

Computer Simulation Model to Train Medical Personnel on Glucose Clamp Procedures. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Perioperative tight glucose control with hyperinsulinemic-normoglycemic clamp technique in cardiac surgery. [2010]

8. United States pubmed.ncbi.nlm.nih.gov

Importance of insulin in subjective, cognitive, and hormonal responses to hypoglycemia in patients with IDDM. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Improved Algorithm for Automated Glucose Clamps. [2017]

10. United States pubmed.ncbi.nlm.nih.gov

The development of a glucose clamp. [2019]