Biomarker Evaluation for Low Blood Sugar

(E-VAL Trial)

Overseen By Bethany Gildersleeve

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Pennington Biomedical Research Center

Must not be taking: Benzodiazepines, Thiazides, Cortisone, others

Disqualifiers: Diabetes, Hypertension, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new method for predicting the risk of low blood sugar (hypoglycemia) in people with diabetes. Researchers are investigating whether brain activity related to glial acetate metabolism (a process involving brain cells) can indicate the likelihood of experiencing low blood sugar while taking insulin. Participants will undergo two procedures a few days apart to measure this activity and their body's response to low blood sugar. Healthy adults without diabetes who meet specific lifestyle and health criteria may be eligible to join. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could enhance diabetes management.

Will I have to stop taking my current medications?

Yes, you will need to stop taking medications that affect glucose metabolism, such as benzodiazepines, thiazide diuretics, cortisone, and prednisone, as well as beta-adrenergic antagonists.

What prior data suggests that this biomarker evaluation is safe?

Research has shown that glial acetate metabolism, the focus of this trial, has been studied in various contexts. One study found that this metabolism increased after participants fasted for 72 hours. This fasting period significantly lowered their blood sugar levels and caused frequent episodes of hypoglycemia.

However, the study reported no serious side effects from measuring glial acetate metabolism itself, suggesting that the assessment method is generally safe. Participants in the trial should not expect major safety concerns from the procedures used to measure this metabolic process. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about evaluating glial acetate metabolism for low blood sugar because it offers a fresh approach compared to traditional treatments like glucose tablets or glucagon injections. Most treatments for low blood sugar work by quickly raising glucose levels, but this method focuses on understanding how the brain's glial cells metabolize acetate, potentially revealing new insights into the body's response to hypoglycemia. By using carbon-13 magnetic resonance spectroscopy, researchers hope to uncover novel pathways and neuroendocrine responses that could lead to more effective and personalized treatment strategies.

What evidence suggests that this biomarker is effective for predicting hypoglycemia?

Research shows that the brain's use of a substance called acetate might help predict low blood sugar in people with diabetes. Studies have found that this process increases when blood sugar levels drop, such as during fasting. In people with type 1 diabetes who don't notice low blood sugar symptoms, this acetate process is even higher. This trial will measure participants' glial acetate metabolism to explore this connection further. If this marker reliably predicts these episodes, it could improve diabetes management by reducing the risk of sudden low blood sugar. ^{1 2 3 6 7}

Who Is on the Research Team?

David McDougal, PhD

Principal Investigator

PBRC

Are You a Good Fit for This Trial?

This trial is for healthy men and women aged 18-40 with a BMI of 20-30 kg/m2. Participants must be medically cleared to join, not pregnant or breastfeeding, consume less than 10 alcoholic drinks per week, have no MRI contraindications, no cardiovascular disease history, normal blood pressure and glucose levels, non-smokers or those who quit over 10 years ago.

Inclusion Criteria

I am a healthy individual.

Medically cleared for participation in the study

Your body mass index (BMI) is between 20 and 30, with a little wiggle room for variation.

Exclusion Criteria

You are not able to have an MRI scan.

I have diabetes or my fasting blood sugar is over 126 mg/dL.

I am taking medication that can affect my blood sugar levels.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

13C Magnetic Resonance Spectroscopy

Participants undergo 13C magnetic resonance spectroscopy to assess glial acetate metabolism

120 minutes

1 visit (in-person)

Hyperinsulinemic-Hypoglycemic Clamp

Participants undergo a hyperinsulinemic-hypoglycemic clamp procedure to measure neuroendocrine response

135 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after procedures

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Glial Acetate Metabolism

Trial Overview The study tests if glial acetate metabolism can predict low blood sugar events in diabetics. It uses a special brain scan (13C-MRS) after an acetate infusion and compares it to the body's response during controlled insulin-induced hypoglycemia using a hyperinsulinemic-hypoglycemic clamp procedure.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 2 Interventions

Participants will have their glial acetate metabolism measured by carbon-13 magnetic resonance spectroscopy as well as their neuroendocrine response to hypoglycemia 3 days later.

