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

Trial Summary

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 data supports the effectiveness of the treatment Glial Acetate Metabolism for low blood sugar?

Research shows that in people with type 1 diabetes, the brain's ability to use acetate, a part of Glial Acetate Metabolism, is increased during low blood sugar episodes. This suggests that the treatment might help maintain brain energy levels when blood sugar is low. ^{1 2 3 4 5}

Is the treatment for low blood sugar generally safe in humans?

Research shows that brain metabolism of acetate and lactate is increased during low blood sugar in both diabetic and non-diabetic individuals, suggesting that the body adapts to maintain brain function. However, specific safety data for humans using this treatment under the name Glial Acetate Metabolism is not directly provided in the studies. ^{2 3 4 6 7}

How does this treatment for low blood sugar differ from other treatments?

This treatment may involve the use of acetate, which is unique because it targets glial cells in the brain and can influence energy metabolism differently than traditional glucose-based treatments. Acetate's role in brain metabolism and its potential to modulate cellular energy status through enzyme acetylation makes it a novel approach compared to standard treatments for low blood sugar. ^{3 8 9 10 11}

What is the purpose of this trial?

Hypoglycemic complications are a major impediment to the maintenance of healthy glucose levels in persons with diabetes. The investigators recently completed a clinical pilot and feasibility study (GLIMPSE, NCT02690168), which identified a novel biomarker, glial acetate metabolism, that appears to predict the susceptibility to hypoglycemia. By providing an assay to predict hypoglycemic events and therefore diabetic complications, the development of this biomarker could significantly improve the treatment of persons with diabetes. The goal of this study is to determine the efficacy of our biomarker for predicting susceptibility to insulin-induced hypoglycemia. In order to accomplish this goal the investigatiors will pair our 13C magnetic resonance spectroscopy procedure to assess glial acetate metabolism, developed in the GLIMPSE study, with a hyperinsulinemic-hypoglycemic clamp procedure, developed in the HYPOCLAMP study (NCT03839511). The two procedures will be separated by a three day interval. The investigators will then correlate the participants' rates of glial acetate metabolism with their neuroendocrine responses to the hypoglycemic clamp. This proof of concept study will test the hypothesis that glial acetate metabolism is inversely proportional to the neuroendocrine response to hypoglycemia, that is, as glial acetate metabolism increases the neuroendocrine response will decrease.

Research Team

David McDougal, PhD

Principal Investigator

PBRC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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. [2022]

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

Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. [2021]

3. Germany 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. [2022]

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

Increased brain monocarboxylic acid transport and utilization in type 1 diabetes. [2019]

5. Brazil pubmed.ncbi.nlm.nih.gov

Decreased astrocytic GFAP expression in streptozotocin-induced diabetes after gliotoxic lesion in the rat brainstem. [2019]

6. United States 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. [2008]

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

Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. [2021]

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

Labeled acetate as a marker of astrocytic metabolism. [2021]

9. England 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. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Acetate transport and utilization in the rat brain. [2021]