Who Is Running the Clinical Trial?

Pennington Biomedical Research Center

Lead Sponsor

Trials

314

Recruited

183,000+

Published Research Related to This Trial

Recurrent hypoglycemia in a rodent model leads to brain adaptations that allow it to function normally during acute hypoglycemic episodes, primarily by enhancing glucose metabolism rather than relying on lactate as a major fuel source.

Lactate plays a crucial role as a 'metabolic regulator' during hypoglycemia, helping to maintain glucose metabolism and preserve neuronal function, even though it does not replace glucose as the main energy substrate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. Herzog, RI., Jiang, L., Herman, P., et al.[2021]

During hypoglycemia, type 1 diabetic (T1D) patients with hypoglycemia unawareness show a significant increase in brain lactate concentrations, more than fivefold higher than in nondiabetic controls, indicating altered brain metabolism under low glucose conditions.

Despite the increased lactate levels, T1D subjects did not show enhanced oxidation of lactate in the brain, suggesting that other metabolic adaptations may play a role in how these patients manage energy during hypoglycemic episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. De Feyter, HM., Mason, GF., Shulman, GI., et al.[2021]

In a study involving five type 1 diabetic subjects and six nondiabetic controls, brain acetate levels were found to be over twofold higher in diabetics during hypoglycemia, suggesting enhanced utilization of non-glucose energy sources.

The increased transport and metabolism of acetate in the brain of type 1 diabetic patients may help maintain brain energy levels during hypoglycemic episodes, indicating a potential adaptive mechanism to counteract low glucose availability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased brain monocarboxylic acid transport and utilization in type 1 diabetes. Mason, GF., Petersen, KF., Lebon, V., et al.[2019]

Individuals with type 1 diabetes, regardless of hypoglycaemia awareness, showed elevated brain glutamate levels compared to non-diabetic controls, indicating potential neurochemical changes associated with diabetes.

The study found that higher glutamate levels correlated with poorer glycaemic control (HbA1c) and the age at which diabetes was diagnosed, suggesting glutamate could serve as an early marker for brain complications related to chronic hyperglycaemia in type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. Wiegers, EC., Rooijackers, HM., van Asten, JJA., et al.[2022]

In a study involving adult male rats, diabetic hyperglycemia significantly reduced the expression of glial fibrillary acidic protein (GFAP) in astrocytes after a gliotoxic injury, indicating impaired astrocyte function due to diabetes.

The research demonstrated that while diabetes affected GFAP expression in response to a specific injury (using ethidium bromide), it did not alter GFAP levels in saline-injected control groups, highlighting the specific impact of diabetic conditions on astrocyte response to injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decreased astrocytic GFAP expression in streptozotocin-induced diabetes after gliotoxic lesion in the rat brainstem. Bondan, EF., Martins, Mde F., Viani, FC.[2019]

Astrocytes play crucial roles in brain function, and specific measurements of their activity are essential for understanding both normal and disease states in the brain.

The use of acetate, particularly labeled with carbon isotopes, has been a valuable tool for studying astrocytic energy metabolism, with various methodologies developed over the past 50 years to investigate brain metabolism in detail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Labeled acetate as a marker of astrocytic metabolism. Wyss, MT., Magistretti, PJ., Buck, A., et al.[2021]

The study found that as plasma acetate levels rise, the brain's ability to utilize acetate increases until it reaches saturation at concentrations above 2-3 mM, indicating a limit to how much acetate the brain can use effectively.

The research revealed that the transport of acetate across the blood-brain barrier is not the limiting factor for its metabolism in glial cells; instead, the limitation occurs after acetate has entered the brain, suggesting that further mechanisms may regulate its utilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetate transport and utilization in the rat brain. Deelchand, DK., Shestov, AA., Koski, DM., et al.[2021]

A 72-hour fast in six healthy men led to a significant increase in glial acetate metabolism (GAM), indicating that fasting-induced hypoglycemia can enhance brain metabolism, with GAM rising from 53.5% to 61.9%.

The increase in GAM was closely linked to the duration of hypoglycemia experienced, suggesting that GAM could serve as a biomarker for predicting susceptibility to hypoglycemic episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glial acetate metabolism is increased following a 72-h fast in metabolically healthy men and correlates with susceptibility to hypoglycemia. McDougal, DH., Darpolor, MM., DuVall, MA., et al.[2022]

Acetate metabolism in the brain does not solely reflect astrocytic activity, as significant amounts are also metabolized in GABAergic neurons, indicating a more complex role than previously thought.

High concentrations of acetate can inhibit its own metabolism and that of glucose, suggesting that changes in acetate levels may affect overall brain metabolism through alterations in enzyme acetylation rather than just glial-neuronal interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation. Rowlands, BD., Klugmann, M., Rae, CD.[2019]

PET imaging with 11C-acetate and 18F-FDG can effectively visualize reactive astrogliosis and neuronal hypometabolism in Alzheimer's disease, as demonstrated in both rodent models and a proof-of-concept study with 11 AD patients.

Increased acetate uptake by reactive astrocytes is linked to cognitive decline in AD, as it enhances GABA synthesis that suppresses neuronal activity, leading to reduced glucose uptake in affected brain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG. Nam, MH., Ko, HY., Kim, D., et al.[2023]

In a study of 26 children with diabetic ketoacidosis (DKA), it was found that cerebral edema formation is significantly associated with initial dehydration and hyperventilation, as indicated by elevated apparent diffusion coefficient (ADC) values during treatment.

The study suggests that factors like initial serum urea nitrogen concentration and respiratory rate are important predictors of edema formation, while initial osmolality and osmotic changes during treatment do not significantly influence this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of clinical and biochemical findings with diabetic ketoacidosis-related cerebral edema in children using magnetic resonance diffusion-weighted imaging. Glaser, NS., Marcin, JP., Wootton-Gorges, SL., et al.[2008]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6153507/

Glial acetate metabolism is increased following a 72-h fast in ... 72 h of fasting significantly reduced blood glucose levels and resulted in a high frequency of hypoglycemic episodes.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29931424/

Glial acetate metabolism is increased following a 72-h fast in ... Results: As expected, 72 h of fasting significantly reduced blood glucose levels and resulted in a high frequency of hypoglycemic episodes. Steady-state GAM ...

3. academic.oup.com academic.oup.com/jcem/article/98/9/3811/2833507

Increased Brain Transport and Metabolism of Acetate in ... We demonstrated increased brain transport and metabolism of acetate in intensively treated T1DM patients with hypoglycemia unawareness and reduced epinephrine ...

4. clinicaltrial.be clinicaltrial.be/en/details/59264?per_page=100&only_recruiting=0&only_eligible=0&only_active=0

Evaluating Glial Acetate Metabolism as a Biomarker of Hyp... This proof of concept study will test the hypothesis that glial acetate metabolism is inversely proportional to the neuroendocrine response to ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1550413124002900

Acetate enables metabolic fitness and cognitive ... Furthermore, acetate infusion in the hypothalamus led to improvements in glucose metabolism, insulin signaling, and cognitive performance in SF mice (Figures 3M ...

6. withpower.com withpower.com/clinical-trials/for-hypoglycemia

Top Hypoglycemia Clinical Trials | Power This proof of concept study will test the hypothesis that glial acetate metabolism is inversely proportional to the neuroendocrine response to hypoglycemia, ...

7. frontiersin.org frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.580171/full

Acetate Revisited: A Key Biomolecule at the Nexus of ... Another study done in murine white blood cells showed that low ACSS2 expression was correlated with a higher degree of glucose intolerance (Wopereis et al., ...